SHS/New_BioRED_Model · Datasets at Hugging Face

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10491763	Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion. The transcription factor hepatocyte nuclear factor (HNF)-6 is an upstream regulator of several genes involved in the pathogenesis of maturity-onset diabetes of the young. We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects. We cloned the coding region as well as the intron-exon boundaries of the HNF-6 gene. We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants. An identified missense variant was examined in association studies and genotype-phenotype studies. We identified two silent and one missense (Pro75 Ala) variant. In an association study the allelic frequency of the Pro75Ala polymorphism was 3.2% (95% confidence interval, 1.9-4.5) in 330 patients with Type II diabetes mellitus compared with 4.2% (2.4-6.0) in 238 age-matched glucose tolerant control subjects. Moreover, in studies of 238 middle-aged glucose tolerant subjects, of 226 glucose tolerant offspring of Type II diabetic patients and of 367 young healthy subjects, the carriers of the polymorphism did not differ from non-carriers in glucose induced serum insulin or C-peptide responses. Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined.	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10788334	Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age < 50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities - 5382insC, C61G, and 4153delA - accounted for 51%, 20%, and 11% of the identified mutations, respectively..	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11054569	Rab6c, a new member of the rab gene family, is involved in drug resistance in MCF7/AdrR cells. A new Rab6 homolog cDNA, Rab6c, was discovered by a hypermethylated DNA fragment probe that was isolated from a human multidrug resistant (MDR) breast cancer cell line, MCF7/AdrR, by the methylation sensitive-representational difference analysis (MS-RDA) technique. Rab6c was found to be under-expressed in MCF7/AdrR and MES-SA/Dx5 (a human MDR uterine sarcoma cell line) compared with their non-MDR parental cell lines. MCF7/AdrR cells expressing the exogenous Rab6c exhibited less resistance to several anti-cancer drugs, such as doxorubicin (DOX), taxol, vinblastine, and vincristine, than the control cells containing the empty vector. Flow cytometry experiments confirmed that the transfectants' diminished resistance to DOX was caused by increased drug accumulation induced by the exogenous Rab6c. These results indicate that Rab6c is involved in drug resistance in MCF7/AdrR cells.	[ "Rab6c", ",", "a", "new", "member", "of", "the", "rab", "gene", "family", ",", "is", "involved", "in", "drug", "resistance", "in", "MCF7/AdrR", "cells", ".", "A", "new", "Rab6", "homolog", "cDNA", ",", "Rab6c", ",", "was", "discovered", "by", "a", "hypermethylated", "DNA", "fragment", "probe", "that", "was", "isolated", "from", "a", "human", "multidrug", "resistant", "(", "MDR", ")", "breast", "cancer", "cell", "line", ",", "MCF7/AdrR", ",", "by", "the", "methylation", "sensitive-representational", "difference", "analysis", "(", "MS-RDA", ")", "technique", ".", "Rab6c", "was", "found", "to", "be", "under-expressed", "in", "MCF7/AdrR", "and", "MES-SA/Dx5", "(", "a", "human", "MDR", "uterine", "sarcoma", "cell", "line", ")", "compared", "with", "their", "non-MDR", "parental", "cell", "lines", ".", "MCF7/AdrR", "cells", "expressing", "the", "exogenous", "Rab6c", "exhibited", "less", "resistance", "to", "several", "anti-cancer", "drugs", ",", "such", "as", "doxorubicin", "(", "DOX", ")", ",", "taxol", ",", "vinblastine", ",", "and", "vincristine", ",", "than", "the", "control", "cells", "containing", "the", "empty", "vector", ".", "Flow", "cytometry", "experiments", "confirmed", "that", "the", "transfectants", "'", "diminished", "resistance", "to", "DOX", "was", "caused", "by", "increased", "drug", "accumulation", "induced", "by", "the", "exogenous", "Rab6c", ".", "These", "results", "indicate", "that", "Rab6c", "is", "involved", "in", "drug", "resistance", "in", "MCF7/AdrR", "cells", "." ]	[ "1", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "6", "0", "0", "0", "0", "1", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "6", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "6", "0", "6", "0", "0", "4", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "6", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "3", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "6", "0", "0" ]
1353340	Late-onset metachromatic leukodystrophy: molecular pathology in two siblings. We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD..	[ "Late-onset", "metachromatic", "leukodystrophy", ":", "molecular", "pathology", "in", "two", "siblings", ".", "We", "report", "on", "a", "new", "allele", "at", "the", "arylsulfatase", "A", "(", "ARSA", ")", "locus", "causing", "late-onset", "metachromatic", "leukodystrophy", "(", "MLD", ")", ".", "In", "that", "allele", "arginine84", ",", "a", "residue", "that", "is", "highly", "conserved", "in", "the", "arylsulfatase", "gene", "family", ",", "is", "replaced", "by", "glutamine", ".", "In", "contrast", "to", "alleles", "that", "cause", "early-onset", "MLD", ",", "the", "arginine84", "to", "glutamine", "substitution", "is", "associated", "with", "some", "residual", "ARSA", "activity", ".", "A", "comparison", "of", "genotypes", ",", "ARSA", "activities", ",", "and", "clinical", "data", "on", "4", "individuals", "carrying", "the", "allele", "of", "81", "patients", "with", "MLD", "examined", ",", "further", "validates", "the", "concept", "that", "different", "degrees", "of", "residual", "ARSA", "activity", "are", "the", "basis", "of", "phenotypical", "variation", "in", "MLD", ".." ]	[ "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "0", "0", "2", "2", "0", "2", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0" ]
15099351	Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is at a locus for autosomal dominant hypercholesterolemia, and recent data indicate that the PCSK9 gene is involved in cholesterol biosynthesis. Mutations within this gene have previously been found to segregate with hypercholesterolemia. In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded. Two novel missense mutations were detected in the catalytic subdomain of the PCSK9 gene. Two patients were heterozygotes for D374Y, and one patient was a double heterozygote for D374Y and N157K. D374Y segregated with hypercholesterolemia in the two former families where family members were available for study. Our findings support the notion that mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia.	[ "Mutations", "in", "the", "PCSK9", "gene", "in", "Norwegian", "subjects", "with", "autosomal", "dominant", "hypercholesterolemia", ".", "Proprotein", "convertase", "subtilisin/kexin", "type", "9", "(", "PCSK9", ")", "is", "at", "a", "locus", "for", "autosomal", "dominant", "hypercholesterolemia", ",", "and", "recent", "data", "indicate", "that", "the", "PCSK9", "gene", "is", "involved", "in", "cholesterol", "biosynthesis", ".", "Mutations", "within", "this", "gene", "have", "previously", "been", "found", "to", "segregate", "with", "hypercholesterolemia", ".", "In", "this", "study", ",", "DNA", "sequencing", "of", "the", "12", "exons", "of", "the", "PCSK9", "gene", "has", "been", "performed", "in", "51", "Norwegian", "subjects", "with", "a", "clinical", "diagnosis", "of", "familial", "hypercholesterolemia", "where", "mutations", "in", "the", "low-density", "lipoprotein", "receptor", "gene", "and", "mutation", "R3500Q", "in", "the", "apolipoprotein", "B-100", "gene", "had", "been", "excluded", ".", "Two", "novel", "missense", "mutations", "were", "detected", "in", "the", "catalytic", "subdomain", "of", "the", "PCSK9", "gene", ".", "Two", "patients", "were", "heterozygotes", "for", "D374Y", ",", "and", "one", "patient", "was", "a", "double", "heterozygote", "for", "D374Y", "and", "N157K", ".", "D374Y", "segregated", "with", "hypercholesterolemia", "in", "the", "two", "former", "families", "where", "family", "members", "were", "available", "for", "study", ".", "Our", "findings", "support", "the", "notion", "that", "mutations", "in", "the", "PCSK9", "gene", "cause", "autosomal", "dominant", "hypercholesterolemia", "." ]	[ "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "2", "2", "0", "1", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "1", "1", "1", "0", "0", "0", "5", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "4", "0", "0", "0", "5", "0", "0", "0", "4", "0", "0", "0", "0", "0", "5", "0", "5", "0", "5", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "2", "2", "2", "0" ]
16005363	Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome. Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.	[ "Identification", "of", "a", "novel", "WFS1", "mutation", "(", "AFF344-345ins", ")", "in", "Japanese", "patients", "with", "Wolfram", "syndrome", ".", "Wolfram", "syndrome", "(", "WFS", ")", "is", "an", "autosomal", "recessive", "disorder", "characterized", "by", "early", "onset", "diabetes", "mellitus", ",", "progressive", "optic", "atrophy", ",", "sensorineural", "deafness", "and", "diabetes", "insipidus", ".", "Affected", "individuals", "may", "also", "have", "renal", "tract", "abnormalities", "as", "well", "as", "neurogical", "and", "psychiatric", "syndromes", ".", "WFS1", "encoding", "a", "transmembrane", "protein", "was", "identified", "as", "the", "gene", "responsible", "for", "WFS", ".", "We", "report", "herein", "a", "Japanese", "family", ",", "of", "which", "two", "members", "had", "this", "syndrome", ".", "In", "the", "WFS1", "gene", "of", "these", "patients", ",", "we", "identified", "a", "novel", "mutation", ",", "a", "nine", "nucleotide", "insertion", "(", "AFF344-345ins", ")", ".", "In", "addition", ",", "one", "of", "these", "patients", "had", "preclinical", "hypopituitarism", ",", "which", "is", "an", "unusual", "feature", "of", "WFS", ".", "As", "only", "the", "two", "family", "members", "homozygous", "for", "the", "mutation", "showed", "WFS", ",", "these", "data", "support", "the", "notion", "that", "this", "mutation", "is", "the", "cause", "of", "WFS", "." ]	[ "0", "0", "0", "0", "1", "0", "0", "5", "0", "0", "0", "4", "0", "2", "2", "0", "2", "2", "0", "2", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "2", "2", "0", "0", "2", "2", "0", "2", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "2", "2", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0" ]
16200390	A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach. Migraine is a common debilitating primary headache disorder with significant mental, physical and social health implications. The brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is involved in nociceptive pathways and has been implicated in the pathophysiology of migraine. With few genetic studies investigating biosynthetic and metabolic enzymes governing the rate of 5-HT activity and their relationship to migraine, it was the objective of this study to assess genetic variants within the human tryptophan hydroxylase (TPH), amino acid decarboxylase (AADC) and monoamine oxidase A (MAOA) genes in migraine susceptibility. This objective was undertaken using a high-throughput DNA pooling experimental design, which proved to be a very accurate, sensitive and specific method of estimating allele frequencies for single nucleotide polymorphism, insertion deletion and variable number tandem repeat loci. Application of DNA pooling to a wide array of genetic loci provides greater scope in the assessment of population-based genetic association study designs. Despite the application of this high-throughput genotyping method, negative results from the two-stage DNA pooling design used to screen loci within the TPH, AADC and MAOA genes did not support their role in migraine susceptibility.	[ "A", "genetic", "analysis", "of", "serotonergic", "biosynthetic", "and", "metabolic", "enzymes", "in", "migraine", "using", "a", "DNA", "pooling", "approach", ".", "Migraine", "is", "a", "common", "debilitating", "primary", "headache", "disorder", "with", "significant", "mental", ",", "physical", "and", "social", "health", "implications", ".", "The", "brain", "neurotransmitter", "5-hydroxytryptamine", "(", "5-HT", ";", "serotonin", ")", "is", "involved", "in", "nociceptive", "pathways", "and", "has", "been", "implicated", "in", "the", "pathophysiology", "of", "migraine", ".", "With", "few", "genetic", "studies", "investigating", "biosynthetic", "and", "metabolic", "enzymes", "governing", "the", "rate", "of", "5-HT", "activity", "and", "their", "relationship", "to", "migraine", ",", "it", "was", "the", "objective", "of", "this", "study", "to", "assess", "genetic", "variants", "within", "the", "human", "tryptophan", "hydroxylase", "(", "TPH", ")", ",", "amino", "acid", "decarboxylase", "(", "AADC", ")", "and", "monoamine", "oxidase", "A", "(", "MAOA", ")", "genes", "in", "migraine", "susceptibility", ".", "This", "objective", "was", "undertaken", "using", "a", "high-throughput", "DNA", "pooling", "experimental", "design", ",", "which", "proved", "to", "be", "a", "very", "accurate", ",", "sensitive", "and", "specific", "method", "of", "estimating", "allele", "frequencies", "for", "single", "nucleotide", "polymorphism", ",", "insertion", "deletion", "and", "variable", "number", "tandem", "repeat", "loci", ".", "Application", "of", "DNA", "pooling", "to", "a", "wide", "array", "of", "genetic", "loci", "provides", "greater", "scope", "in", "the", "assessment", "of", "population-based", "genetic", "association", "study", "designs", ".", "Despite", "the", "application", "of", "this", "high-throughput", "genotyping", "method", ",", "negative", "results", "from", "the", "two-stage", "DNA", "pooling", "design", "used", "to", "screen", "loci", "within", "the", "TPH", ",", "AADC", "and", "MAOA", "genes", "did", "not", "support", "their", "role", "in", "migraine", "susceptibility", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "3", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "1", "1", "0", "1", "0", "0", "1", "1", "1", "0", "1", "0", "0", "1", "1", "1", "0", "1", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0" ]
16596970	Pilocarpine seizures cause age-dependent impairment in auditory location discrimination. Children who have status epilepticus have continuous or rapidly repeating seizures that may be life-threatening and may cause life-long changes in brain and behavior. The extent to which status epilepticus causes deficits in auditory discrimination is unknown. A naturalistic auditory location discrimination method was used to evaluate this question using an animal model of status epilepticus. Male Sprague-Dawley rats were injected with saline on postnatal day (P) 20, or a convulsant dose of pilocarpine on P20 or P45. Pilocarpine on either day induced status epilepticus; status epilepticus at P45 resulted in CA3 cell loss and spontaneous seizures, whereas P20 rats had no cell loss or spontaneous seizures. Mature rats were trained with sound-source location and sound-silence discriminations. Control (saline P20) rats acquired both discriminations immediately. In status epilepticus (P20) rats, acquisition of the sound-source location discrimination was moderately impaired. Status epilepticus (P45) rats failed to acquire either sound-source location or sound-silence discriminations. Status epilepticus in rat causes an age-dependent, long-term impairment in auditory discrimination. This impairment may explain one cause of impaired auditory location discrimination in humans.	[ "Pilocarpine", "seizures", "cause", "age-dependent", "impairment", "in", "auditory", "location", "discrimination", ".", "Children", "who", "have", "status", "epilepticus", "have", "continuous", "or", "rapidly", "repeating", "seizures", "that", "may", "be", "life-threatening", "and", "may", "cause", "life-long", "changes", "in", "brain", "and", "behavior", ".", "The", "extent", "to", "which", "status", "epilepticus", "causes", "deficits", "in", "auditory", "discrimination", "is", "unknown", ".", "A", "naturalistic", "auditory", "location", "discrimination", "method", "was", "used", "to", "evaluate", "this", "question", "using", "an", "animal", "model", "of", "status", "epilepticus", ".", "Male", "Sprague-Dawley", "rats", "were", "injected", "with", "saline", "on", "postnatal", "day", "(", "P", ")", "20", ",", "or", "a", "convulsant", "dose", "of", "pilocarpine", "on", "P20", "or", "P45", ".", "Pilocarpine", "on", "either", "day", "induced", "status", "epilepticus", ";", "status", "epilepticus", "at", "P45", "resulted", "in", "CA3", "cell", "loss", "and", "spontaneous", "seizures", ",", "whereas", "P20", "rats", "had", "no", "cell", "loss", "or", "spontaneous", "seizures", ".", "Mature", "rats", "were", "trained", "with", "sound-source", "location", "and", "sound-silence", "discriminations", ".", "Control", "(", "saline", "P20", ")", "rats", "acquired", "both", "discriminations", "immediately", ".", "In", "status", "epilepticus", "(", "P20", ")", "rats", ",", "acquisition", "of", "the", "sound-source", "location", "discrimination", "was", "moderately", "impaired", ".", "Status", "epilepticus", "(", "P45", ")", "rats", "failed", "to", "acquire", "either", "sound-source", "location", "or", "sound-silence", "discriminations", ".", "Status", "epilepticus", "in", "rat", "causes", "an", "age-dependent", ",", "long-term", "impairment", "in", "auditory", "discrimination", ".", "This", "impairment", "may", "explain", "one", "cause", "of", "impaired", "auditory", "location", "discrimination", "in", "humans", "." ]	[ "3", "2", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "2", "2", "0", "2", "2", "0", "0", "0", "0", "6", "0", "0", "0", "0", "2", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "2", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "4", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "4", "0" ]
17683901	An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia. Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7500. In more than 98% of cases, the disease is associated with a G to A or G to C substitution at nucleotide position 1138 (p.G380R) of the fibroblast growth factor receptor 3 (FGFR3) gene. We have developed a sensitive single tube tetra-primer PCR assay to detect both the c.1138G>A and c.1138G>C mutations and can successfully distinguish DNA samples that are homozygous and heterozygous for the c.1138G>A mutation. Titration studies showed that the assay could reliably detect one copy of the mutant allele in a mix of 100 wild-type alleles. The assay has been tested in 50 healthy controls, 3 known patients with achondroplasia, and 5 amniotic fluids suspected of having achondroplasia and for whom we had previously determined the genotypes for the c.1138G>A mutation by PCR-RFLP. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for FGFR3 p.G380R genotyping, which could be used even in "low-tech" laboratories.	[ "An", "improved", "tetra-primer", "PCR", "approach", "for", "the", "detection", "of", "the", "FGFR3", "G380R", "mutation", "responsible", "for", "achondroplasia", ".", "Achondroplasia", "is", "the", "most", "common", "form", "of", "dwarfism", "and", "has", "an", "incidence", "of", "approximately", "1/7500", ".", "In", "more", "than", "98", "%", "of", "cases", ",", "the", "disease", "is", "associated", "with", "a", "G", "to", "A", "or", "G", "to", "C", "substitution", "at", "nucleotide", "position", "1138", "(", "p.G380R", ")", "of", "the", "fibroblast", "growth", "factor", "receptor", "3", "(", "FGFR3", ")", "gene", ".", "We", "have", "developed", "a", "sensitive", "single", "tube", "tetra-primer", "PCR", "assay", "to", "detect", "both", "the", "c.1138G", ">", "A", "and", "c.1138G", ">", "C", "mutations", "and", "can", "successfully", "distinguish", "DNA", "samples", "that", "are", "homozygous", "and", "heterozygous", "for", "the", "c.1138G", ">", "A", "mutation", ".", "Titration", "studies", "showed", "that", "the", "assay", "could", "reliably", "detect", "one", "copy", "of", "the", "mutant", "allele", "in", "a", "mix", "of", "100", "wild-type", "alleles", ".", "The", "assay", "has", "been", "tested", "in", "50", "healthy", "controls", ",", "3", "known", "patients", "with", "achondroplasia", ",", "and", "5", "amniotic", "fluids", "suspected", "of", "having", "achondroplasia", "and", "for", "whom", "we", "had", "previously", "determined", "the", "genotypes", "for", "the", "c.1138G", ">", "A", "mutation", "by", "PCR-RFLP", ".", "We", "have", "observed", "complete", "concordance", "between", "methods", ".", "Our", "tetra-primer", "PCR", "assay", "is", "sensitive", ",", "low-cost", ",", "and", "easy", "to", "use", "method", "for", "FGFR3", "p.G380R", "genotyping", ",", "which", "could", "be", "used", "even", "in", "``", "low-tech", "''", "laboratories", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "5", "0", "0", "0", "1", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
18166824	Genetic investigation of four meiotic genes in women with premature ovarian failure. OBJECTIVE: The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF). DESIGN: Case-control study. METHODS: Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls). RESULTS: A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V). CONCLUSIONS: The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of the MSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon.	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18408250	A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects. METHODS: We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion-deletion polymorphism in the IRF5 gene. We performed 2 sets of case-control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays. RESULTS: A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated. CONCLUSIONS: These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.	[ "A", "single", "nucleotide", "polymorphism", "in", "the", "IRF5", "promoter", "region", "is", "associated", "with", "susceptibility", "to", "rheumatoid", "arthritis", "in", "the", "Japanese", "population", ".", "OBJECTIVES", ":", "Interferon", "regulatory", "factor", "5", "(", "IRF5", ")", "is", "a", "member", "of", "the", "IRF", "family", "of", "transcription", "factors", ",", "which", "regulate", "the", "production", "of", "proinflammatory", "cytokines", ".", "Polymorphisms", "in", "the", "IRF5", "gene", "have", "been", "associated", "with", "susceptibility", "to", "systemic", "lupus", "erythaematosus", "(", "SLE", ")", "in", "Caucasian", "and", "Asian", "populations", ",", "but", "their", "involvement", "in", "other", "autoimmune", "diseases", "is", "still", "uncertain", ".", "Here", ",", "we", "assessed", "the", "genetic", "role", "of", "IRF5", "in", "susceptibility", "to", "rheumatoid", "arthritis", "(", "RA", ")", "in", "Japanese", "subjects", ".", "METHODS", ":", "We", "selected", "13", "single", "nucleotide", "polymorphisms", "(", "SNPs", ")", "and", "a", "CGGGG", "insertion-deletion", "polymorphism", "in", "the", "IRF5", "gene", ".", "We", "performed", "2", "sets", "of", "case-control", "comparisons", "using", "Japanese", "subjects", "(", "first", "set", ":", "830", "patients", "with", "RA", "and", "658", "controls", ";", "second", "set", ":", "1112", "patients", "with", "RA", "and", "940", "controls", ")", ",", "and", "then", "performed", "a", "stratified", "analysis", "using", "human", "leukocyte", "antigen", "(", "HLA", ")", "-DRB1", "shared", "epitope", "(", "SE", ")", "status", ".", "We", "genotyped", "the", "SNPs", "using", "TaqMan", "assays", ".", "RESULTS", ":", "A", "significant", "association", "of", "the", "rs729302", "A", "allele", "with", "RA", "susceptibility", "was", "found", "in", "both", "sets", "(", "odds", "ratio", "(", "OR", ")", "1.22", ",", "95", "%", "CI", "1.09", "to", "1.35", ",", "p", "<", "0.001", "in", "the", "combined", "analysis", ")", ".", "When", "the", "patients", "were", "stratified", "by", "the", "SE", ",", "the", "rs729302", "A", "allele", "was", "found", "to", "confer", "increased", "risk", "to", "RA", "in", "patients", "that", "were", "SE", "negative", "(", "OR", "1.50", ",", "95", "%", "CI", "1.17", "to", "1.92", ",", "p", "=", "0.001", ")", "as", "compared", "with", "patients", "carrying", "the", "SE", "(", "OR", "1.11", ",", "95", "%", "CI", "0.93", "to", "1.33", ",", "p", "=", "0.24", ")", ".", "In", "both", "sets", ",", "no", "genotyped", "polymorphisms", "were", "significantly", "associated", "with", "RA", "susceptibility", ",", "but", "rs729302", "was", "significantly", "associated", ".", "CONCLUSIONS", ":", "These", "findings", "indicate", "that", "the", "promoter", "polymorphism", "of", "IRF5", "is", "a", "genetic", "factor", "conferring", "predisposition", "to", "RA", ",", "and", "that", "it", "contributes", "considerably", "to", "disease", "pathogenesis", "in", "patients", "that", "were", "SE", "negative", "." ]	[ "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "1", "1", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0" ]
18439317	Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese. BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD. METHODS: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test. RESULTS: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele. CONCLUSION: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.	[ "Association", "between", "promoter", "-1607", "polymorphism", "of", "MMP1", "and", "lumbar", "disc", "disease", "in", "Southern", "Chinese", ".", "BACKGROUND", ":", "Matrix", "metalloproteinases", "(", "MMPs", ")", "are", "involved", "in", "the", "degradation", "of", "the", "extracellular", "matrix", "of", "the", "intervertebral", "disc", ".", "A", "SNP", "for", "guanine", "insertion/deletion", "(", "G/D", ")", ",", "the", "-1607", "promoter", "polymorphism", ",", "of", "the", "MMP1", "gene", "was", "found", "significantly", "affecting", "promoter", "activity", "and", "corresponding", "transcription", "level", ".", "Hence", "it", "is", "a", "good", "candidate", "for", "genetic", "studies", "in", "DDD", ".", "METHODS", ":", "Southern", "Chinese", "volunteers", "between", "18", "and", "55", "years", "were", "recruited", "from", "the", "population", ".", "DDD", "in", "the", "lumbar", "spine", "was", "defined", "by", "MRI", "using", "Schneiderman", "'s", "classification", ".", "Genomic", "DNA", "was", "isolated", "from", "the", "leukocytes", "and", "genotyping", "was", "performed", "using", "the", "Sequenom", "platform", ".", "Association", "and", "Hardy-Weinberg", "equilibrium", "checking", "were", "assessed", "by", "Chi-square", "test", "and", "Mann-Whitney", "U", "test", ".", "RESULTS", ":", "Our", "results", "showed", "substantial", "evidence", "of", "association", "between", "-1607", "promoter", "polymorphism", "of", "MMP1", "and", "DDD", "in", "the", "Southern", "Chinese", "subjects", ".", "D", "allelic", "was", "significantly", "associated", "with", "DDD", "(", "p", "value", "=", "0.027", ",", "odds", "ratio", "=", "1.41", "with", "95", "%", "CI", "=", "1.04-1.90", ")", "while", "Genotypic", "association", "on", "the", "presence", "of", "D", "allele", "was", "also", "significantly", "associated", "with", "DDD", "(", "p", "value", "=", "0.046", ",", "odds", "ratio", "=", "1.50", "with", "95", "%", "CI", "=", "1.01-2.24", ")", ".", "Further", "age", "stratification", "showed", "significant", "genotypic", "as", "well", "as", "allelic", "association", "in", "the", "group", "of", "over", "40", "years", "(", "genotypic", ":", "p", "value", "=", "0.035", ",", "odds", "ratio", "=", "1.617", "with", "95", "%", "CI", "=", "1.033-2.529", ";", "allelic", ":", "p", "value", "=", "0.033", ",", "odds", "ratio", "=", "1.445", "with", "95", "%", "CI", "=", "1.029-2.029", ")", ".", "Disc", "bulge", ",", "annular", "tears", "and", "the", "Schmorl", "'s", "nodes", "were", "not", "associated", "with", "the", "D", "allele", ".", "CONCLUSION", ":", "We", "demonstrated", "that", "individuals", "with", "the", "presence", "of", "D", "allele", "for", "the", "-1607", "promoter", "polymorphism", "of", "MMP1", "are", "about", "1.5", "times", "more", "susceptible", "to", "develop", "DDD", "when", "compared", "with", "those", "having", "G", "allele", "only", ".", "Further", "association", "was", "identified", "in", "individuals", "over", "40", "years", "of", "age", ".", "Disc", "bulge", ",", "annular", "tear", "as", "well", "as", "Schmorl", "'s", "nodes", "were", "not", "associated", "with", "this", "polymorphism", "." ]	[ "0", "0", "0", "0", "0", "0", "1", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
18681856	Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene. OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease.	[ "Expanding", "clinical", "spectrum", "of", "non-autoimmune", "hyperthyroidism", "due", "to", "an", "activating", "germline", "mutation", ",", "p.M453T", ",", "in", "the", "thyrotropin", "receptor", "gene", ".", "OBJECTIVE", ":", "To", "describe", "clinical", "and", "genetic", "features", "of", "a", "Thai", "family", "with", "non-autoimmune", "hyperthyroidism", "(", "NAH", ")", "caused", "by", "an", "activating", "germline", "mutation", "in", "the", "thyrotropin", "receptor", "(", "TSHR", ")", "gene", ".", "PATIENTS", ":", "Three", "affected", "individuals", "from", "the", "same", "family", "(", "a", "father", "and", "his", "two", "children", ")", "were", "studied", ".", "Clinical", "and", "imaging", "findings", "were", "reviewed", "and", "compared", ".", "GENETIC", "ANALYSIS", ":", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "leukocytes", "and", "mutation", "analysis", "of", "the", "entire", "coding", "sequence", "of", "the", "TSHR", "gene", "was", "performed", "in", "both", "children", "and", "their", "parents", "by", "direct", "DNA", "sequencing", ".", "RESULTS", ":", "A", "heterozygous", "germline", "T", "to", "C", "transition", "in", "exon", "10", "of", "the", "TSHR", "gene", "(", "c.1358T", "--", ">", "C", ")", "resulting", "in", "the", "substitution", "of", "methionine", "(", "ATG", ")", "by", "threonine", "(", "ACG", ")", "at", "codon", "453", "(", "p.M453T", ")", "was", "identified", "in", "the", "father", "and", "his", "two", "children", ".", "They", "presented", "with", "different", "clinical", "severity", "and", "variable", "age", "of", "onset", ".", "In", "addition", "to", "hyperthyroidism", ",", "ventriculomegaly", "and", "bilateral", "shortening", "of", "the", "fifth", "metacarpal", "bones", "and", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "were", "consistently", "found", "in", "all", "affected", "individuals", ".", "CONCLUSIONS", ":", "Ventriculomegaly", "and", "bilateral", "shortening", "of", "the", "fifth", "metacarpal", "bones", "and", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "might", "be", "characteristic", "features", "of", "NAH", "because", "of", "an", "activating", "TSHR", "germline", "mutation", ".", "In", "addition", ",", "the", "shortening", "of", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "has", "never", "been", "previously", "described", ",", "expanding", "the", "phenotypic", "spectrum", "of", "the", "disease", "." ]	[ "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "1", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
19728177	Prolonged hypothermia as a bridge to recovery for cerebral edema and intracranial hypertension associated with fulminant hepatic failure. BACKGROUND: To review evidence-based treatment options in patients with cerebral edema complicating fulminant hepatic failure (FHF) and discuss the potential applications of hypothermia. METHOD: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with FHF from acetaminophen and resultant cerebral edema. RESULTS: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from acetaminophen which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed FHF from acetaminophen and cerebral edema. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her cerebral edema and intracranial hypertension. At discharge, she had complete recovery of neurological and hepatic functions. CONCLUSION: In patients with FHF and cerebral edema from acetaminophen overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted.	[ "Prolonged", "hypothermia", "as", "a", "bridge", "to", "recovery", "for", "cerebral", "edema", "and", "intracranial", "hypertension", "associated", "with", "fulminant", "hepatic", "failure", ".", "BACKGROUND", ":", "To", "review", "evidence-based", "treatment", "options", "in", "patients", "with", "cerebral", "edema", "complicating", "fulminant", "hepatic", "failure", "(", "FHF", ")", "and", "discuss", "the", "potential", "applications", "of", "hypothermia", ".", "METHOD", ":", "Case-based", "observations", "from", "a", "medical", "intensive", "care", "unit", "(", "MICU", ")", "in", "a", "tertiary", "care", "facility", "in", "a", "27-year-old", "female", "with", "FHF", "from", "acetaminophen", "and", "resultant", "cerebral", "edema", ".", "RESULTS", ":", "Our", "patient", "was", "admitted", "to", "the", "MICU", "after", "being", "found", "unresponsive", "with", "presumed", "toxicity", "from", "acetaminophen", "which", "was", "ingested", "over", "a", "2-day", "period", ".", "The", "patient", "had", "depressed", "of", "mental", "status", "lasting", "at", "least", "24", "h", "prior", "to", "admission", ".", "Initial", "evaluation", "confirmed", "FHF", "from", "acetaminophen", "and", "cerebral", "edema", ".", "The", "patient", "was", "treated", "with", "hyperosmolar", "therapy", ",", "hyperventilation", ",", "sedation", ",", "and", "chemical", "paralysis", ".", "Her", "intracranial", "pressure", "remained", "elevated", "despite", "maximal", "medical", "therapy", ".", "We", "then", "initiated", "therapeutic", "hypothermia", "which", "was", "continued", "for", "5", "days", ".", "At", "re-warming", ",", "patient", "had", "resolution", "of", "her", "cerebral", "edema", "and", "intracranial", "hypertension", ".", "At", "discharge", ",", "she", "had", "complete", "recovery", "of", "neurological", "and", "hepatic", "functions", ".", "CONCLUSION", ":", "In", "patients", "with", "FHF", "and", "cerebral", "edema", "from", "acetaminophen", "overdose", ",", "prolonged", "therapeutic", "hypothermia", "could", "potentially", "be", "used", "as", "a", "life", "saving", "therapy", "and", "a", "bridge", "to", "hepatic", "and", "neurological", "recovery", ".", "A", "clinical", "trial", "of", "hypothermia", "in", "patients", "with", "this", "condition", "is", "warranted", "." ]	[ "0", "2", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "3", "0", "0", "2", "2", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "3", "0", "2", "2", "0", "0", "4", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "2", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "2", "2", "0", "3", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "4", "0", "0", "0", "0", "0", "0" ]
20606392	Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain. BACKGROUND/AIMS: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity. METHOD: Serum and DNA samples from the proband and his parents were analyzed. RESULTS: The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration. CONCLUSION: Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations.	[ "Atypical", "GH", "insensitivity", "syndrome", "and", "severe", "insulin-like", "growth", "factor-I", "deficiency", "resulting", "from", "compound", "heterozygous", "mutations", "of", "the", "GH", "receptor", ",", "including", "a", "novel", "frameshift", "mutation", "affecting", "the", "intracellular", "domain", ".", "BACKGROUND/AIMS", ":", "GH", "insensitivity", "and", "IGF", "deficiency", "may", "result", "from", "aberrations", "of", "the", "GH", "receptor", "(", "GHR", ")", ".", "We", "describe", "a", "4-year-old", "child", "with", "modest", "growth", "failure", "and", "normal", "serum", "concentrations", "of", "GH-binding", "protein", "(", "GHBP", ")", ",", "but", "clinical", "evidence", "of", "GH", "insensitivity", ".", "METHOD", ":", "Serum", "and", "DNA", "samples", "from", "the", "proband", "and", "his", "parents", "were", "analyzed", ".", "RESULTS", ":", "The", "child", "had", "a", "height", "of", "-4", "SD", ",", "elevated", "serum", "GH", "concentrations", ",", "abnormally", "low", "serum", "IGF-I", "and", "IGFBP-3", "concentrations", "and", "normal", "GHBP", "concentrations", ".", "DNA", "analysis", "revealed", "compound", "heterozygosity", "for", "mutations", "of", "GHR", ",", "including", "a", "previously", "reported", "R211H", "mutation", "and", "a", "novel", "duplication", "of", "a", "nucleotide", "in", "exon", "9", "(", "899dupC", ")", ",", "the", "latter", "resulting", "in", "a", "frameshift", "and", "a", "premature", "stop", "codon", ".", "Treatment", "with", "recombinant", "DNA-derived", "IGF-I", "resulted", "in", "growth", "acceleration", ".", "CONCLUSION", ":", "Mutations", "affecting", "the", "intracellular", "domain", "of", "the", "GHR", "can", "result", "in", "GH", "insensitivity", "and", "IGF", "deficiency", ",", "despite", "normal", "serum", "concentrations", "of", "GHBP", ".", "The", "presence", "of", "clinical", "and", "biochemical", "evidence", "of", "GH", "resistance", "is", "sufficient", "to", "consider", "the", "possibility", "of", "aberrations", "of", "the", "GHR", ",", "even", "in", "the", "presence", "of", "normal", "serum", "GHBP", "concentrations", "." ]	[ "0", "2", "2", "2", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "2", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0" ]
20806042	A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree. PURPOSE: To identify the underlying genetic defect in a four-generation family of Chinese origin with autosomal dominant congenital cataract-microcornea syndrome (CCMC). METHODS: All individuals in the study underwent a full clinical examination and the details of history were collected . Genomic DNA extracted from peripheral blood was amplified by polymerase chain reaction (PCR) method and the exons of all candidate genes were sequenced. RESULTS: Direct sequencing of the encoding regions of the candidate genes revealed a heterozygous mutation c.592C-->T in exon 2 of the gap junction protein, alpha 8 (GJA8) gene. This mutation was responsible for the familial disorder through the substitution of a highly conserved arginine to tryptophan at codon 198 (p.R198W). This change co-segregated with all affected members of the family, but was not detected either in the non-carrier relatives or in the 100 normal controls. CONCLUSIONS: This report is the first to relate p.R198W mutation in GJA8 with CCMC. The result expands the mutation spectrum of GJA8 in associated with congenital cataract and microcornea, and implies that this gene has direct involvement with the development of the lens as well as the other anterior segment of the eye.	[ "A", "novel", "mutation", "in", "GJA8", "causing", "congenital", "cataract-microcornea", "syndrome", "in", "a", "Chinese", "pedigree", ".", "PURPOSE", ":", "To", "identify", "the", "underlying", "genetic", "defect", "in", "a", "four-generation", "family", "of", "Chinese", "origin", "with", "autosomal", "dominant", "congenital", "cataract-microcornea", "syndrome", "(", "CCMC", ")", ".", "METHODS", ":", "All", "individuals", "in", "the", "study", "underwent", "a", "full", "clinical", "examination", "and", "the", "details", "of", "history", "were", "collected", ".", "Genomic", "DNA", "extracted", "from", "peripheral", "blood", "was", "amplified", "by", "polymerase", "chain", "reaction", "(", "PCR", ")", "method", "and", "the", "exons", "of", "all", "candidate", "genes", "were", "sequenced", ".", "RESULTS", ":", "Direct", "sequencing", "of", "the", "encoding", "regions", "of", "the", "candidate", "genes", "revealed", "a", "heterozygous", "mutation", "c.592C", "--", ">", "T", "in", "exon", "2", "of", "the", "gap", "junction", "protein", ",", "alpha", "8", "(", "GJA8", ")", "gene", ".", "This", "mutation", "was", "responsible", "for", "the", "familial", "disorder", "through", "the", "substitution", "of", "a", "highly", "conserved", "arginine", "to", "tryptophan", "at", "codon", "198", "(", "p.R198W", ")", ".", "This", "change", "co-segregated", "with", "all", "affected", "members", "of", "the", "family", ",", "but", "was", "not", "detected", "either", "in", "the", "non-carrier", "relatives", "or", "in", "the", "100", "normal", "controls", ".", "CONCLUSIONS", ":", "This", "report", "is", "the", "first", "to", "relate", "p.R198W", "mutation", "in", "GJA8", "with", "CCMC", ".", "The", "result", "expands", "the", "mutation", "spectrum", "of", "GJA8", "in", "associated", "with", "congenital", "cataract", "and", "microcornea", ",", "and", "implies", "that", "this", "gene", "has", "direct", "involvement", "with", "the", "development", "of", "the", "lens", "as", "well", "as", "the", "other", "anterior", "segment", "of", "the", "eye", "." ]	[ "0", "0", "0", "0", "1", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "0", "1", "1", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "1", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
21163864	The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy. INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI. RESULTS: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM. CONCLUSION: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM.	[ "The", "M235T", "polymorphism", "of", "the", "angiotensinogen", "gene", "in", "South", "Indian", "patients", "of", "hypertrophic", "cardiomyopathy", ".", "INTRODUCTION", ":", "Hypertrophic", "cardiomyopathy", "(", "HCM", ")", "is", "a", "complex", "disorder", "and", "genetically", "transmitted", "cardiac", "disease", "with", "a", "diverse", "clinical", "course", ".", "The", "objective", "of", "the", "present", "study", "was", "to", "examine", "the", "association", "of", "the", "T704C", "polymorphism", "of", "exon", "2", "of", "the", "angiotensinogen", "(", "AGT", ")", "gene", "with", "HCM", "in", "a", "South", "Indian", "population", "from", "Andhra", "Pradesh", ".", "Subjects", "and", "methods", ".", "One-hundred", "and", "fifty", "HCM", "(", "90", "sporadic", "hypertrophic", "cardiomyopathy", "[", "SHCM", "]", "and", "60", "familial", "hypertrophic", "cardiomyopathy", "[", "FHCM", "]", ")", "patients", "and", "165", "age-", "and", "sex-matched", "normal", "healthy", "controls", "without", "known", "hypertension", "and", "left", "ventricular", "hypertrophy", "were", "included", "in", "the", "study", ".", "DNA", "was", "isolated", "from", "peripheral", "leukocytes", "and", "the", "region", "of", "interest", "in", "the", "AGT", "gene", "bearing", "a", "missense", "mutation", "methionine", "to", "threonine", "substitution", "at", "codon", "235", "(", "M235T", ")", "of", "exon", "2", ",", "was", "amplified", "by", "polymerase", "chain", "reaction", "(", "PCR", ")", ".", "The", "PCR", "products", "were", "subjected", "to", "restriction", "digestion", "with", "the", "enzyme", "SfaNI", ".", "RESULTS", ":", "Significant", "differences", "were", "detected", "in", "genotypic", "distribution", "(", "p", "=", "0.04", ")", "as", "well", "as", "the", "allelic", "frequency", "(", "p", "=", "0.003", ")", "between", "the", "SHCM", "patients", "and", "controls", ".", "The", "polymorphism", "did", "not", "show", "any", "association", "with", "FHCM", ".", "CONCLUSION", ":", "Our", "results", "suggest", "that", "the", "T", "allele", "of", "the", "AGT", "gene", "is", "significantly", "associated", "with", "SHCM", "in", "a", "South", "Indian", "population", "from", "Andhra", "Pradesh", ".", "However", ",", "we", "did", "not", "find", "significant", "association", "of", "this", "polymorphism", "with", "FHCM", "." ]	[ "0", "5", "0", "0", "0", "1", "0", "0", "0", "0", "4", "0", "2", "2", "0", "0", "0", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "2", "2", "2", "0", "2", "0", "0", "0", "2", "2", "2", "0", "2", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0" ]
21682595	XRCC1 Arg399Gln gene polymorphism and the risk of systemic lupus erythematosus in the Polish population. It has been shown that DNA repair is reduced in patients with systemic lupus erythematosus (SLE) and that the X-ray repair cross-complementing (XRCC1) Arg399Gln (rs25487) polymorphism may contribute to DNA repair. We evaluated the frequency of the XRCC1 Arg399Gln substitution in patients with SLE (n=265) and controls (n=360) in a sample of the Polish population. The odds ratio (OR) for SLE patients with the Gln/Gln versus Gln/Arg or Arg/Arg genotypes was 1.553 (95% confidence interval [CI]=0.9573-2.520; p=0.0729). OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.551 (95% CI=1.122-2.144, p=0.0077). The OR for the 399 Gln allele in patients with SLE was 1.406 (95% CI=1.111-1.779, p=0.0045). There was also a statistically significant p-value of the (2) test for the trend observed in the XRCC1 Arg399Gln polymorphism (ptrend=0.0048). We also found a significant contribution of the Gln/Gln or Arg/Gln versus Arg/Arg genotype to the presence of either the malar rash or photosensitivity manifestations of SLE OR=2.241 (1.328-3.781, p=0.0023, pcorr=0.0414). Moreover, the meta-analysis of Taiwanese Han Chinese, Brazilian, and Polish populations showed that the Gln/Gln or Gln/Arg genotype and Gln allele were associated with SLE incidence. OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.440 (95% CI=1.15-1.80, p=0.0019) and OR for the Gln allele was 1.27 (95% CI=1.08-1.51, p=0.0051). Our studies may confirm that the XRCC1 Arg399Gln polymorphism may increase the risk of incidence of SLE and the occurrence of some SLE manifestations.	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24126708	Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients. Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.	[ "Association", "of", "common", "genetic", "variants", "of", "HOMER1", "gene", "with", "levodopa", "adverse", "effects", "in", "Parkinson", "'s", "disease", "patients", ".", "Levodopa", "is", "the", "most", "effective", "symptomatic", "therapy", "for", "Parkinson", "'s", "disease", ",", "but", "its", "chronic", "use", "could", "lead", "to", "chronic", "adverse", "outcomes", ",", "such", "as", "motor", "fluctuations", ",", "dyskinesia", "and", "visual", "hallucinations", ".", "HOMER1", "is", "a", "protein", "with", "pivotal", "function", "in", "glutamate", "transmission", ",", "which", "has", "been", "related", "to", "the", "pathogenesis", "of", "these", "complications", ".", "This", "study", "investigates", "whether", "polymorphisms", "in", "the", "HOMER1", "gene", "promoter", "region", "are", "associated", "with", "the", "occurrence", "of", "the", "chronic", "complications", "of", "levodopa", "therapy", ".", "A", "total", "of", "205", "patients", "with", "idiopathic", "Parkinson", "'s", "disease", "were", "investigated", ".", "Patients", "were", "genotyped", "for", "rs4704559", ",", "rs10942891", "and", "rs4704560", "by", "allelic", "discrimination", "with", "Taqman", "assays", ".", "The", "rs4704559", "G", "allele", "was", "associated", "with", "a", "lower", "prevalence", "of", "dyskinesia", "(", "prevalence", "ratio", "(", "PR", ")", "=0.615", ",", "95", "%", "confidence", "interval", "(", "CI", ")", "0.426-0.887", ",", "P=0.009", ")", "and", "visual", "hallucinations", "(", "PR=0.515", ",", "95", "%", "CI", "0.295-0.899", ",", "P=0.020", ")", ".", "Our", "data", "suggest", "that", "HOMER1", "rs4704559", "G", "allele", "has", "a", "protective", "role", "for", "the", "development", "of", "levodopa", "adverse", "effects", "." ]	[ "0", "0", "0", "0", "0", "0", "1", "0", "0", "3", "0", "0", "0", "2", "2", "2", "4", "0", "3", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "1", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "2", "2", "0", "0", "0", "4", "0", "0", "0", "5", "0", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0" ]
25983002	Inhibition of LDHA suppresses tumor progression in prostate cancer. A key hallmark of cancer cells is their altered metabolism, known as Warburg effect. Lactate dehydrogenase A (LDHA) executes the final step of aerobic glycolysis and has been reported to be involved in the tumor progression. However, the function of LDHA in prostate cancer has not been studied. In current study, we observed overexpression of LDHA in the clinical prostate cancer samples compared with benign prostate hyperplasia tissues as demonstrated by immunohistochemistry and real-time qPCR. Attenuated expression of LDHA by siRNA or inhibition of LDHA activities by FX11 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of PC-3 and DU145 cells. Mechanistically, decreased Warburg effect as demonstrated by reduced glucose consumption and lactate secretion and reduced expression of MMP-9, PLAU, and cathepsin B were found after LDHA knockdown or FX11 treatment in PC-3 and DU145 cells. Taken together, our study revealed the oncogenic role of LDHA in prostate cancer and suggested that LDHA might be a potential therapeutic target.	[ "Inhibition", "of", "LDHA", "suppresses", "tumor", "progression", "in", "prostate", "cancer", ".", "A", "key", "hallmark", "of", "cancer", "cells", "is", "their", "altered", "metabolism", ",", "known", "as", "Warburg", "effect", ".", "Lactate", "dehydrogenase", "A", "(", "LDHA", ")", "executes", "the", "final", "step", "of", "aerobic", "glycolysis", "and", "has", "been", "reported", "to", "be", "involved", "in", "the", "tumor", "progression", ".", "However", ",", "the", "function", "of", "LDHA", "in", "prostate", "cancer", "has", "not", "been", "studied", ".", "In", "current", "study", ",", "we", "observed", "overexpression", "of", "LDHA", "in", "the", "clinical", "prostate", "cancer", "samples", "compared", "with", "benign", "prostate", "hyperplasia", "tissues", "as", "demonstrated", "by", "immunohistochemistry", "and", "real-time", "qPCR", ".", "Attenuated", "expression", "of", "LDHA", "by", "siRNA", "or", "inhibition", "of", "LDHA", "activities", "by", "FX11", "inhibited", "cell", "proliferation", ",", "migration", ",", "invasion", ",", "and", "promoted", "cell", "apoptosis", "of", "PC-3", "and", "DU145", "cells", ".", "Mechanistically", ",", "decreased", "Warburg", "effect", "as", "demonstrated", "by", "reduced", "glucose", "consumption", "and", "lactate", "secretion", "and", "reduced", "expression", "of", "MMP-9", ",", "PLAU", ",", "and", "cathepsin", "B", "were", "found", "after", "LDHA", "knockdown", "or", "FX11", "treatment", "in", "PC-3", "and", "DU145", "cells", ".", "Taken", "together", ",", "our", "study", "revealed", "the", "oncogenic", "role", "of", "LDHA", "in", "prostate", "cancer", "and", "suggested", "that", "LDHA", "might", "be", "a", "potential", "therapeutic", "target", "." ]	[ "0", "0", "1", "0", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "2", "2", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "6", "0", "6", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "1", "1", "0", "0", "0", "1", "0", "0", "3", "0", "0", "6", "0", "6", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "2", "2", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0" ]
27640183	Erythropoietin does not activate erythropoietin receptor signaling or lipolytic pathways in human subcutaneous white adipose tissue in vivo. BACKGROUND: Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo. METHOD: Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA). RESULTS: No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA. CONCLUSION: Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.	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28411266	Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease. Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacological therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120,286 participants in the UK Biobank and summary association results from four large-scale genome-wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes, and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (odds ratio [OR] 0.93; 95% CI 0.91, 0.95; P = 1.2 x 10(-11)). The variant was associated with increased BMI (+0.062 kg/m(2); 95% CI 0.037, 0.086; P = 8.1 x 10(-7)) but lower waist-to-hip ratio adjusted for BMI, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98; 95% CI 0.96, 0.99; P = 5.9 x 10(-4)). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease.	[ "Genetic", "Variation", "at", "the", "Sulfonylurea", "Receptor", ",", "Type", "2", "Diabetes", ",", "and", "Coronary", "Heart", "Disease", ".", "Despite", "widespread", "clinical", "use", "in", "the", "treatment", "of", "type", "2", "diabetes", ",", "the", "impact", "of", "sulfonylurea", "therapy", "on", "cardiovascular", "outcomes", "remains", "uncertain", ".", "Studies", "of", "naturally", "occurring", "genetic", "variation", "can", "be", "used", "to", "anticipate", "the", "expected", "clinical", "consequences", "of", "a", "pharmacological", "therapy", ".", "A", "common", "missense", "variant", "in", "the", "gene", "encoding", "a", "component", "of", "the", "sulfonylurea", "receptor", "(", "ABCC8", "p.A1369S", ")", "promotes", "closure", "of", "the", "target", "channel", "of", "sulfonylurea", "therapy", "and", "is", "associated", "with", "increased", "insulin", "secretion", ",", "thus", "mimicking", "the", "effects", "of", "sulfonylurea", "therapy", ".", "Using", "individual-level", "data", "from", "120,286", "participants", "in", "the", "UK", "Biobank", "and", "summary", "association", "results", "from", "four", "large-scale", "genome-wide", "association", "studies", ",", "we", "examined", "the", "impact", "of", "this", "variant", "on", "cardiometabolic", "traits", ",", "type", "2", "diabetes", ",", "and", "coronary", "heart", "disease", ".", "The", "p.A1369S", "variant", "was", "associated", "with", "a", "significantly", "lower", "risk", "of", "type", "2", "diabetes", "(", "odds", "ratio", "[", "OR", "]", "0.93", ";", "95", "%", "CI", "0.91", ",", "0.95", ";", "P", "=", "1.2", "x", "10", "(", "-11", ")", ")", ".", "The", "variant", "was", "associated", "with", "increased", "BMI", "(", "+0.062", "kg/m", "(", "2", ")", ";", "95", "%", "CI", "0.037", ",", "0.086", ";", "P", "=", "8.1", "x", "10", "(", "-7", ")", ")", "but", "lower", "waist-to-hip", "ratio", "adjusted", "for", "BMI", ",", "a", "marker", "of", "abdominal", "fat", "distribution", ".", "Furthermore", ",", "p.A1369S", "was", "associated", "with", "a", "reduced", "risk", "of", "coronary", "heart", "disease", "(", "OR", "0.98", ";", "95", "%", "CI", "0.96", ",", "0.99", ";", "P", "=", "5.9", "x", "10", "(", "-4", ")", ")", ".", "These", "results", "suggest", "that", ",", "despite", "a", "known", "association", "with", "increased", "weight", ",", "long-term", "sulfonylurea", "therapy", "may", "reduce", "the", "risk", "of", "coronary", "heart", "disease", "." ]	[ "0", "0", "0", "0", "1", "1", "0", "2", "2", "2", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "5", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "2", "2", "2", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0" ]
7468724	Cardiovascular complications associated with terbutaline treatment for preterm labor. Severe cardiovascular complications occurred in eight of 160 patients treated with terbutaline for preterm labor. Associated corticosteroid therapy and twin gestations appear to be predisposing factors. Potential mechanisms of the pathophysiology are briefly discussed.	[ "Cardiovascular", "complications", "associated", "with", "terbutaline", "treatment", "for", "preterm", "labor", ".", "Severe", "cardiovascular", "complications", "occurred", "in", "eight", "of", "160", "patients", "treated", "with", "terbutaline", "for", "preterm", "labor", ".", "Associated", "corticosteroid", "therapy", "and", "twin", "gestations", "appear", "to", "be", "predisposing", "factors", ".", "Potential", "mechanisms", "of", "the", "pathophysiology", "are", "briefly", "discussed", "." ]	[ "2", "2", "0", "0", "3", "0", "0", "2", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "4", "0", "0", "3", "0", "2", "2", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
7668252	Cloning of human very-long-chain acyl-coenzyme A dehydrogenase and molecular characterization of its deficiency in two patients. Two overlapping cDNA clones (1, 991 bp and 736 bp, respectively) encoding the precursor of human mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) were cloned and sequenced. The cDNA inserts of these clones together encompass a region of 2, 177 bases, encoding the entire protein of 655 amino acids, including a 40-amino acid leader peptide and a 615-amino acid mature polypeptide. PCR-amplified VLCAD cDNAs were sequenced in cultured fibroblasts from two VLCAD-deficient patients. In both patients, a 105-bp deletion encompassing bases 1078-1182 in VLCAD cDNA was identified. The deletion seems to occur due to exon skipping during processing of VLCAD pre-mRNA. This is the first demonstration of a mutation causing VLCAD deficiency. Quantitative cDNA expression of normal human VLCAD was performed in the patients fibroblasts, using vaccinia viral system, which demonstrated that the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients fibroblasts. In patient fibroblasts, raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts, which may offer important information for the rational design of future somatic gene therapy for VLCAD deficiency..	[ "Cloning", "of", "human", "very-long-chain", "acyl-coenzyme", "A", "dehydrogenase", "and", "molecular", "characterization", "of", "its", "deficiency", "in", "two", "patients", ".", "Two", "overlapping", "cDNA", "clones", "(", "1", ",", "991", "bp", "and", "736", "bp", ",", "respectively", ")", "encoding", "the", "precursor", "of", "human", "mitochondrial", "very-long-chain", "acyl-coenzyme", "A", "dehydrogenase", "(", "VLCAD", ")", "were", "cloned", "and", "sequenced", ".", "The", "cDNA", "inserts", "of", "these", "clones", "together", "encompass", "a", "region", "of", "2", ",", "177", "bases", ",", "encoding", "the", "entire", "protein", "of", "655", "amino", "acids", ",", "including", "a", "40-amino", "acid", "leader", "peptide", "and", "a", "615-amino", "acid", "mature", "polypeptide", ".", "PCR-amplified", "VLCAD", "cDNAs", "were", "sequenced", "in", "cultured", "fibroblasts", "from", "two", "VLCAD-deficient", "patients", ".", "In", "both", "patients", ",", "a", "105-bp", "deletion", "encompassing", "bases", "1078-1182", "in", "VLCAD", "cDNA", "was", "identified", ".", "The", "deletion", "seems", "to", "occur", "due", "to", "exon", "skipping", "during", "processing", "of", "VLCAD", "pre-mRNA", ".", "This", "is", "the", "first", "demonstration", "of", "a", "mutation", "causing", "VLCAD", "deficiency", ".", "Quantitative", "cDNA", "expression", "of", "normal", "human", "VLCAD", "was", "performed", "in", "the", "patients", "fibroblasts", ",", "using", "vaccinia", "viral", "system", ",", "which", "demonstrated", "that", "the", "deficiency", "of", "the", "normal", "VLCAD", "protein", "causes", "impaired", "long-chain", "fatty", "acid", "beta-oxidation", "activity", "in", "the", "patients", "fibroblasts", ".", "In", "patient", "fibroblasts", ",", "raising", "VLCAD", "activity", "to", "approximately", "20", "%", "of", "normal", "control", "fibroblast", "activity", "raised", "palmitic", "acid", "beta-oxidation", "flux", "to", "the", "level", "found", "in", "control", "fibroblasts", ",", "which", "may", "offer", "important", "information", "for", "the", "rational", "design", "of", "future", "somatic", "gene", "therapy", "for", "VLCAD", "deficiency", ".." ]	[ "0", "0", "4", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "4", "0", "0", "5", "5", "5", "5", "5", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "4", "1", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "2", "0", "0", "3", "3", "3", "0", "0", "0", "0", "4", "0", "0", "0", "4", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0" ]
8002973	Adrenoleukodystrophy gene encodes an 80 kDa membrane protein. An antibody against the synthetic C-terminal peptides deduced from the cDNA of the gene responsible for X-linked adrenoleukodystrophy (ALD) was produced to characterize the product of the ALD gene. The antibody reacted with the 80 kDa band protein in control fibroblasts, while no bands were detected in the fibroblasts from a patient with ALD (# 163), in which mRNA of the ALD gene was undetectable based on Northern blot analysis. The 293T cells transfected with the full-coding cDNA inserted in the expression vector produced a new 80 kDa protein, as detected by Western blot. In an immunocytological study, the staining was in a punctate pattern, in the normal fibroblasts. However, there was no punctate staining in the # 163 cells. These data thus indicate that the ALD gene encodes an 80 kDa membrane protein..	[ "Adrenoleukodystrophy", "gene", "encodes", "an", "80", "kDa", "membrane", "protein", ".", "An", "antibody", "against", "the", "synthetic", "C-terminal", "peptides", "deduced", "from", "the", "cDNA", "of", "the", "gene", "responsible", "for", "X-linked", "adrenoleukodystrophy", "(", "ALD", ")", "was", "produced", "to", "characterize", "the", "product", "of", "the", "ALD", "gene", ".", "The", "antibody", "reacted", "with", "the", "80", "kDa", "band", "protein", "in", "control", "fibroblasts", ",", "while", "no", "bands", "were", "detected", "in", "the", "fibroblasts", "from", "a", "patient", "with", "ALD", "(", "#", "163", ")", ",", "in", "which", "mRNA", "of", "the", "ALD", "gene", "was", "undetectable", "based", "on", "Northern", "blot", "analysis", ".", "The", "293T", "cells", "transfected", "with", "the", "full-coding", "cDNA", "inserted", "in", "the", "expression", "vector", "produced", "a", "new", "80", "kDa", "protein", ",", "as", "detected", "by", "Western", "blot", ".", "In", "an", "immunocytological", "study", ",", "the", "staining", "was", "in", "a", "punctate", "pattern", ",", "in", "the", "normal", "fibroblasts", ".", "However", ",", "there", "was", "no", "punctate", "staining", "in", "the", "#", "163", "cells", ".", "These", "data", "thus", "indicate", "that", "the", "ALD", "gene", "encodes", "an", "80", "kDa", "membrane", "protein", ".." ]	[ "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "6", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0" ]
8755918	Mutations associated with variant phenotypes in ataxia-telangiectasia. We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10% -15% of A-T families identified in the United Kingdom). In 10 of these families, all the homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice-donor site. The second A-T allele has a different mutation in each patient. We show that the less severe phenotype in these patients is caused by some degree of normal splicing, which occurs as an alternative product from the insertion-containing allele. The level of the 137-bp PCR product containing the insertion was lowest in two patients who showed a later onset of cerebellar ataxia. A further four families who do not have this insertion have been identified. Mutations detected in two of four of these are missense mutations, normally rare in A-T patients. The demonstration of mutations giving rise to a slightly milder phenotype in A-T raises the interesting question of what range of phenotypes might occur in individuals in whom both mutations are milder. One possibility might be that individuals who are compound heterozygotes for ATM mutations are more common than we realize..	[ "Mutations", "associated", "with", "variant", "phenotypes", "in", "ataxia-telangiectasia", ".", "We", "have", "identified", "14", "families", "with", "ataxia-telangiectasia", "(", "A-T", ")", "in", "which", "mutation", "of", "the", "ATM", "gene", "is", "associated", "with", "a", "less", "severe", "clinical", "and", "cellular", "phenotype", "(", "approximately", "10", "%", "-15", "%", "of", "A-T", "families", "identified", "in", "the", "United", "Kingdom", ")", ".", "In", "10", "of", "these", "families", ",", "all", "the", "homozygotes", "have", "a", "137-bp", "insertion", "in", "their", "cDNA", "caused", "by", "a", "point", "mutation", "in", "a", "sequence", "resembling", "a", "splice-donor", "site", ".", "The", "second", "A-T", "allele", "has", "a", "different", "mutation", "in", "each", "patient", ".", "We", "show", "that", "the", "less", "severe", "phenotype", "in", "these", "patients", "is", "caused", "by", "some", "degree", "of", "normal", "splicing", ",", "which", "occurs", "as", "an", "alternative", "product", "from", "the", "insertion-containing", "allele", ".", "The", "level", "of", "the", "137-bp", "PCR", "product", "containing", "the", "insertion", "was", "lowest", "in", "two", "patients", "who", "showed", "a", "later", "onset", "of", "cerebellar", "ataxia", ".", "A", "further", "four", "families", "who", "do", "not", "have", "this", "insertion", "have", "been", "identified", ".", "Mutations", "detected", "in", "two", "of", "four", "of", "these", "are", "missense", "mutations", ",", "normally", "rare", "in", "A-T", "patients", ".", "The", "demonstration", "of", "mutations", "giving", "rise", "to", "a", "slightly", "milder", "phenotype", "in", "A-T", "raises", "the", "interesting", "question", "of", "what", "range", "of", "phenotypes", "might", "occur", "in", "individuals", "in", "whom", "both", "mutations", "are", "milder", ".", "One", "possibility", "might", "be", "that", "individuals", "who", "are", "compound", "heterozygotes", "for", "ATM", "mutations", "are", "more", "common", "than", "we", "realize", ".." ]	[ "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0" ]
9746003	Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Carbamazepine and vigabatrin are contraindicated in typical absence seizures. Of 18 consecutive referrals of children with resistant typical absences only, eight were erroneously treated with carbamazepine either as monotherapy or as an add-on. Vigabatrin was also used in the treatment of two children. Frequency of absences increased in four children treated with carbamazepine and two of these developed myoclonic jerks, which resolved on withdrawal of carbamazepine. Absences were aggravated in both cases where vigabatrin was added on to concurrent treatment. Optimal control of the absences was achieved with sodium valproate, lamotrigine, or ethosuximide alone or in combination.	[ "Inappropriate", "use", "of", "carbamazepine", "and", "vigabatrin", "in", "typical", "absence", "seizures", ".", "Carbamazepine", "and", "vigabatrin", "are", "contraindicated", "in", "typical", "absence", "seizures", ".", "Of", "18", "consecutive", "referrals", "of", "children", "with", "resistant", "typical", "absences", "only", ",", "eight", "were", "erroneously", "treated", "with", "carbamazepine", "either", "as", "monotherapy", "or", "as", "an", "add-on", ".", "Vigabatrin", "was", "also", "used", "in", "the", "treatment", "of", "two", "children", ".", "Frequency", "of", "absences", "increased", "in", "four", "children", "treated", "with", "carbamazepine", "and", "two", "of", "these", "developed", "myoclonic", "jerks", ",", "which", "resolved", "on", "withdrawal", "of", "carbamazepine", ".", "Absences", "were", "aggravated", "in", "both", "cases", "where", "vigabatrin", "was", "added", "on", "to", "concurrent", "treatment", ".", "Optimal", "control", "of", "the", "absences", "was", "achieved", "with", "sodium", "valproate", ",", "lamotrigine", ",", "or", "ethosuximide", "alone", "or", "in", "combination", "." ]	[ "0", "0", "0", "3", "0", "3", "0", "0", "2", "2", "0", "3", "0", "3", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "3", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0" ]
15609295	Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome. Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient.	[ "Compound", "heterozygosity", "for", "a", "novel", "nine-nucleotide", "deletion", "and", "the", "Asn45Ser", "missense", "mutation", "in", "the", "glycoprotein", "IX", "gene", "in", "a", "patient", "with", "Bernard-Soulier", "syndrome", ".", "Bernard-Soulier", "syndrome", "(", "BSS", ")", "is", "a", "rare", "inherited", "bleeding", "disorder", "due", "to", "quantitative", "or", "qualitative", "abnormalities", "in", "the", "platelet", "glycoprotein", "(", "GP", ")", "Ib/IX/V", "complex", ",", "the", "major", "von", "Willebrand", "factor", "receptor", ".", "The", "complex", "comprises", "four", "subunits", ",", "each", "encoded", "by", "a", "separate", "gene", ".", "Several", "mutations", "have", "been", "described", "for", "each", "of", "the", "subunits", ",", "except", "for", "GPV", ",", "as", "a", "cause", "of", "BSS", ".", "We", "describe", "here", "the", "genetic", "basis", "of", "the", "disorder", "in", "a", "child", "with", "BSS", ".", "Flow-cytometric", "analysis", "of", "the", "patient", "'s", "platelets", "showed", "a", "markedly", "reduced", "surface", "expression", "of", "all", "three", "glycoproteins", "of", "the", "GPIb/IX/V", "complex", ".", "DNA", "sequencing", "analysis", "showed", "the", "patient", "to", "be", "a", "compound", "heterozygote", "for", "two", "mutations", "in", "the", "GPIX", "gene", ",", "a", "novel", "nine-nucleotide", "deletion", "starting", "at", "position", "1952", "of", "the", "gene", "that", "changes", "asparagine", "86", "for", "alanine", "and", "eliminates", "amino", "acids", "87", ",", "88", ",", "and", "89", "(", "arginine", ",", "threonine", ",", "and", "proline", ")", "and", "a", "previously", "reported", "point", "mutation", "that", "changes", "the", "codon", "asparagine", "(", "AAC", ")", "for", "serine", "(", "AGC", ")", "at", "residue", "45", ".", "Her", "mother", "was", "heterozygous", "for", "the", "Asn45Ser", "mutation", ",", "and", "her", "father", ",", "for", "the", "nine-nucleotide", "deletion", ".", "Our", "findings", "suggest", "that", "the", "additive", "effects", "of", "both", "mutations", "in", "the", "GPIX", "gene", "are", "responsible", "for", "the", "BSS", "phenotype", "of", "the", "patient", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "1", "1", "0", "0", "0", "4", "0", "2", "2", "0", "2", "2", "0", "2", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "1", "0", "0", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "0", "0", "4", "0" ]
16288197	Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree. PURPOSE: Congenital microcoria is a rare autosomal dominant developmental disorder of the iris associated with myopia and juvenile open angle glaucoma. Linkage to the chromosomal locus 13q31-q32 has previously been reported in a large French family. In the current study, a three generation Asian Indian family with 15 congenital microcoria (pupils with a diameter <2 mm) affected members was studied for linkage to candidate microsatellite markers at the 13q31-q32 locus. METHODS: Twenty-four members of the family were clinically examined and genomic DNA was extracted. Microsatellite markers at 13q31-q32 were PCR amplified and run on an ABI Prism 310 genetic analyzer and genotyped with the GeneScan analysis. Two point and multipoint linkage analyses were performed using the MLINK and SUPERLINK programs. RESULTS: Peak two point LOD scores of 3.5, 4.7, and 5.3 were found co-incident with consecutive markers D13S154, DCT, and D13S1280. Multipoint analysis revealed a 4 cM region encompassing D13S1300 to D13S1280 where the LOD remains just over 6.0 Thus we confirm localization of the congenital microcoria locus to chromosomal locus 13q31-q32. In addition, eight individuals who had both microcoria and glaucoma were screened for glaucoma genes: myocilin (MYOC), optineurin (OPTN) and CYP1B1. Using direct sequencing a point mutation (144 G>A) resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five of the eight glaucoma patients, but not in unaffected family members and 100 unrelated controls. CONCLUSIONS: We have confirmed the localization of the congenital microcoria locus (MCOR) to 13q31-q32 in a large Asian Indian family and conclude that current information suggests this is a single locus disorder and genetically homogeneous. When combined with the initial linkage paper our haplotype and linkage data map the MCOR locus to a 6-7 cM region between D13S265 and D13S1280. The DCT locus, a member of the tyrosinase family involved in pigmentation, maps within this region. Data presented here supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma, although this observation is complicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), a mutation known to be associated with glaucoma in India. Fine mapping and candidate gene analysis continues with the hope that characterizing the micocoria gene will lead to a better understanding of microcoria and glaucoma causation. The relationship between microcoria, glaucoma, and the MYOC Q48H mutation in this family is discussed.	[ "Genetic", "homogeneity", "for", "inherited", "congenital", "microcoria", "loci", "in", "an", "Asian", "Indian", "pedigree", ".", "PURPOSE", ":", "Congenital", "microcoria", "is", "a", "rare", "autosomal", "dominant", "developmental", "disorder", "of", "the", "iris", "associated", "with", "myopia", "and", "juvenile", "open", "angle", "glaucoma", ".", "Linkage", "to", "the", "chromosomal", "locus", "13q31-q32", "has", "previously", "been", "reported", "in", "a", "large", "French", "family", ".", "In", "the", "current", "study", ",", "a", "three", "generation", "Asian", "Indian", "family", "with", "15", "congenital", "microcoria", "(", "pupils", "with", "a", "diameter", "<", "2", "mm", ")", "affected", "members", "was", "studied", "for", "linkage", "to", "candidate", "microsatellite", "markers", "at", "the", "13q31-q32", "locus", ".", "METHODS", ":", "Twenty-four", "members", "of", "the", "family", "were", "clinically", "examined", "and", "genomic", "DNA", "was", "extracted", ".", "Microsatellite", "markers", "at", "13q31-q32", "were", "PCR", "amplified", "and", "run", "on", "an", "ABI", "Prism", "310", "genetic", "analyzer", "and", "genotyped", "with", "the", "GeneScan", "analysis", ".", "Two", "point", "and", "multipoint", "linkage", "analyses", "were", "performed", "using", "the", "MLINK", "and", "SUPERLINK", "programs", ".", "RESULTS", ":", "Peak", "two", "point", "LOD", "scores", "of", "3.5", ",", "4.7", ",", "and", "5.3", "were", "found", "co-incident", "with", "consecutive", "markers", "D13S154", ",", "DCT", ",", "and", "D13S1280", ".", "Multipoint", "analysis", "revealed", "a", "4", "cM", "region", "encompassing", "D13S1300", "to", "D13S1280", "where", "the", "LOD", "remains", "just", "over", "6.0", "Thus", "we", "confirm", "localization", "of", "the", "congenital", "microcoria", "locus", "to", "chromosomal", "locus", "13q31-q32", ".", "In", "addition", ",", "eight", "individuals", "who", "had", "both", "microcoria", "and", "glaucoma", "were", "screened", "for", "glaucoma", "genes", ":", "myocilin", "(", "MYOC", ")", ",", "optineurin", "(", "OPTN", ")", "and", "CYP1B1", ".", "Using", "direct", "sequencing", "a", "point", "mutation", "(", "144", "G", ">", "A", ")", "resulting", "in", "a", "Q48H", "substitution", "in", "exon", "1", "of", "the", "MYOC", "gene", "was", "observed", "in", "five", "of", "the", "eight", "glaucoma", "patients", ",", "but", "not", "in", "unaffected", "family", "members", "and", "100", "unrelated", "controls", ".", "CONCLUSIONS", ":", "We", "have", "confirmed", "the", "localization", "of", "the", "congenital", "microcoria", "locus", "(", "MCOR", ")", "to", "13q31-q32", "in", "a", "large", "Asian", "Indian", "family", "and", "conclude", "that", "current", "information", "suggests", "this", "is", "a", "single", "locus", "disorder", "and", "genetically", "homogeneous", ".", "When", "combined", "with", "the", "initial", "linkage", "paper", "our", "haplotype", "and", "linkage", "data", "map", "the", "MCOR", "locus", "to", "a", "6-7", "cM", "region", "between", "D13S265", "and", "D13S1280", ".", "The", "DCT", "locus", ",", "a", "member", "of", "the", "tyrosinase", "family", "involved", "in", "pigmentation", ",", "maps", "within", "this", "region", ".", "Data", "presented", "here", "supports", "the", "hypothesis", "that", "congenital", "microcoria", "is", "a", "potential", "risk", "factor", "for", "glaucoma", ",", "although", "this", "observation", "is", "complicated", "by", "the", "partial", "segregation", "of", "MYOC", "Q48H", "(", "1q24.3-q25.2", ")", ",", "a", "mutation", "known", "to", "be", "associated", "with", "glaucoma", "in", "India", ".", "Fine", "mapping", "and", "candidate", "gene", "analysis", "continues", "with", "the", "hope", "that", "characterizing", "the", "micocoria", "gene", "will", "lead", "to", "a", "better", "understanding", "of", "microcoria", "and", "glaucoma", "causation", ".", "The", "relationship", "between", "microcoria", ",", "glaucoma", ",", "and", "the", 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17177139	A novel mutation (E333D) in the thyroid hormone beta receptor causing resistance to thyroid hormone syndrome. Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.	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17634480	Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. PURPOSE: The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer. PATIENTS AND METHODS: We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer. RESULTS: Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes. CONCLUSION: These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.	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15748645	Photochemoprevention of ultraviolet B signaling and photocarcinogenesis. Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.	[ "Photochemoprevention", "of", "ultraviolet", "B", "signaling", "and", "photocarcinogenesis", ".", "Exposure", "to", "solar", "radiation", ",", "particularly", "its", "ultraviolet", "(", "UV", ")", "B", "component", ",", "has", "a", "variety", "of", "harmful", "effects", "on", "human", "health", ".", "Some", "of", "these", "effects", "include", "sunburn", "cell", "formation", ",", "basal", "and", "squamous", "cell", "cancers", ",", "melanoma", ",", "cataracts", ",", "photoaging", "of", "the", "skin", ",", "and", "immune", "suppression", ".", "Amongst", "these", "various", "adverse", "effects", "of", "UV", "radiation", ",", "skin", "cancer", "is", "of", "the", "greatest", "concern", ".", "Over", "the", "years", ",", "changes", "in", "lifestyle", "has", "led", "to", "a", "significant", "increase", "in", "the", "amount", "of", "UV", "radiation", "that", "people", "receive", ",", "and", "this", "consequently", "has", "led", "to", "a", "surge", "in", "the", "incidence", "of", "skin", "cancer", ".", "The", "development", "of", "skin", "cancer", "is", "a", "complex", "multistage", "phenomenon", "involving", "three", "distinct", "stages", "exemplified", "by", "initiation", ",", "promotion", "and", "progression", "stages", ".", "Each", "of", "these", "stages", "is", "mediated", "via", "alterations", "in", "various", "cellular", ",", "biochemical", ",", "and", "molecular", "changes", ".", "Initiation", ",", "the", "first", "step", "in", "the", "carcinogenesis", "process", "is", "essentially", "an", "irreversible", "step", "in", "which", "genetic", "alterations", "occur", "in", "genes", "that", "ultimately", "leads", "to", "DNA", "modification", "and", "fixation", "of", "mutation", ".", "Tumor", "promotion", "is", "the", "essential", "process", "in", "cancer", "development", "involving", "clonal", "expansion", "of", "initiated", "cells", "giving", "rise", "to", "pre-malignant", "and", "then", "to", "malignant", "lesions", ",", "essentially", "by", "alterations", "in", "signal", "transduction", "pathways", ".", "Tumor", "progression", "involves", "the", "conversion", "of", "pre-malignant", "and", "malignant", "lesions", "into", "an", "invasive", "and", "potentially", "metastatic", "malignant", "tumor", ".", "All", "these", "processes", "for", "skin", "cancer", "development", "involve", "stimulation", "of", "DNA", "synthesis", ",", "DNA", "damage", "and", "proliferation", ",", "inflammation", ",", "immunosuppression", ",", "epidermal", "hyperplasia", ",", "cell", "cycle", "dysregulation", ",", "depletion", "of", "antioxidant", "defenses", ",", "impairment", "of", "signal", "transduction", "pathways", ",", "induction", "of", "cyclooxygenase", ",", "increase", "in", "prostaglandin", "synthesis", ",", "and", "induction", "of", "ornithine", "decarboxylase", ".", "Photochemoprevention", "has", "been", "appreciated", "as", "a", "viable", "approach", "to", "reduce", "the", "occurrence", "of", "skin", "cancer", "and", "in", "recent", "years", ",", "the", "use", "of", "agents", ",", "especially", "botanical", "antioxidants", ",", "present", "in", "the", "common", "diet", "and", "beverages", "consumed", "by", "human", "population", "have", "gained", "considerable", "attention", "as", "photochemopreventive", "agents", "for", "human", "use", ".", "Many", "such", "agents", "have", "also", "found", "a", "place", "in", "skin", "care", "products", ".", "Although", "this", "is", "more", "common", "in", "oriental", "countries", ",", "its", "popularity", "is", "significantly", "growing", "in", "western", "countries", ".", "In", "this", "article", ",", "we", "have", "summarized", "the", "available", "information", "of", "laboratory", "studies", "on", "UVB-mediated", "signaling", "that", "can", "be", "exploited", "as", "targets", "for", "photochemoprevention", ".", "We", "suggest", "that", "the", "use", "of", "skin", "care", "products", "supplemented", "with", "proven", "chemopreventive", "agents", "in", "conjunction", "with", "the", "use", "of", "sunscreens", "along", "with", "educational", "efforts", "may", "be", "an", "effective", "strategy", "for", "reducing", "UV-induced", "photodamage", "and", "skin", "cancer", "in", "humans", ".", "The", "mechanistic", "basis", "for", "the", "use", "of", "such", "products", "is", "discussed", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", 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16543197	A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis. PURPOSE: To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. MATERIALS AND METHODS: The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. RESULTS: All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. CONCLUSION: Although hyperopia has been associated with LCA, it is typically moderate and variable between patients with the same mutation. In addition, some CRB1 mutations can be associated with either RP or LCA. We have shown that hyperopia and LCA are linked to the mutant CRB1 gene itself and are not dependent on unlinked modifiers.	[ "A", "G1103R", "mutation", "in", "CRB1", "is", "co-inherited", "with", "high", "hyperopia", "and", "Leber", "congenital", "amaurosis", ".", "PURPOSE", ":", "To", "identify", "the", "genetic", "basis", "of", "recessive", "inheritance", "of", "high", "hyperopia", "and", "Leber", "congenital", "amaurosis", "(", "LCA", ")", "in", "a", "family", "of", "Middle", "Eastern", "origin", ".", "MATERIALS", "AND", "METHODS", ":", "The", "patients", "were", "examined", "using", "standard", "ophthalmic", "techniques", ".", "DNA", "samples", "were", "obtained", "and", "genetic", "linkage", "was", "carried", "out", "using", "polymorphic", "markers", "flanking", "the", "known", "genes", "and", "loci", "for", "LCA", ".", "Exons", "were", "amplified", "and", "sequenced", ".", "RESULTS", ":", "All", "four", "members", "of", "this", "family", "affected", "by", "LCA", "showed", "high", "to", "extreme", "hyperopia", ",", "with", "average", "spherical", "refractive", "errors", "ranging", "from", "+5.00", "to", "+10.00", ".", "Linkage", "was", "obtained", "to", "1q31.3", "with", "a", "maximal", "LOD", "score", "of", "5.20", "and", "a", "mutation", "found", "in", "exon", "9", "of", "the", "CRB1", "gene", ",", "causing", "a", "G1103R", "substitution", "at", "a", "highly", "conserved", "site", "in", "the", "protein", ".", "CRB1", "is", "a", "vertebrate", "homolog", "of", "the", "Drosophila", "crumbs", "gene", ",", "which", "is", "required", "for", "photoreceptor", "morphogenesis", ",", "and", "has", "been", "associated", "with", "either", "retinitis", "pigmentosa", "(", "RP", ")", "or", "LCA", ".", "This", "sequence", "variant", "has", "previously", "been", "reported", "as", "a", "compound", "heterozygote", "in", "one", "sporadic", "LCA", "patient", ".", "CONCLUSION", ":", "Although", "hyperopia", "has", "been", "associated", "with", "LCA", ",", "it", "is", "typically", "moderate", "and", "variable", "between", "patients", "with", "the", "same", "mutation", ".", "In", "addition", ",", "some", "CRB1", "mutations", "can", "be", "associated", "with", "either", "RP", "or", "LCA", ".", "We", "have", "shown", "that", "hyperopia", "and", "LCA", "are", "linked", "to", "the", "mutant", "CRB1", "gene", "itself", "and", "are", "not", "dependent", "on", "unlinked", "modifiers", "." ]	[ "0", "5", "0", "0", "1", "0", "0", "0", "0", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "4", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "2", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
20477932	Cocaine causes memory and learning impairments in rats: involvement of nuclear factor kappa B and oxidative stress, and prevention by topiramate. Different mechanisms have been suggested for cocaine toxicity including an increase in oxidative stress but the association between oxidative status in the brain and cocaine induced-behaviour is poorly understood. Nuclear factor kappa B (NFkappaB) is a sensor of oxidative stress and participates in memory formation that could be involved in drug toxicity and addiction mechanisms. Therefore NFkappaB activity, oxidative stress, neuronal nitric oxide synthase (nNOS) activity, spatial learning and memory as well as the effect of topiramate, a previously proposed therapy for cocaine addiction, were evaluated in an experimental model of cocaine administration in rats. NFkappaB activity was decreased in the frontal cortex of cocaine treated rats, as well as GSH concentration and glutathione peroxidase activity in the hippocampus, whereas nNOS activity in the hippocampus was increased. Memory retrieval of experiences acquired prior to cocaine administration was impaired and negatively correlated with NFkappaB activity in the frontal cortex. In contrast, learning of new tasks was enhanced and correlated with the increase of nNOS activity and the decrease of glutathione peroxidase. These results provide evidence for a possible mechanistic role of oxidative and nitrosative stress and NFkappaB in the alterations induced by cocaine. Topiramate prevented all the alterations observed, showing novel neuroprotective properties.	[ "Cocaine", "causes", "memory", "and", "learning", "impairments", "in", "rats", ":", "involvement", "of", "nuclear", "factor", "kappa", "B", "and", "oxidative", "stress", ",", "and", "prevention", "by", "topiramate", ".", "Different", "mechanisms", "have", "been", "suggested", "for", "cocaine", "toxicity", "including", "an", "increase", "in", "oxidative", "stress", "but", "the", "association", "between", "oxidative", "status", "in", "the", "brain", "and", "cocaine", "induced-behaviour", "is", "poorly", "understood", ".", "Nuclear", "factor", "kappa", "B", "(", "NFkappaB", ")", "is", "a", "sensor", "of", "oxidative", "stress", "and", "participates", "in", "memory", "formation", "that", "could", "be", "involved", "in", "drug", "toxicity", "and", "addiction", "mechanisms", ".", "Therefore", "NFkappaB", "activity", ",", "oxidative", "stress", ",", "neuronal", "nitric", "oxide", "synthase", "(", "nNOS", ")", "activity", ",", "spatial", "learning", "and", "memory", "as", "well", "as", "the", "effect", "of", "topiramate", ",", "a", "previously", "proposed", "therapy", "for", "cocaine", "addiction", ",", "were", "evaluated", "in", "an", "experimental", "model", "of", "cocaine", "administration", "in", "rats", ".", "NFkappaB", "activity", "was", "decreased", "in", "the", "frontal", "cortex", "of", "cocaine", "treated", "rats", ",", "as", "well", "as", "GSH", "concentration", "and", "glutathione", "peroxidase", "activity", "in", "the", "hippocampus", ",", "whereas", "nNOS", "activity", "in", "the", "hippocampus", "was", "increased", ".", "Memory", "retrieval", "of", "experiences", "acquired", "prior", "to", "cocaine", "administration", "was", "impaired", "and", "negatively", "correlated", "with", "NFkappaB", "activity", "in", "the", "frontal", "cortex", ".", "In", "contrast", ",", "learning", "of", "new", "tasks", "was", "enhanced", "and", "correlated", "with", "the", "increase", "of", "nNOS", "activity", "and", "the", "decrease", "of", "glutathione", "peroxidase", ".", "These", "results", "provide", "evidence", "for", "a", "possible", "mechanistic", "role", "of", "oxidative", "and", "nitrosative", "stress", "and", "NFkappaB", "in", "the", "alterations", "induced", "by", "cocaine", ".", "Topiramate", "prevented", "all", "the", "alterations", "observed", ",", "showing", "novel", "neuroprotective", "properties", "." ]	[ "3", "0", "2", "2", "2", "2", "0", "4", "0", "0", "0", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "3", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "4", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "4", "0", "0", "0", "0", "3", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
28348168	FGFR2 is required for airway basal cell self-renewal and terminal differentiation. Airway stem cells slowly self-renew and produce differentiated progeny to maintain homeostasis throughout the lifespan of an individual. Mutations in the molecular regulators of these processes may drive cancer or degenerative disease, but are also potential therapeutic targets. Conditionally deleting one copy of FGF receptor 2 (FGFR2) in adult mouse airway basal cells results in self-renewal and differentiation phenotypes. We show that FGFR2 signalling correlates with maintenance of expression of a key transcription factor for basal cell self-renewal and differentiation: SOX2. This heterozygous phenotype illustrates that subtle changes in receptor tyrosine kinase signalling can have significant effects, perhaps providing an explanation for the numerous changes seen in cancer.	[ "FGFR2", "is", "required", "for", "airway", "basal", "cell", "self-renewal", "and", "terminal", "differentiation", ".", "Airway", "stem", "cells", "slowly", "self-renew", "and", "produce", "differentiated", "progeny", "to", "maintain", "homeostasis", "throughout", "the", "lifespan", "of", "an", "individual", ".", "Mutations", "in", "the", "molecular", "regulators", "of", "these", "processes", "may", "drive", "cancer", "or", "degenerative", "disease", ",", "but", "are", "also", "potential", "therapeutic", "targets", ".", "Conditionally", "deleting", "one", "copy", "of", "FGF", "receptor", "2", "(", "FGFR2", ")", "in", "adult", "mouse", "airway", "basal", "cells", "results", "in", "self-renewal", "and", "differentiation", "phenotypes", ".", "We", "show", "that", "FGFR2", "signalling", "correlates", "with", "maintenance", "of", "expression", "of", "a", "key", "transcription", "factor", "for", "basal", "cell", "self-renewal", "and", "differentiation", ":", "SOX2", ".", "This", "heterozygous", "phenotype", "illustrates", "that", "subtle", "changes", "in", "receptor", "tyrosine", "kinase", "signalling", "can", "have", "significant", "effects", ",", "perhaps", "providing", "an", "explanation", "for", "the", "numerous", "changes", "seen", "in", "cancer", "." ]	[ "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "1", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0" ]
16418600	Genetic investigation of the TSPYL1 gene in sudden infant death syndrome. BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.	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16904497	Cauda equina syndrome after epidural steroid injection: a case report. OBJECTIVE: Conventional treatment methods of lumbusacral radiculopathy are physical therapy, epidural steroid injections, oral medications, and spinal manipulative therapy. Cauda equina syndrome is a rare complication of epidural anesthesia. The following case is a report of cauda equina syndrome possibly caused by epidural injection of triamcinolone and bupivacaine. CLINICAL FEATURES: A 50-year-old woman with low back and right leg pain was scheduled for epidural steroid injection. INTERVENTION AND OUTCOME: An 18-gauge Touhy needle was inserted until loss of resistance occurred at the L4-5 level. Spread of the contrast medium within the epidural space was determined by radiographic imaging. After verifying the epidural space, bupivacaine and triamcinolone diacetate were injected. After the injection, there was a reduction in radicular symptoms. Three hours later, she complained of perineal numbness and lower extremity weakness. The neurologic evaluation revealed loss of sensation in the saddle area and medial aspect of her right leg. There was a decrease in the perception of pinprick test. Deep-tendon reflexes were decreased especially in the right leg. She was unable to urinate. The patient's symptoms improved slightly over the next few hours. She had a gradual return of motor function and ability of feeling Foley catheter. All of the symptoms were completely resolved over the next 8 hours. CONCLUSION: Complications associated with epidural steroid injections are rare. Clinical examination and continued vigilance for neurologic deterioration after epidural steroid injections is important.	[ "Cauda", "equina", "syndrome", "after", "epidural", "steroid", "injection", ":", "a", "case", "report", ".", "OBJECTIVE", ":", "Conventional", "treatment", "methods", "of", "lumbusacral", "radiculopathy", "are", "physical", "therapy", ",", "epidural", "steroid", "injections", ",", "oral", "medications", ",", "and", "spinal", "manipulative", "therapy", ".", "Cauda", "equina", "syndrome", "is", "a", "rare", "complication", "of", "epidural", "anesthesia", ".", "The", "following", "case", "is", "a", "report", "of", "cauda", "equina", "syndrome", "possibly", "caused", "by", "epidural", "injection", "of", "triamcinolone", "and", "bupivacaine", ".", "CLINICAL", "FEATURES", ":", "A", "50-year-old", "woman", "with", "low", "back", "and", "right", "leg", "pain", "was", "scheduled", "for", "epidural", "steroid", "injection", ".", "INTERVENTION", "AND", "OUTCOME", ":", "An", "18-gauge", "Touhy", "needle", "was", "inserted", "until", "loss", "of", "resistance", "occurred", "at", "the", "L4-5", "level", ".", "Spread", "of", "the", "contrast", "medium", "within", "the", "epidural", "space", "was", "determined", "by", "radiographic", "imaging", ".", "After", "verifying", "the", "epidural", "space", ",", "bupivacaine", "and", "triamcinolone", "diacetate", "were", "injected", ".", "After", "the", "injection", ",", "there", "was", "a", "reduction", "in", "radicular", "symptoms", ".", "Three", "hours", "later", ",", "she", "complained", "of", "perineal", "numbness", "and", "lower", "extremity", "weakness", ".", "The", "neurologic", "evaluation", "revealed", "loss", "of", "sensation", "in", "the", "saddle", "area", "and", "medial", "aspect", "of", "her", "right", "leg", ".", "There", "was", "a", "decrease", "in", "the", "perception", "of", "pinprick", "test", ".", "Deep-tendon", "reflexes", "were", "decreased", "especially", "in", "the", "right", "leg", ".", "She", "was", "unable", "to", "urinate", ".", "The", "patient", "'s", "symptoms", "improved", "slightly", "over", "the", "next", "few", "hours", ".", "She", "had", "a", "gradual", "return", "of", "motor", "function", "and", "ability", "of", "feeling", "Foley", "catheter", ".", "All", "of", "the", "symptoms", "were", "completely", "resolved", "over", "the", "next", "8", "hours", ".", "CONCLUSION", ":", "Complications", "associated", "with", "epidural", "steroid", "injections", "are", "rare", ".", "Clinical", "examination", "and", "continued", "vigilance", "for", "neurologic", "deterioration", "after", "epidural", "steroid", "injections", "is", "important", "." ]	[ "2", "2", "2", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "2", "2", "2", "2", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "3", "0", "0", "0", "0" ]
17083016	Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease. BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.	[ "Genetic", "polymorphism", "of", "the", "binding", "domain", "of", "surfactant", "protein-A2", "increases", "susceptibility", "to", "meningococcal", "disease", ".", "BACKGROUND", ":", "Meningococcal", "disease", "occurs", "after", "colonization", "of", "the", "nasopharynx", "with", "Neisseria", "meningitidis", ".", "Surfactant", "protein", "(", "SP", ")", "-A", "and", "SP-D", "are", "pattern-recognition", "molecules", "of", "the", "respiratory", "tract", "that", "activate", "inflammatory", "and", "phagocytic", "defences", "after", "binding", "to", "microbial", "sugars", ".", "Variation", "in", "the", "genes", "of", "the", "surfactant", "proteins", "affects", "the", "expression", "and", "function", "of", "these", "molecules", ".", "METHODS", ":", "Allele", "frequencies", "of", "SP-A1", ",", "SP-A2", ",", "and", "SP-D", "were", "determined", "by", "polymerase", "chain", "reaction", "in", "303", "patients", "with", "microbiologically", "proven", "meningococcal", "disease", ",", "including", "18", "patients", "who", "died", ",", "and", "222", "healthy", "control", "subjects", ".", "RESULTS", ":", "Homozygosity", "of", "allele", "1A1", "of", "SP-A2", "increased", "the", "risk", "of", "meningococcal", "disease", "(", "odds", "ratio", "[", "OR", "]", ",", "7.4", ";", "95", "%", "confidence", "interval", "[", "CI", "]", ",", "1.3-42.4", ")", ";", "carriage", "of", "1A5", "reduced", "the", "risk", "(", "OR", ",", "0.3", ";", "95", "%", "CI", ",", "0.1-0.97", ")", ".", "An", "analysis", "of", "the", "multiple", "single-nucleotide", "polymorphisms", "in", "SP-A", "demonstrated", "that", "homozygosity", "for", "alleles", "encoding", "lysine", "(", "in", "1A1", ")", "rather", "than", "glutamine", "(", "in", "1A5", ")", "at", "amino", "acid", "223", "in", "the", "carbohydrate", "recognition", "domain", "was", "associated", "with", "an", "increased", "risk", "of", "meningococcal", "disease", "(", "OR", ",", "6.7", ";", "95", "%", "CI", ",", "1.4-31.5", ")", ".", "Carriage", "of", "alleles", "encoding", "lysine", "at", "residue", "223", "was", "found", "in", "61", "%", "of", "patients", "who", "died", ",", "compared", "with", "35", "%", "of", "those", "who", "survived", "(", "OR", "adjusted", "for", "age", ",", "2.9", ";", "95", "%", "CI", ",", "1.1-7.7", ")", ".", "Genetic", "variation", "of", "SP-A1", "and", "SP-D", "was", "not", "associated", "with", "meningococcal", "disease", ".", "CONCLUSIONS", ":", "Gene", "polymorphism", "resulting", "in", "the", "substitution", "of", "glutamine", "with", "lysine", "at", "residue", "223", "in", "the", "carbohydrate", "recognition", "domain", "of", "SP-A2", "increases", "susceptibility", "to", "meningococcal", "disease", ",", "as", "well", "as", "the", "risk", "of", "death", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "0", "0", "2", "2", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "1", "1", "1", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "2", "2", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "0", "0", "3", "0", "0", "0", "1", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "2", "0" ]
17910065	A novel missense mutation in the paired domain of human PAX9 causes oligodontia. PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype.	[ "A", "novel", "missense", "mutation", "in", "the", "paired", "domain", "of", "human", "PAX9", "causes", "oligodontia", ".", "PAX9", "and", "MSX1", "are", "transcription", "factors", "that", "play", "essential", "roles", "in", "craniofacial", "and", "limb", "development", ".", "In", "humans", ",", "mutations", "in", "both", "genes", "are", "associated", "with", "nonsyndromic", "and", "syndromic", "oligodontia", ",", "respectively", ".", "We", "screened", "one", "family", "with", "nonsyndromic", "oligodontia", "for", "mutations", "in", "PAX9", "and", "MSX1", ".", "Single", "stranded", "conformational", "polymorphism", "(", "SSCP", ")", "analysis", "and", "sequencing", "revealed", "a", "novel", "heterozygous", "C139T", "transition", "in", "PAX9", "in", "the", "affected", "members", "of", "the", "family", ".", "There", "were", "no", "mutations", "detected", "in", "the", "entire", "coding", "sequence", "of", "MSX1", ".", "The", "C139T", "mutation", ",", "predicted", "to", "result", "in", "the", "substitution", "of", "an", "arginine", "by", "a", "tryptophan", "(", "R47W", ")", "in", "the", "N-terminal", "subdomain", ",", "affected", "conserved", "residues", "in", "the", "PAX9", "paired", "domain", ".", "To", "elucidate", "the", "pathogenic", "mechanism", "producing", "oligodontia", "phenotype", "caused", "by", "this", "mutation", ",", "we", "analyzed", "the", "binding", "of", "wild-type", "and", "mutant", "PAX9", "paired", "domain", "protein", "to", "double-stranded", "DNA", "targets", ".", "The", "R47W", "mutation", "dramatically", "reduced", "DNA", "binding", "suggesting", "that", "the", "mutant", "protein", "with", "consequent", "haploinsufficiency", "results", "in", "a", "clinical", "phenotype", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "1", "0", "2", "0", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
20846357	A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome. BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. AIM: To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. RESULTS: The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). CONCLUSIONS: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.	[ "A", "novel", "mutation", "in", "the", "connexin", "26", "gene", "(", "GJB2", ")", "in", "a", "child", "with", "clinical", "and", "histological", "features", "of", "keratitis-ichthyosis-deafness", "(", "KID", ")", "syndrome", ".", "BACKGROUND", ":", "Keratitis-ichthyosis-deafness", "(", "KID", ")", "syndrome", "is", "a", "rare", "congenital", "ectodermal", "disorder", ",", "caused", "by", "heterozygous", "missense", "mutation", "in", "GJB2", ",", "encoding", "the", "gap", "junction", "protein", "connexin", "26", ".", "The", "commonest", "mutation", "is", "the", "p.Asp50Asn", "mutation", ",", "and", "only", "a", "few", "other", "mutations", "have", "been", "described", "to", "date", ".", "AIM", ":", "To", "report", "the", "fatal", "clinical", "course", "and", "characterize", "the", "genetic", "background", "of", "a", "premature", "male", "neonate", "with", "the", "clinical", "and", "histological", "features", "of", "KID", "syndrome", ".", "METHODS", ":", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "and", "used", "for", "PCR", "amplification", "of", "the", "GJB2", "gene", ".", "Direct", "sequencing", "was", "used", "for", "mutation", "analysis", ".", "RESULTS", ":", "The", "clinical", "features", "included", "hearing", "impairment", ",", "ichthyosiform", "erythroderma", "with", "hyperkeratotic", "plaques", ",", "palmoplantar", "keratoderma", ",", "alopecia", "of", "the", "scalp", "and", "eyelashes", ",", "and", "a", "thick", "vernix", "caseosa-like", "covering", "of", "the", "scalp", ".", "On", "histological", "analysis", ",", "features", "characteristic", "of", "KID", "syndrome", ",", "such", "as", "acanthosis", "and", "papillomatosis", "of", "the", "epidermis", "with", "basket-weave", "hyperkeratosis", ",", "were", "seen", ".", "The", "skin", "symptoms", "were", "treated", "successfully", "with", "acitretin", "0.5", "mg/kg", ".", "The", "boy", "developed", "intraventricular", "and", "intracerebral", "haemorrhage", ",", "leading", "to", "hydrocephalus", ".", "His", "condition", "was", "further", "complicated", "by", "septicaemia", "and", "meningitis", "caused", "by", "infection", "with", "extended-spectrum", "beta-lactamase-producing", "Klebsiella", "pneumoniae", ".", "Severe", "respiratory", "failure", "followed", ",", "and", "the", "child", "died", "at", "46", "weeks", "of", "gestational", "age", "(", "13", "weeks", "postnatally", ")", ".", "Sequencing", "of", "the", "GJB2", "gene", "showed", "that", "the", "child", "was", "heterozygous", "for", "a", "novel", "nucleotide", "change", ",", "c.263C", ">", "T", ",", "in", "exon", "2", ",", "leading", "to", "a", "substitution", "of", "alanine", "for", "valine", "at", "position", "88", "(", "p.Ala88Val", ")", ".", "CONCLUSIONS", ":", "This", "study", "has", "identified", "a", "new", "heterozygous", "de", "novo", "mutation", "in", "the", "Cx26", "gene", "(", "c.263C", ">", "T", ";", "p.Ala88Val", ")", "leading", "to", "KID", "syndrome", "." ]	[ "0", "0", "0", "0", "0", "1", "1", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "0", "0", "0", "0", "2", "2", "0", "2", "2", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "2", "0", "0", "0", "2", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "5", "5", "5", "0", "5", "0", "0", "0", "2", "2", "0" ]
26115410	Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps. BACKGROUND: Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer. OBJECTIVES: This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure. DISCUSSION: Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects. CONCLUSIONS: Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes.	[ "Mechanisms", "Underlying", "Latent", "Disease", "Risk", "Associated", "with", "Early-Life", "Arsenic", "Exposure", ":", "Current", "Research", "Trends", "and", "Scientific", "Gaps", ".", "BACKGROUND", ":", "Millions", "of", "individuals", "worldwide", ",", "particularly", "those", "living", "in", "rural", "and", "developing", "areas", ",", "are", "exposed", "to", "harmful", "levels", "of", "inorganic", "arsenic", "(", "iAs", ")", "in", "their", "drinking", "water", ".", "Inorganic", "As", "exposure", "during", "key", "developmental", "periods", "is", "associated", "with", "a", "variety", "of", "adverse", "health", "effects", "including", "those", "that", "are", "evident", "in", "adulthood", ".", "There", "is", "considerable", "interest", "in", "identifying", "the", "molecular", "mechanisms", "that", "relate", "early-life", "iAs", "exposure", "to", "the", "development", "of", "these", "latent", "diseases", ",", "particularly", "in", "relationship", "to", "cancer", ".", "OBJECTIVES", ":", "This", "work", "summarizes", "research", "on", "the", "molecular", "mechanisms", "that", "underlie", "the", "increased", "risk", "of", "cancer", "development", "in", "adulthood", "that", "is", "associated", "with", "early-life", "iAs", "exposure", ".", "DISCUSSION", ":", "Epigenetic", "reprogramming", "that", "imparts", "functional", "changes", "in", "gene", "expression", ",", "the", "development", "of", "cancer", "stem", "cells", ",", "and", "immunomodulation", "are", "plausible", "underlying", "mechanisms", "by", "which", "early-life", "iAs", "exposure", "elicits", "latent", "carcinogenic", "effects", ".", "CONCLUSIONS", ":", "Evidence", "is", "mounting", "that", "relates", "early-life", "iAs", "exposure", "and", "cancer", "development", "later", "in", "life", ".", "Future", "research", "should", "include", "animal", "studies", "that", "address", "mechanistic", "hypotheses", "and", "studies", "of", "human", "populations", "that", "integrate", "early-life", "exposure", ",", "molecular", "alterations", ",", "and", "latent", "disease", "outcomes", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "3", "0", "3", "0", "0", "0", "0", "0", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
15807692	Identification of novel type VII collagen gene mutations resulting in severe recessive dystrophic epidermolysis bullosa. In this work, we studied the proband in a small nuclear family of Chinese and Dutch/German descent and identified two novel mutations in the type VII collagen gene leading to recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens variant (HS-RDEB). The maternal mutation is a single base pair deletion of a cytosine nucleotide in exon 26, designated 3472delC, resulting in a frameshift and a premature termination codon (PTC) within the same exon, 7 bp downstream of the site of the mutation. The paternal mutation is a G-->A transition located at the 5' donor splice site within intron 51, designated IVS51 + 1G-->A. This mutation leads to the activation of a cryptic splice site, 32 bp downstream of the mutation site and to subsequent aberrant out-of-frame splicing, resulting in two alternative mRNA transcripts and a downstream PTC. To our knowledge, these two mutations have not been previously reported. These findings extend the body of evidence for compound heterozygous mutations leading to HS-RDEB and provide the basis for prenatal diagnosis in this family.	[ "Identification", "of", "novel", "type", "VII", "collagen", "gene", "mutations", "resulting", "in", "severe", "recessive", "dystrophic", "epidermolysis", "bullosa", ".", "In", "this", "work", ",", "we", "studied", "the", "proband", "in", "a", "small", "nuclear", "family", "of", "Chinese", "and", "Dutch/German", "descent", "and", "identified", "two", "novel", "mutations", "in", "the", "type", "VII", "collagen", "gene", "leading", "to", "recessive", "dystrophic", "epidermolysis", "bullosa", ",", "Hallopeau-Siemens", "variant", "(", "HS-RDEB", ")", ".", "The", "maternal", "mutation", "is", "a", "single", "base", "pair", "deletion", "of", "a", "cytosine", "nucleotide", "in", "exon", "26", ",", "designated", "3472delC", ",", "resulting", "in", "a", "frameshift", "and", "a", "premature", "termination", "codon", "(", "PTC", ")", "within", "the", "same", "exon", ",", "7", "bp", "downstream", "of", "the", "site", "of", "the", "mutation", ".", "The", "paternal", "mutation", "is", "a", "G", "--", ">", "A", "transition", "located", "at", "the", "5", "'", "donor", "splice", "site", "within", "intron", "51", ",", "designated", "IVS51", "+", "1G", "--", ">", "A", ".", "This", "mutation", "leads", "to", "the", "activation", "of", "a", "cryptic", "splice", "site", ",", "32", "bp", "downstream", "of", "the", "mutation", "site", "and", "to", "subsequent", "aberrant", "out-of-frame", "splicing", ",", "resulting", "in", "two", "alternative", "mRNA", "transcripts", "and", "a", "downstream", "PTC", ".", "To", "our", "knowledge", ",", "these", "two", "mutations", "have", "not", "been", "previously", "reported", ".", "These", "findings", "extend", "the", "body", "of", "evidence", "for", "compound", "heterozygous", "mutations", "leading", "to", "HS-RDEB", "and", "provide", "the", "basis", "for", "prenatal", "diagnosis", "in", "this", "family", "." ]	[ "0", "0", "0", "0", "1", "1", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "0", "0", "2", "2", "2", "2", "0", "2", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
16157158	A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study. Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.	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17192049	Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer. CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer.	[ "Cytochrome", "p4501A1", "gene", "variants", "as", "susceptibility", "marker", "for", "prostate", "cancer", ".", "CYP1A1", "activates", "environmental", "procarcinogens", "and", "catalyzes", "oxidative", "metabolism", "of", "estrogens", "and", "is", "likely", "to", "play", "an", "important", "role", "in", "the", "etiology", "of", "prostate", "cancer", ".", "To", "evaluate", "this", "phenomenon", ",", "the", "association", "between", "two", "single", "nucleotide", "polymorphisms", "(", "A", "to", "G", "transition", "in", "exon7", "leading", "to", "amino", "acid", "substitution", "Ile462Val", "and", "T3801C", "at", "3'UTR", ")", "of", "CYP1A1", "gene", "in", "prostate", "cancer", "were", "analyzed", "in", "a", "case-control", "study", "of", "100", "individuals", "in", "South", "Indian", "population", ".", "The", "estimated", "relative", "risk", "was", "significantly", "high", "for", "individuals", "with", "w1/m1", "genotype", "at", "3'UTR", "of", "CYP1A1", "gene", "(", "OR-4.64", ";", "95", "%", "CI", "=", "1.51-14.86", ";", "P", "<", "0.01", ")", "whereas", "the", "CYP1A1", "Ile/Val", "genotype", "(", "w2/m2", ")", "on", "exon", "7", "was", "found", "to", "be", "associated", "with", "a", "decreased", "risk", "for", "prostate", "cancer", "(", "OR-0.17", ";", "95", "%", "CI", "=", "0.02-0.89", ";", "P=0.03", ")", ".", "A", "Stratified", "analysis", "of", "the", "genotypes", "with", "age", "of", "onset", "and", "tumor", "grade", "showed", "the", "w1/m1", "genotype", "to", "be", "significantly", "associated", "with", "an", "early", "age", "of", "onset", ";", "however", "the", "tumor", "grades", "did", "not", "have", "significant", "association", "with", "the", "variant", "genotypes", ".", "Thus", "the", "present", "study", "indicates", "that", "individuals", "with", "the", "variant", "w1/m1", "genotype", "exhibit", "an", "increased", "risk", "while", "those", "with", "w2/m2", "genotype", "exhibit", "a", "decreased", "risk", "for", "prostate", "cancer", "." ]	[ "1", "1", "0", "0", "0", "0", "0", "0", "2", "2", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "5", "0", "0", "0", "0", "1", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0" ]

10491763

Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion. The transcription factor hepatocyte nuclear factor (HNF)-6 is an upstream regulator of several genes involved in the pathogenesis of maturity-onset diabetes of the young. We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects. We cloned the coding region as well as the intron-exon boundaries of the HNF-6 gene. We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants. An identified missense variant was examined in association studies and genotype-phenotype studies. We identified two silent and one missense (Pro75 Ala) variant. In an association study the allelic frequency of the Pro75Ala polymorphism was 3.2% (95% confidence interval, 1.9-4.5) in 330 patients with Type II diabetes mellitus compared with 4.2% (2.4-6.0) in 238 age-matched glucose tolerant control subjects. Moreover, in studies of 238 middle-aged glucose tolerant subjects, of 226 glucose tolerant offspring of Type II diabetic patients and of 367 young healthy subjects, the carriers of the polymorphism did not differ from non-carriers in glucose induced serum insulin or C-peptide responses. Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined.

[ "Hepatocyte", "nuclear", "factor-6", ":", "associations", "between", "genetic", "variability", "and", "type", "II", "diabetes", "and", "between", "genetic", "variability", "and", "estimates", "of", "insulin", "secretion", ".", "The", "transcription", "factor", "hepatocyte", "nuclear", "factor", "(", "HNF", ")", "-6", "is", "an", "upstream", "regulator", "of", "several", "genes", "involved", "in", "the", "pathogenesis", "of", "maturity-onset", "diabetes", "of", "the", "young", ".", "We", "therefore", "tested", "the", "hypothesis", "that", "variability", "in", "the", "HNF-6", "gene", "is", "associated", "with", "subsets", "of", "Type", "II", "(", "non-insulin-dependent", ")", "diabetes", "mellitus", "and", "estimates", "of", "insulin", "secretion", "in", "glucose", "tolerant", "subjects", ".", "We", "cloned", "the", "coding", "region", "as", "well", "as", "the", "intron-exon", "boundaries", "of", "the", "HNF-6", "gene", ".", "We", "then", "examined", "them", "on", "genomic", "DNA", "in", "six", "MODY", "probands", "without", "mutations", "in", "the", "MODY1", ",", "MODY3", "and", "MODY4", "genes", "and", "in", "54", "patients", "with", "late-onset", "Type", "II", "diabetes", "by", "combined", "single", "strand", "conformational", "polymorphism-heteroduplex", "analysis", "followed", "by", "direct", "sequencing", "of", "identified", "variants", ".", "An", "identified", "missense", "variant", "was", "examined", "in", "association", "studies", "and", "genotype-phenotype", "studies", ".", "We", "identified", "two", "silent", "and", "one", "missense", "(", "Pro75", "Ala", ")", "variant", ".", "In", "an", "association", "study", "the", "allelic", "frequency", "of", "the", "Pro75Ala", "polymorphism", "was", "3.2", "%", "(", "95", "%", "confidence", "interval", ",", "1.9-4.5", ")", "in", "330", "patients", "with", "Type", "II", "diabetes", "mellitus", "compared", "with", "4.2", "%", "(", "2.4-6.0", ")", "in", "238", "age-matched", "glucose", "tolerant", "control", "subjects", ".", "Moreover", ",", "in", "studies", "of", "238", "middle-aged", "glucose", "tolerant", "subjects", ",", "of", "226", "glucose", "tolerant", "offspring", "of", "Type", "II", "diabetic", "patients", "and", "of", "367", "young", "healthy", "subjects", ",", "the", "carriers", "of", "the", "polymorphism", "did", "not", "differ", "from", "non-carriers", "in", "glucose", "induced", "serum", "insulin", "or", "C-peptide", "responses", ".", "Mutations", "in", "the", "coding", "region", "of", "the", "HNF-6", "gene", "are", "not", "associated", "with", "Type", "II", "diabetes", "or", "with", "changes", "in", "insulin", "responses", "to", "glucose", "among", "the", "Caucasians", "examined", "." ]

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10788334

Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age < 50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities - 5382insC, C61G, and 4153delA - accounted for 51%, 20%, and 11% of the identified mutations, respectively..

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11054569

Rab6c, a new member of the rab gene family, is involved in drug resistance in MCF7/AdrR cells. A new Rab6 homolog cDNA, Rab6c, was discovered by a hypermethylated DNA fragment probe that was isolated from a human multidrug resistant (MDR) breast cancer cell line, MCF7/AdrR, by the methylation sensitive-representational difference analysis (MS-RDA) technique. Rab6c was found to be under-expressed in MCF7/AdrR and MES-SA/Dx5 (a human MDR uterine sarcoma cell line) compared with their non-MDR parental cell lines. MCF7/AdrR cells expressing the exogenous Rab6c exhibited less resistance to several anti-cancer drugs, such as doxorubicin (DOX), taxol, vinblastine, and vincristine, than the control cells containing the empty vector. Flow cytometry experiments confirmed that the transfectants' diminished resistance to DOX was caused by increased drug accumulation induced by the exogenous Rab6c. These results indicate that Rab6c is involved in drug resistance in MCF7/AdrR cells.

[ "Rab6c", ",", "a", "new", "member", "of", "the", "rab", "gene", "family", ",", "is", "involved", "in", "drug", "resistance", "in", "MCF7/AdrR", "cells", ".", "A", "new", "Rab6", "homolog", "cDNA", ",", "Rab6c", ",", "was", "discovered", "by", "a", "hypermethylated", "DNA", "fragment", "probe", "that", "was", "isolated", "from", "a", "human", "multidrug", "resistant", "(", "MDR", ")", "breast", "cancer", "cell", "line", ",", "MCF7/AdrR", ",", "by", "the", "methylation", "sensitive-representational", "difference", "analysis", "(", "MS-RDA", ")", "technique", ".", "Rab6c", "was", "found", "to", "be", "under-expressed", "in", "MCF7/AdrR", "and", "MES-SA/Dx5", "(", "a", "human", "MDR", "uterine", "sarcoma", "cell", "line", ")", "compared", "with", "their", "non-MDR", "parental", "cell", "lines", ".", "MCF7/AdrR", "cells", "expressing", "the", "exogenous", "Rab6c", "exhibited", "less", "resistance", "to", "several", "anti-cancer", "drugs", ",", "such", "as", "doxorubicin", "(", "DOX", ")", ",", "taxol", ",", "vinblastine", ",", "and", "vincristine", ",", "than", "the", "control", "cells", "containing", "the", "empty", "vector", ".", "Flow", "cytometry", "experiments", "confirmed", "that", "the", "transfectants", "'", "diminished", "resistance", "to", "DOX", "was", "caused", "by", "increased", "drug", "accumulation", "induced", "by", "the", "exogenous", "Rab6c", ".", "These", "results", "indicate", "that", "Rab6c", "is", "involved", "in", "drug", "resistance", "in", "MCF7/AdrR", "cells", "." ]

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1353340

Late-onset metachromatic leukodystrophy: molecular pathology in two siblings. We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD..

[ "Late-onset", "metachromatic", "leukodystrophy", ":", "molecular", "pathology", "in", "two", "siblings", ".", "We", "report", "on", "a", "new", "allele", "at", "the", "arylsulfatase", "A", "(", "ARSA", ")", "locus", "causing", "late-onset", "metachromatic", "leukodystrophy", "(", "MLD", ")", ".", "In", "that", "allele", "arginine84", ",", "a", "residue", "that", "is", "highly", "conserved", "in", "the", "arylsulfatase", "gene", "family", ",", "is", "replaced", "by", "glutamine", ".", "In", "contrast", "to", "alleles", "that", "cause", "early-onset", "MLD", ",", "the", "arginine84", "to", "glutamine", "substitution", "is", "associated", "with", "some", "residual", "ARSA", "activity", ".", "A", "comparison", "of", "genotypes", ",", "ARSA", "activities", ",", "and", "clinical", "data", "on", "4", "individuals", "carrying", "the", "allele", "of", "81", "patients", "with", "MLD", "examined", ",", "further", "validates", "the", "concept", "that", "different", "degrees", "of", "residual", "ARSA", "activity", "are", "the", "basis", "of", "phenotypical", "variation", "in", "MLD", ".." ]

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15099351

Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is at a locus for autosomal dominant hypercholesterolemia, and recent data indicate that the PCSK9 gene is involved in cholesterol biosynthesis. Mutations within this gene have previously been found to segregate with hypercholesterolemia. In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded. Two novel missense mutations were detected in the catalytic subdomain of the PCSK9 gene. Two patients were heterozygotes for D374Y, and one patient was a double heterozygote for D374Y and N157K. D374Y segregated with hypercholesterolemia in the two former families where family members were available for study. Our findings support the notion that mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia.

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16005363

Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome. Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.

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16200390

A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach. Migraine is a common debilitating primary headache disorder with significant mental, physical and social health implications. The brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is involved in nociceptive pathways and has been implicated in the pathophysiology of migraine. With few genetic studies investigating biosynthetic and metabolic enzymes governing the rate of 5-HT activity and their relationship to migraine, it was the objective of this study to assess genetic variants within the human tryptophan hydroxylase (TPH), amino acid decarboxylase (AADC) and monoamine oxidase A (MAOA) genes in migraine susceptibility. This objective was undertaken using a high-throughput DNA pooling experimental design, which proved to be a very accurate, sensitive and specific method of estimating allele frequencies for single nucleotide polymorphism, insertion deletion and variable number tandem repeat loci. Application of DNA pooling to a wide array of genetic loci provides greater scope in the assessment of population-based genetic association study designs. Despite the application of this high-throughput genotyping method, negative results from the two-stage DNA pooling design used to screen loci within the TPH, AADC and MAOA genes did not support their role in migraine susceptibility.

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16596970

Pilocarpine seizures cause age-dependent impairment in auditory location discrimination. Children who have status epilepticus have continuous or rapidly repeating seizures that may be life-threatening and may cause life-long changes in brain and behavior. The extent to which status epilepticus causes deficits in auditory discrimination is unknown. A naturalistic auditory location discrimination method was used to evaluate this question using an animal model of status epilepticus. Male Sprague-Dawley rats were injected with saline on postnatal day (P) 20, or a convulsant dose of pilocarpine on P20 or P45. Pilocarpine on either day induced status epilepticus; status epilepticus at P45 resulted in CA3 cell loss and spontaneous seizures, whereas P20 rats had no cell loss or spontaneous seizures. Mature rats were trained with sound-source location and sound-silence discriminations. Control (saline P20) rats acquired both discriminations immediately. In status epilepticus (P20) rats, acquisition of the sound-source location discrimination was moderately impaired. Status epilepticus (P45) rats failed to acquire either sound-source location or sound-silence discriminations. Status epilepticus in rat causes an age-dependent, long-term impairment in auditory discrimination. This impairment may explain one cause of impaired auditory location discrimination in humans.

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17683901

An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia. Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7500. In more than 98% of cases, the disease is associated with a G to A or G to C substitution at nucleotide position 1138 (p.G380R) of the fibroblast growth factor receptor 3 (FGFR3) gene. We have developed a sensitive single tube tetra-primer PCR assay to detect both the c.1138G>A and c.1138G>C mutations and can successfully distinguish DNA samples that are homozygous and heterozygous for the c.1138G>A mutation. Titration studies showed that the assay could reliably detect one copy of the mutant allele in a mix of 100 wild-type alleles. The assay has been tested in 50 healthy controls, 3 known patients with achondroplasia, and 5 amniotic fluids suspected of having achondroplasia and for whom we had previously determined the genotypes for the c.1138G>A mutation by PCR-RFLP. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for FGFR3 p.G380R genotyping, which could be used even in "low-tech" laboratories.

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18166824

Genetic investigation of four meiotic genes in women with premature ovarian failure. OBJECTIVE: The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF). DESIGN: Case-control study. METHODS: Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls). RESULTS: A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V). CONCLUSIONS: The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of the MSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon.

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18408250

A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects. METHODS: We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion-deletion polymorphism in the IRF5 gene. We performed 2 sets of case-control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays. RESULTS: A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated. CONCLUSIONS: These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.

[ "A", "single", "nucleotide", "polymorphism", "in", "the", "IRF5", "promoter", "region", "is", "associated", "with", "susceptibility", "to", "rheumatoid", "arthritis", "in", "the", "Japanese", "population", ".", "OBJECTIVES", ":", "Interferon", "regulatory", "factor", "5", "(", "IRF5", ")", "is", "a", "member", "of", "the", "IRF", "family", "of", "transcription", "factors", ",", "which", "regulate", "the", "production", "of", "proinflammatory", "cytokines", ".", "Polymorphisms", "in", "the", "IRF5", "gene", "have", "been", "associated", "with", "susceptibility", "to", "systemic", "lupus", "erythaematosus", "(", "SLE", ")", "in", "Caucasian", "and", "Asian", "populations", ",", "but", "their", "involvement", "in", "other", "autoimmune", "diseases", "is", "still", "uncertain", ".", "Here", ",", "we", "assessed", "the", "genetic", "role", "of", "IRF5", "in", "susceptibility", "to", "rheumatoid", "arthritis", "(", "RA", ")", "in", "Japanese", "subjects", ".", "METHODS", ":", "We", "selected", "13", "single", "nucleotide", "polymorphisms", "(", "SNPs", ")", "and", "a", "CGGGG", "insertion-deletion", "polymorphism", "in", "the", "IRF5", "gene", ".", "We", "performed", "2", "sets", "of", "case-control", "comparisons", "using", "Japanese", "subjects", "(", "first", "set", ":", "830", "patients", "with", "RA", "and", "658", "controls", ";", "second", "set", ":", "1112", "patients", "with", "RA", "and", "940", "controls", ")", ",", "and", "then", "performed", "a", "stratified", "analysis", "using", "human", "leukocyte", "antigen", "(", "HLA", ")", "-DRB1", "shared", "epitope", "(", "SE", ")", "status", ".", "We", "genotyped", "the", "SNPs", "using", "TaqMan", "assays", ".", "RESULTS", ":", "A", "significant", "association", "of", "the", "rs729302", "A", "allele", "with", "RA", "susceptibility", "was", "found", "in", "both", "sets", "(", "odds", "ratio", "(", "OR", ")", "1.22", ",", "95", "%", "CI", "1.09", "to", "1.35", ",", "p", "<", "0.001", "in", "the", "combined", "analysis", ")", ".", "When", "the", "patients", "were", "stratified", "by", "the", "SE", ",", "the", "rs729302", "A", "allele", "was", "found", "to", "confer", "increased", "risk", "to", "RA", "in", "patients", "that", "were", "SE", "negative", "(", "OR", "1.50", ",", "95", "%", "CI", "1.17", "to", "1.92", ",", "p", "=", "0.001", ")", "as", "compared", "with", "patients", "carrying", "the", "SE", "(", "OR", "1.11", ",", "95", "%", "CI", "0.93", "to", "1.33", ",", "p", "=", "0.24", ")", ".", "In", "both", "sets", ",", "no", "genotyped", "polymorphisms", "were", "significantly", "associated", "with", "RA", "susceptibility", ",", "but", "rs729302", "was", "significantly", "associated", ".", "CONCLUSIONS", ":", "These", "findings", "indicate", "that", "the", "promoter", "polymorphism", "of", "IRF5", "is", "a", "genetic", "factor", "conferring", "predisposition", "to", "RA", ",", "and", "that", "it", "contributes", "considerably", "to", "disease", "pathogenesis", "in", "patients", "that", "were", "SE", "negative", "." ]

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18439317

Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese. BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD. METHODS: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test. RESULTS: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele. CONCLUSION: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.

[ "Association", "between", "promoter", "-1607", "polymorphism", "of", "MMP1", "and", "lumbar", "disc", "disease", "in", "Southern", "Chinese", ".", "BACKGROUND", ":", "Matrix", "metalloproteinases", "(", "MMPs", ")", "are", "involved", "in", "the", "degradation", "of", "the", "extracellular", "matrix", "of", "the", "intervertebral", "disc", ".", "A", "SNP", "for", "guanine", "insertion/deletion", "(", "G/D", ")", ",", "the", "-1607", "promoter", "polymorphism", ",", "of", "the", "MMP1", "gene", "was", "found", "significantly", "affecting", "promoter", "activity", "and", "corresponding", "transcription", "level", ".", "Hence", "it", "is", "a", "good", "candidate", "for", "genetic", "studies", "in", "DDD", ".", "METHODS", ":", "Southern", "Chinese", "volunteers", "between", "18", "and", "55", "years", "were", "recruited", "from", "the", "population", ".", "DDD", "in", "the", "lumbar", "spine", "was", "defined", "by", "MRI", "using", "Schneiderman", "'s", "classification", ".", "Genomic", "DNA", "was", "isolated", "from", "the", "leukocytes", "and", "genotyping", "was", "performed", "using", "the", "Sequenom", "platform", ".", "Association", "and", "Hardy-Weinberg", "equilibrium", "checking", "were", "assessed", "by", "Chi-square", "test", "and", "Mann-Whitney", "U", "test", ".", "RESULTS", ":", "Our", "results", "showed", "substantial", "evidence", "of", "association", "between", "-1607", "promoter", "polymorphism", "of", "MMP1", "and", "DDD", "in", "the", "Southern", "Chinese", "subjects", ".", "D", "allelic", "was", "significantly", "associated", "with", "DDD", "(", "p", "value", "=", "0.027", ",", "odds", "ratio", "=", "1.41", "with", "95", "%", "CI", "=", "1.04-1.90", ")", "while", "Genotypic", "association", "on", "the", "presence", "of", "D", "allele", "was", "also", "significantly", "associated", "with", "DDD", "(", "p", "value", "=", "0.046", ",", "odds", "ratio", "=", "1.50", "with", "95", "%", "CI", "=", "1.01-2.24", ")", ".", "Further", "age", "stratification", "showed", "significant", "genotypic", "as", "well", "as", "allelic", "association", "in", "the", "group", "of", "over", "40", "years", "(", "genotypic", ":", "p", "value", "=", "0.035", ",", "odds", "ratio", "=", "1.617", "with", "95", "%", "CI", "=", "1.033-2.529", ";", "allelic", ":", "p", "value", "=", "0.033", ",", "odds", "ratio", "=", "1.445", "with", "95", "%", "CI", "=", "1.029-2.029", ")", ".", "Disc", "bulge", ",", "annular", "tears", "and", "the", "Schmorl", "'s", "nodes", "were", "not", "associated", "with", "the", "D", "allele", ".", "CONCLUSION", ":", "We", "demonstrated", "that", "individuals", "with", "the", "presence", "of", "D", "allele", "for", "the", "-1607", "promoter", "polymorphism", "of", "MMP1", "are", "about", "1.5", "times", "more", "susceptible", "to", "develop", "DDD", "when", "compared", "with", "those", "having", "G", "allele", "only", ".", "Further", "association", "was", "identified", "in", "individuals", "over", "40", "years", "of", "age", ".", "Disc", "bulge", ",", "annular", "tear", "as", "well", "as", "Schmorl", "'s", "nodes", "were", "not", "associated", "with", "this", "polymorphism", "." ]

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18681856

Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene. OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease.

[ "Expanding", "clinical", "spectrum", "of", "non-autoimmune", "hyperthyroidism", "due", "to", "an", "activating", "germline", "mutation", ",", "p.M453T", ",", "in", "the", "thyrotropin", "receptor", "gene", ".", "OBJECTIVE", ":", "To", "describe", "clinical", "and", "genetic", "features", "of", "a", "Thai", "family", "with", "non-autoimmune", "hyperthyroidism", "(", "NAH", ")", "caused", "by", "an", "activating", "germline", "mutation", "in", "the", "thyrotropin", "receptor", "(", "TSHR", ")", "gene", ".", "PATIENTS", ":", "Three", "affected", "individuals", "from", "the", "same", "family", "(", "a", "father", "and", "his", "two", "children", ")", "were", "studied", ".", "Clinical", "and", "imaging", "findings", "were", "reviewed", "and", "compared", ".", "GENETIC", "ANALYSIS", ":", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "leukocytes", "and", "mutation", "analysis", "of", "the", "entire", "coding", "sequence", "of", "the", "TSHR", "gene", "was", "performed", "in", "both", "children", "and", "their", "parents", "by", "direct", "DNA", "sequencing", ".", "RESULTS", ":", "A", "heterozygous", "germline", "T", "to", "C", "transition", "in", "exon", "10", "of", "the", "TSHR", "gene", "(", "c.1358T", "--", ">", "C", ")", "resulting", "in", "the", "substitution", "of", "methionine", "(", "ATG", ")", "by", "threonine", "(", "ACG", ")", "at", "codon", "453", "(", "p.M453T", ")", "was", "identified", "in", "the", "father", "and", "his", "two", "children", ".", "They", "presented", "with", "different", "clinical", "severity", "and", "variable", "age", "of", "onset", ".", "In", "addition", "to", "hyperthyroidism", ",", "ventriculomegaly", "and", "bilateral", "shortening", "of", "the", "fifth", "metacarpal", "bones", "and", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "were", "consistently", "found", "in", "all", "affected", "individuals", ".", "CONCLUSIONS", ":", "Ventriculomegaly", "and", "bilateral", "shortening", "of", "the", "fifth", "metacarpal", "bones", "and", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "might", "be", "characteristic", "features", "of", "NAH", "because", "of", "an", "activating", "TSHR", "germline", "mutation", ".", "In", "addition", ",", "the", "shortening", "of", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "has", "never", "been", "previously", "described", ",", "expanding", "the", "phenotypic", "spectrum", "of", "the", "disease", "." ]

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19728177

Prolonged hypothermia as a bridge to recovery for cerebral edema and intracranial hypertension associated with fulminant hepatic failure. BACKGROUND: To review evidence-based treatment options in patients with cerebral edema complicating fulminant hepatic failure (FHF) and discuss the potential applications of hypothermia. METHOD: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with FHF from acetaminophen and resultant cerebral edema. RESULTS: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from acetaminophen which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed FHF from acetaminophen and cerebral edema. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her cerebral edema and intracranial hypertension. At discharge, she had complete recovery of neurological and hepatic functions. CONCLUSION: In patients with FHF and cerebral edema from acetaminophen overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted.

[ "Prolonged", "hypothermia", "as", "a", "bridge", "to", "recovery", "for", "cerebral", "edema", "and", "intracranial", "hypertension", "associated", "with", "fulminant", "hepatic", "failure", ".", "BACKGROUND", ":", "To", "review", "evidence-based", "treatment", "options", "in", "patients", "with", "cerebral", "edema", "complicating", "fulminant", "hepatic", "failure", "(", "FHF", ")", "and", "discuss", "the", "potential", "applications", "of", "hypothermia", ".", "METHOD", ":", "Case-based", "observations", "from", "a", "medical", "intensive", "care", "unit", "(", "MICU", ")", "in", "a", "tertiary", "care", "facility", "in", "a", "27-year-old", "female", "with", "FHF", "from", "acetaminophen", "and", "resultant", "cerebral", "edema", ".", "RESULTS", ":", "Our", "patient", "was", "admitted", "to", "the", "MICU", "after", "being", "found", "unresponsive", "with", "presumed", "toxicity", "from", "acetaminophen", "which", "was", "ingested", "over", "a", "2-day", "period", ".", "The", "patient", "had", "depressed", "of", "mental", "status", "lasting", "at", "least", "24", "h", "prior", "to", "admission", ".", "Initial", "evaluation", "confirmed", "FHF", "from", "acetaminophen", "and", "cerebral", "edema", ".", "The", "patient", "was", "treated", "with", "hyperosmolar", "therapy", ",", "hyperventilation", ",", "sedation", ",", "and", "chemical", "paralysis", ".", "Her", "intracranial", "pressure", "remained", "elevated", "despite", "maximal", "medical", "therapy", ".", "We", "then", "initiated", "therapeutic", "hypothermia", "which", "was", "continued", "for", "5", "days", ".", "At", "re-warming", ",", "patient", "had", "resolution", "of", "her", "cerebral", "edema", "and", "intracranial", "hypertension", ".", "At", "discharge", ",", "she", "had", "complete", "recovery", "of", "neurological", "and", "hepatic", "functions", ".", "CONCLUSION", ":", "In", "patients", "with", "FHF", "and", "cerebral", "edema", "from", "acetaminophen", "overdose", ",", "prolonged", "therapeutic", "hypothermia", "could", "potentially", "be", "used", "as", "a", "life", "saving", "therapy", "and", "a", "bridge", "to", "hepatic", "and", "neurological", "recovery", ".", "A", "clinical", "trial", "of", "hypothermia", "in", "patients", "with", "this", "condition", "is", "warranted", "." ]

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20606392

Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain. BACKGROUND/AIMS: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity. METHOD: Serum and DNA samples from the proband and his parents were analyzed. RESULTS: The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration. CONCLUSION: Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations.

[ "Atypical", "GH", "insensitivity", "syndrome", "and", "severe", "insulin-like", "growth", "factor-I", "deficiency", "resulting", "from", "compound", "heterozygous", "mutations", "of", "the", "GH", "receptor", ",", "including", "a", "novel", "frameshift", "mutation", "affecting", "the", "intracellular", "domain", ".", "BACKGROUND/AIMS", ":", "GH", "insensitivity", "and", "IGF", "deficiency", "may", "result", "from", "aberrations", "of", "the", "GH", "receptor", "(", "GHR", ")", ".", "We", "describe", "a", "4-year-old", "child", "with", "modest", "growth", "failure", "and", "normal", "serum", "concentrations", "of", "GH-binding", "protein", "(", "GHBP", ")", ",", "but", "clinical", "evidence", "of", "GH", "insensitivity", ".", "METHOD", ":", "Serum", "and", "DNA", "samples", "from", "the", "proband", "and", "his", "parents", "were", "analyzed", ".", "RESULTS", ":", "The", "child", "had", "a", "height", "of", "-4", "SD", ",", "elevated", "serum", "GH", "concentrations", ",", "abnormally", "low", "serum", "IGF-I", "and", "IGFBP-3", "concentrations", "and", "normal", "GHBP", "concentrations", ".", "DNA", "analysis", "revealed", "compound", "heterozygosity", "for", "mutations", "of", "GHR", ",", "including", "a", "previously", "reported", "R211H", "mutation", "and", "a", "novel", "duplication", "of", "a", "nucleotide", "in", "exon", "9", "(", "899dupC", ")", ",", "the", "latter", "resulting", "in", "a", "frameshift", "and", "a", "premature", "stop", "codon", ".", "Treatment", "with", "recombinant", "DNA-derived", "IGF-I", "resulted", "in", "growth", "acceleration", ".", "CONCLUSION", ":", "Mutations", "affecting", "the", "intracellular", "domain", "of", "the", "GHR", "can", "result", "in", "GH", "insensitivity", "and", "IGF", "deficiency", ",", "despite", "normal", "serum", "concentrations", "of", "GHBP", ".", "The", "presence", "of", "clinical", "and", "biochemical", "evidence", "of", "GH", "resistance", "is", "sufficient", "to", "consider", "the", "possibility", "of", "aberrations", "of", "the", "GHR", ",", "even", "in", "the", "presence", "of", "normal", "serum", "GHBP", "concentrations", "." ]

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20806042

A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree. PURPOSE: To identify the underlying genetic defect in a four-generation family of Chinese origin with autosomal dominant congenital cataract-microcornea syndrome (CCMC). METHODS: All individuals in the study underwent a full clinical examination and the details of history were collected . Genomic DNA extracted from peripheral blood was amplified by polymerase chain reaction (PCR) method and the exons of all candidate genes were sequenced. RESULTS: Direct sequencing of the encoding regions of the candidate genes revealed a heterozygous mutation c.592C-->T in exon 2 of the gap junction protein, alpha 8 (GJA8) gene. This mutation was responsible for the familial disorder through the substitution of a highly conserved arginine to tryptophan at codon 198 (p.R198W). This change co-segregated with all affected members of the family, but was not detected either in the non-carrier relatives or in the 100 normal controls. CONCLUSIONS: This report is the first to relate p.R198W mutation in GJA8 with CCMC. The result expands the mutation spectrum of GJA8 in associated with congenital cataract and microcornea, and implies that this gene has direct involvement with the development of the lens as well as the other anterior segment of the eye.

[ "A", "novel", "mutation", "in", "GJA8", "causing", "congenital", "cataract-microcornea", "syndrome", "in", "a", "Chinese", "pedigree", ".", "PURPOSE", ":", "To", "identify", "the", "underlying", "genetic", "defect", "in", "a", "four-generation", "family", "of", "Chinese", "origin", "with", "autosomal", "dominant", "congenital", "cataract-microcornea", "syndrome", "(", "CCMC", ")", ".", "METHODS", ":", "All", "individuals", "in", "the", "study", "underwent", "a", "full", "clinical", "examination", "and", "the", "details", "of", "history", "were", "collected", ".", "Genomic", "DNA", "extracted", "from", "peripheral", "blood", "was", "amplified", "by", "polymerase", "chain", "reaction", "(", "PCR", ")", "method", "and", "the", "exons", "of", "all", "candidate", "genes", "were", "sequenced", ".", "RESULTS", ":", "Direct", "sequencing", "of", "the", "encoding", "regions", "of", "the", "candidate", "genes", "revealed", "a", "heterozygous", "mutation", "c.592C", "--", ">", "T", "in", "exon", "2", "of", "the", "gap", "junction", "protein", ",", "alpha", "8", "(", "GJA8", ")", "gene", ".", "This", "mutation", "was", "responsible", "for", "the", "familial", "disorder", "through", "the", "substitution", "of", "a", "highly", "conserved", "arginine", "to", "tryptophan", "at", "codon", "198", "(", "p.R198W", ")", ".", "This", "change", "co-segregated", "with", "all", "affected", "members", "of", "the", "family", ",", "but", "was", "not", "detected", "either", "in", "the", "non-carrier", "relatives", "or", "in", "the", "100", "normal", "controls", ".", "CONCLUSIONS", ":", "This", "report", "is", "the", "first", "to", "relate", "p.R198W", "mutation", "in", "GJA8", "with", "CCMC", ".", "The", "result", "expands", "the", "mutation", "spectrum", "of", "GJA8", "in", "associated", "with", "congenital", "cataract", "and", "microcornea", ",", "and", "implies", "that", "this", "gene", "has", "direct", "involvement", "with", "the", "development", "of", "the", "lens", "as", "well", "as", "the", "other", "anterior", "segment", "of", "the", "eye", "." ]

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21163864

The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy. INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI. RESULTS: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM. CONCLUSION: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM.

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21682595

XRCC1 Arg399Gln gene polymorphism and the risk of systemic lupus erythematosus in the Polish population. It has been shown that DNA repair is reduced in patients with systemic lupus erythematosus (SLE) and that the X-ray repair cross-complementing (XRCC1) Arg399Gln (rs25487) polymorphism may contribute to DNA repair. We evaluated the frequency of the XRCC1 Arg399Gln substitution in patients with SLE (n=265) and controls (n=360) in a sample of the Polish population. The odds ratio (OR) for SLE patients with the Gln/Gln versus Gln/Arg or Arg/Arg genotypes was 1.553 (95% confidence interval [CI]=0.9573-2.520; p=0.0729). OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.551 (95% CI=1.122-2.144, p=0.0077). The OR for the 399 Gln allele in patients with SLE was 1.406 (95% CI=1.111-1.779, p=0.0045). There was also a statistically significant p-value of the (2) test for the trend observed in the XRCC1 Arg399Gln polymorphism (ptrend=0.0048). We also found a significant contribution of the Gln/Gln or Arg/Gln versus Arg/Arg genotype to the presence of either the malar rash or photosensitivity manifestations of SLE OR=2.241 (1.328-3.781, p=0.0023, pcorr=0.0414). Moreover, the meta-analysis of Taiwanese Han Chinese, Brazilian, and Polish populations showed that the Gln/Gln or Gln/Arg genotype and Gln allele were associated with SLE incidence. OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.440 (95% CI=1.15-1.80, p=0.0019) and OR for the Gln allele was 1.27 (95% CI=1.08-1.51, p=0.0051). Our studies may confirm that the XRCC1 Arg399Gln polymorphism may increase the risk of incidence of SLE and the occurrence of some SLE manifestations.

[ "XRCC1", "Arg399Gln", "gene", "polymorphism", "and", "the", "risk", "of", "systemic", "lupus", "erythematosus", "in", "the", "Polish", "population", ".", "It", "has", "been", "shown", "that", "DNA", "repair", "is", "reduced", "in", "patients", "with", "systemic", "lupus", "erythematosus", "(", "SLE", ")", "and", "that", "the", "X-ray", "repair", "cross-complementing", "(", "XRCC1", ")", "Arg399Gln", "(", "rs25487", ")", "polymorphism", "may", "contribute", "to", "DNA", "repair", ".", "We", "evaluated", "the", "frequency", "of", "the", "XRCC1", "Arg399Gln", "substitution", "in", "patients", "with", "SLE", "(", "n=265", ")", "and", "controls", "(", "n=360", ")", "in", "a", "sample", "of", "the", "Polish", "population", ".", "The", "odds", "ratio", "(", "OR", ")", "for", "SLE", "patients", "with", "the", "Gln/Gln", "versus", "Gln/Arg", "or", "Arg/Arg", "genotypes", "was", "1.553", "(", "95", "%", "confidence", "interval", "[", "CI", "]", "=0.9573-2.520", ";", "p=0.0729", ")", ".", "OR", "for", "the", "Gln/Gln", "or", "Gln/Arg", "versus", "Arg/Arg", "genotype", "was", "1.551", "(", "95", "%", "CI=1.122-2.144", ",", "p=0.0077", ")", ".", "The", "OR", "for", "the", "399", "Gln", "allele", "in", "patients", "with", "SLE", "was", "1.406", "(", "95", "%", "CI=1.111-1.779", ",", "p=0.0045", ")", ".", "There", "was", "also", "a", "statistically", "significant", "p-value", "of", "the", "(", "2", ")", "test", "for", "the", "trend", "observed", "in", "the", "XRCC1", "Arg399Gln", "polymorphism", "(", "ptrend=0.0048", ")", ".", "We", "also", "found", "a", "significant", "contribution", "of", "the", "Gln/Gln", "or", "Arg/Gln", "versus", "Arg/Arg", "genotype", "to", "the", "presence", "of", "either", "the", "malar", "rash", "or", "photosensitivity", "manifestations", "of", "SLE", "OR=2.241", "(", "1.328-3.781", ",", "p=0.0023", ",", "pcorr=0.0414", ")", ".", "Moreover", ",", "the", "meta-analysis", "of", "Taiwanese", "Han", "Chinese", ",", "Brazilian", ",", "and", "Polish", "populations", "showed", "that", "the", "Gln/Gln", "or", "Gln/Arg", "genotype", "and", "Gln", "allele", "were", "associated", "with", "SLE", "incidence", ".", "OR", "for", "the", "Gln/Gln", "or", "Gln/Arg", "versus", "Arg/Arg", "genotype", "was", "1.440", "(", "95", "%", "CI=1.15-1.80", ",", "p=0.0019", ")", "and", "OR", "for", "the", "Gln", "allele", "was", "1.27", "(", "95", "%", "CI=1.08-1.51", ",", "p=0.0051", ")", ".", "Our", "studies", "may", "confirm", "that", "the", "XRCC1", "Arg399Gln", "polymorphism", "may", "increase", "the", "risk", "of", "incidence", "of", "SLE", "and", "the", "occurrence", "of", "some", "SLE", "manifestations", "." ]

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24126708

Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients. Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.

[ "Association", "of", "common", "genetic", "variants", "of", "HOMER1", "gene", "with", "levodopa", "adverse", "effects", "in", "Parkinson", "'s", "disease", "patients", ".", "Levodopa", "is", "the", "most", "effective", "symptomatic", "therapy", "for", "Parkinson", "'s", "disease", ",", "but", "its", "chronic", "use", "could", "lead", "to", "chronic", "adverse", "outcomes", ",", "such", "as", "motor", "fluctuations", ",", "dyskinesia", "and", "visual", "hallucinations", ".", "HOMER1", "is", "a", "protein", "with", "pivotal", "function", "in", "glutamate", "transmission", ",", "which", "has", "been", "related", "to", "the", "pathogenesis", "of", "these", "complications", ".", "This", "study", "investigates", "whether", "polymorphisms", "in", "the", "HOMER1", "gene", "promoter", "region", "are", "associated", "with", "the", "occurrence", "of", "the", "chronic", "complications", "of", "levodopa", "therapy", ".", "A", "total", "of", "205", "patients", "with", "idiopathic", "Parkinson", "'s", "disease", "were", "investigated", ".", "Patients", "were", "genotyped", "for", "rs4704559", ",", "rs10942891", "and", "rs4704560", "by", "allelic", "discrimination", "with", "Taqman", "assays", ".", "The", "rs4704559", "G", "allele", "was", "associated", "with", "a", "lower", "prevalence", "of", "dyskinesia", "(", "prevalence", "ratio", "(", "PR", ")", "=0.615", ",", "95", "%", "confidence", "interval", "(", "CI", ")", "0.426-0.887", ",", "P=0.009", ")", "and", "visual", "hallucinations", "(", "PR=0.515", ",", "95", "%", "CI", "0.295-0.899", ",", "P=0.020", ")", ".", "Our", "data", "suggest", "that", "HOMER1", "rs4704559", "G", "allele", "has", "a", "protective", "role", "for", "the", "development", "of", "levodopa", "adverse", "effects", "." ]

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25983002

Inhibition of LDHA suppresses tumor progression in prostate cancer. A key hallmark of cancer cells is their altered metabolism, known as Warburg effect. Lactate dehydrogenase A (LDHA) executes the final step of aerobic glycolysis and has been reported to be involved in the tumor progression. However, the function of LDHA in prostate cancer has not been studied. In current study, we observed overexpression of LDHA in the clinical prostate cancer samples compared with benign prostate hyperplasia tissues as demonstrated by immunohistochemistry and real-time qPCR. Attenuated expression of LDHA by siRNA or inhibition of LDHA activities by FX11 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of PC-3 and DU145 cells. Mechanistically, decreased Warburg effect as demonstrated by reduced glucose consumption and lactate secretion and reduced expression of MMP-9, PLAU, and cathepsin B were found after LDHA knockdown or FX11 treatment in PC-3 and DU145 cells. Taken together, our study revealed the oncogenic role of LDHA in prostate cancer and suggested that LDHA might be a potential therapeutic target.

[ "Inhibition", "of", "LDHA", "suppresses", "tumor", "progression", "in", "prostate", "cancer", ".", "A", "key", "hallmark", "of", "cancer", "cells", "is", "their", "altered", "metabolism", ",", "known", "as", "Warburg", "effect", ".", "Lactate", "dehydrogenase", "A", "(", "LDHA", ")", "executes", "the", "final", "step", "of", "aerobic", "glycolysis", "and", "has", "been", "reported", "to", "be", "involved", "in", "the", "tumor", "progression", ".", "However", ",", "the", "function", "of", "LDHA", "in", "prostate", "cancer", "has", "not", "been", "studied", ".", "In", "current", "study", ",", "we", "observed", "overexpression", "of", "LDHA", "in", "the", "clinical", "prostate", "cancer", "samples", "compared", "with", "benign", "prostate", "hyperplasia", "tissues", "as", "demonstrated", "by", "immunohistochemistry", "and", "real-time", "qPCR", ".", "Attenuated", "expression", "of", "LDHA", "by", "siRNA", "or", "inhibition", "of", "LDHA", "activities", "by", "FX11", "inhibited", "cell", "proliferation", ",", "migration", ",", "invasion", ",", "and", "promoted", "cell", "apoptosis", "of", "PC-3", "and", "DU145", "cells", ".", "Mechanistically", ",", "decreased", "Warburg", "effect", "as", "demonstrated", "by", "reduced", "glucose", "consumption", "and", "lactate", "secretion", "and", "reduced", "expression", "of", "MMP-9", ",", "PLAU", ",", "and", "cathepsin", "B", "were", "found", "after", "LDHA", "knockdown", "or", "FX11", "treatment", "in", "PC-3", "and", "DU145", "cells", ".", "Taken", "together", ",", "our", "study", "revealed", "the", "oncogenic", "role", "of", "LDHA", "in", "prostate", "cancer", "and", "suggested", "that", "LDHA", "might", "be", "a", "potential", "therapeutic", "target", "." ]

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27640183

Erythropoietin does not activate erythropoietin receptor signaling or lipolytic pathways in human subcutaneous white adipose tissue in vivo. BACKGROUND: Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo. METHOD: Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA). RESULTS: No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA. CONCLUSION: Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.

[ "Erythropoietin", "does", "not", "activate", "erythropoietin", "receptor", "signaling", "or", "lipolytic", "pathways", "in", "human", "subcutaneous", "white", "adipose", "tissue", "in", "vivo", ".", "BACKGROUND", ":", "Erythropoietin", "(", "Epo", ")", "exerts", "direct", "effects", "on", "white", "adipose", "tissue", "(", "WAT", ")", "in", "mice", "in", "addition", "to", "its", "erythropoietic", "effects", ",", "and", "in", "humans", "Epo", "increases", "resting", "energy", "expenditure", "and", "affect", "serum", "lipid", "levels", ",", "but", "direct", "effects", "of", "Epo", "in", "human", "WAT", "have", "not", "been", "documented", ".", "We", "therefore", "investigated", "the", "effects", "of", "acute", "and", "prolonged", "Epo", "exposure", "on", "human", "WAT", "in", "vivo", ".", "METHOD", ":", "Data", "were", "obtained", "from", "two", "clinical", "trials", ":", "1", ")", "acute", "Epo", "exposure", "(", "rHuEpo", ",", "400", "IU/kg", ")", "followed", "by", "WAT", "biopsies", "after", "1", "h", "and", "2", ")", "10", "weeks", "treatment", "with", "the", "erythropoiesis-stimulating", "agent", "(", "ESA", ")", "Darbepoietin-alpha", ".", "Biopsies", "were", "analyzed", "by", "PCR", "for", "Epo", "receptor", "(", "Epo-R", ")", "mRNA", ".", "A", "new", "and", "highly", "specific", "antibody", "(", "A82", ",", "Amgen", ")", "was", "used", "to", "evaluate", "the", "presence", "of", "Epo-R", "by", "western", "blot", "analysis", "in", "addition", "to", "Epo-R", "signaling", "proteins", "(", "Akt", ",", "STAT5", ",", "p70s6k", ",", "LYN", ",", "and", "p38MAPK", ")", ",", "activation", "of", "lipolytic", "pathways", "(", "ATGL", ",", "HSL", ",", "CGI-58", ",", "G0S2", ",", "Perilipin", ",", "Cidea", ",", "Cidec", ",", "AMPK", ",", "and", "ACC", ")", ",", "and", "mitochondrial", "biogenesis", "(", "VDAC", ",", "HSP90", ",", "PDH", ",", "and", "SDHA", ")", ".", "RESULTS", ":", "No", "evidence", "of", "in", "vivo", "activation", "of", "the", "Epo-R", "in", "WAT", "could", "be", "documented", "despite", "detectable", "levels", "of", "Epo-R", "mRNA", ".", "CONCLUSION", ":", "Thus", ",", "in", "contradiction", "to", "animal", "studies", ",", "Epo", "treatment", "within", "a", "physiological", "relevant", "range", "in", "humans", "does", "not", "exert", "direct", "effects", "in", "a", "subcutaneous", "WAT", "." ]

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28411266

Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease. Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacological therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120,286 participants in the UK Biobank and summary association results from four large-scale genome-wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes, and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (odds ratio [OR] 0.93; 95% CI 0.91, 0.95; P = 1.2 x 10(-11)). The variant was associated with increased BMI (+0.062 kg/m(2); 95% CI 0.037, 0.086; P = 8.1 x 10(-7)) but lower waist-to-hip ratio adjusted for BMI, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98; 95% CI 0.96, 0.99; P = 5.9 x 10(-4)). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease.

[ "Genetic", "Variation", "at", "the", "Sulfonylurea", "Receptor", ",", "Type", "2", "Diabetes", ",", "and", "Coronary", "Heart", "Disease", ".", "Despite", "widespread", "clinical", "use", "in", "the", "treatment", "of", "type", "2", "diabetes", ",", "the", "impact", "of", "sulfonylurea", "therapy", "on", "cardiovascular", "outcomes", "remains", "uncertain", ".", "Studies", "of", "naturally", "occurring", "genetic", "variation", "can", "be", "used", "to", "anticipate", "the", "expected", "clinical", "consequences", "of", "a", "pharmacological", "therapy", ".", "A", "common", "missense", "variant", "in", "the", "gene", "encoding", "a", "component", "of", "the", "sulfonylurea", "receptor", "(", "ABCC8", "p.A1369S", ")", "promotes", "closure", "of", "the", "target", "channel", "of", "sulfonylurea", "therapy", "and", "is", "associated", "with", "increased", "insulin", "secretion", ",", "thus", "mimicking", "the", "effects", "of", "sulfonylurea", "therapy", ".", "Using", "individual-level", "data", "from", "120,286", "participants", "in", "the", "UK", "Biobank", "and", "summary", "association", "results", "from", "four", "large-scale", "genome-wide", "association", "studies", ",", "we", "examined", "the", "impact", "of", "this", "variant", "on", "cardiometabolic", "traits", ",", "type", "2", "diabetes", ",", "and", "coronary", "heart", "disease", ".", "The", "p.A1369S", "variant", "was", "associated", "with", "a", "significantly", "lower", "risk", "of", "type", "2", "diabetes", "(", "odds", "ratio", "[", "OR", "]", "0.93", ";", "95", "%", "CI", "0.91", ",", "0.95", ";", "P", "=", "1.2", "x", "10", "(", "-11", ")", ")", ".", "The", "variant", "was", "associated", "with", "increased", "BMI", "(", "+0.062", "kg/m", "(", "2", ")", ";", "95", "%", "CI", "0.037", ",", "0.086", ";", "P", "=", "8.1", "x", "10", "(", "-7", ")", ")", "but", "lower", "waist-to-hip", "ratio", "adjusted", "for", "BMI", ",", "a", "marker", "of", "abdominal", "fat", "distribution", ".", "Furthermore", ",", "p.A1369S", "was", "associated", "with", "a", "reduced", "risk", "of", "coronary", "heart", "disease", "(", "OR", "0.98", ";", "95", "%", "CI", "0.96", ",", "0.99", ";", "P", "=", "5.9", "x", "10", "(", "-4", ")", ")", ".", "These", "results", "suggest", "that", ",", "despite", "a", "known", "association", "with", "increased", "weight", ",", "long-term", "sulfonylurea", "therapy", "may", "reduce", "the", "risk", "of", "coronary", "heart", "disease", "." ]

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7468724

Cardiovascular complications associated with terbutaline treatment for preterm labor. Severe cardiovascular complications occurred in eight of 160 patients treated with terbutaline for preterm labor. Associated corticosteroid therapy and twin gestations appear to be predisposing factors. Potential mechanisms of the pathophysiology are briefly discussed.

[ "Cardiovascular", "complications", "associated", "with", "terbutaline", "treatment", "for", "preterm", "labor", ".", "Severe", "cardiovascular", "complications", "occurred", "in", "eight", "of", "160", "patients", "treated", "with", "terbutaline", "for", "preterm", "labor", ".", "Associated", "corticosteroid", "therapy", "and", "twin", "gestations", "appear", "to", "be", "predisposing", "factors", ".", "Potential", "mechanisms", "of", "the", "pathophysiology", "are", "briefly", "discussed", "." ]

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7668252

Cloning of human very-long-chain acyl-coenzyme A dehydrogenase and molecular characterization of its deficiency in two patients. Two overlapping cDNA clones (1, 991 bp and 736 bp, respectively) encoding the precursor of human mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) were cloned and sequenced. The cDNA inserts of these clones together encompass a region of 2, 177 bases, encoding the entire protein of 655 amino acids, including a 40-amino acid leader peptide and a 615-amino acid mature polypeptide. PCR-amplified VLCAD cDNAs were sequenced in cultured fibroblasts from two VLCAD-deficient patients. In both patients, a 105-bp deletion encompassing bases 1078-1182 in VLCAD cDNA was identified. The deletion seems to occur due to exon skipping during processing of VLCAD pre-mRNA. This is the first demonstration of a mutation causing VLCAD deficiency. Quantitative cDNA expression of normal human VLCAD was performed in the patients fibroblasts, using vaccinia viral system, which demonstrated that the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients fibroblasts. In patient fibroblasts, raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts, which may offer important information for the rational design of future somatic gene therapy for VLCAD deficiency..

[ "Cloning", "of", "human", "very-long-chain", "acyl-coenzyme", "A", "dehydrogenase", "and", "molecular", "characterization", "of", "its", "deficiency", "in", "two", "patients", ".", "Two", "overlapping", "cDNA", "clones", "(", "1", ",", "991", "bp", "and", "736", "bp", ",", "respectively", ")", "encoding", "the", "precursor", "of", "human", "mitochondrial", "very-long-chain", "acyl-coenzyme", "A", "dehydrogenase", "(", "VLCAD", ")", "were", "cloned", "and", "sequenced", ".", "The", "cDNA", "inserts", "of", "these", "clones", "together", "encompass", "a", "region", "of", "2", ",", "177", "bases", ",", "encoding", "the", "entire", "protein", "of", "655", "amino", "acids", ",", "including", "a", "40-amino", "acid", "leader", "peptide", "and", "a", "615-amino", "acid", "mature", "polypeptide", ".", "PCR-amplified", "VLCAD", "cDNAs", "were", "sequenced", "in", "cultured", "fibroblasts", "from", "two", "VLCAD-deficient", "patients", ".", "In", "both", "patients", ",", "a", "105-bp", "deletion", "encompassing", "bases", "1078-1182", "in", "VLCAD", "cDNA", "was", "identified", ".", "The", "deletion", "seems", "to", "occur", "due", "to", "exon", "skipping", "during", "processing", "of", "VLCAD", "pre-mRNA", ".", "This", "is", "the", "first", "demonstration", "of", "a", "mutation", "causing", "VLCAD", "deficiency", ".", "Quantitative", "cDNA", "expression", "of", "normal", "human", "VLCAD", "was", "performed", "in", "the", "patients", "fibroblasts", ",", "using", "vaccinia", "viral", "system", ",", "which", "demonstrated", "that", "the", "deficiency", "of", "the", "normal", "VLCAD", "protein", "causes", "impaired", "long-chain", "fatty", "acid", "beta-oxidation", "activity", "in", "the", "patients", "fibroblasts", ".", "In", "patient", "fibroblasts", ",", "raising", "VLCAD", "activity", "to", "approximately", "20", "%", "of", "normal", "control", "fibroblast", "activity", "raised", "palmitic", "acid", "beta-oxidation", "flux", "to", "the", "level", "found", "in", "control", "fibroblasts", ",", "which", "may", "offer", "important", "information", "for", "the", "rational", "design", "of", "future", "somatic", "gene", "therapy", "for", "VLCAD", "deficiency", ".." ]

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8002973

Adrenoleukodystrophy gene encodes an 80 kDa membrane protein. An antibody against the synthetic C-terminal peptides deduced from the cDNA of the gene responsible for X-linked adrenoleukodystrophy (ALD) was produced to characterize the product of the ALD gene. The antibody reacted with the 80 kDa band protein in control fibroblasts, while no bands were detected in the fibroblasts from a patient with ALD (# 163), in which mRNA of the ALD gene was undetectable based on Northern blot analysis. The 293T cells transfected with the full-coding cDNA inserted in the expression vector produced a new 80 kDa protein, as detected by Western blot. In an immunocytological study, the staining was in a punctate pattern, in the normal fibroblasts. However, there was no punctate staining in the # 163 cells. These data thus indicate that the ALD gene encodes an 80 kDa membrane protein..

[ "Adrenoleukodystrophy", "gene", "encodes", "an", "80", "kDa", "membrane", "protein", ".", "An", "antibody", "against", "the", "synthetic", "C-terminal", "peptides", "deduced", "from", "the", "cDNA", "of", "the", "gene", "responsible", "for", "X-linked", "adrenoleukodystrophy", "(", "ALD", ")", "was", "produced", "to", "characterize", "the", "product", "of", "the", "ALD", "gene", ".", "The", "antibody", "reacted", "with", "the", "80", "kDa", "band", "protein", "in", "control", "fibroblasts", ",", "while", "no", "bands", "were", "detected", "in", "the", "fibroblasts", "from", "a", "patient", "with", "ALD", "(", "#", "163", ")", ",", "in", "which", "mRNA", "of", "the", "ALD", "gene", "was", "undetectable", "based", "on", "Northern", "blot", "analysis", ".", "The", "293T", "cells", "transfected", "with", "the", "full-coding", "cDNA", "inserted", "in", "the", "expression", "vector", "produced", "a", "new", "80", "kDa", "protein", ",", "as", "detected", "by", "Western", "blot", ".", "In", "an", "immunocytological", "study", ",", "the", "staining", "was", "in", "a", "punctate", "pattern", ",", "in", "the", "normal", "fibroblasts", ".", "However", ",", "there", "was", "no", "punctate", "staining", "in", "the", "#", "163", "cells", ".", "These", "data", "thus", "indicate", "that", "the", "ALD", "gene", "encodes", "an", "80", "kDa", "membrane", "protein", ".." ]

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8755918

Mutations associated with variant phenotypes in ataxia-telangiectasia. We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10% -15% of A-T families identified in the United Kingdom). In 10 of these families, all the homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice-donor site. The second A-T allele has a different mutation in each patient. We show that the less severe phenotype in these patients is caused by some degree of normal splicing, which occurs as an alternative product from the insertion-containing allele. The level of the 137-bp PCR product containing the insertion was lowest in two patients who showed a later onset of cerebellar ataxia. A further four families who do not have this insertion have been identified. Mutations detected in two of four of these are missense mutations, normally rare in A-T patients. The demonstration of mutations giving rise to a slightly milder phenotype in A-T raises the interesting question of what range of phenotypes might occur in individuals in whom both mutations are milder. One possibility might be that individuals who are compound heterozygotes for ATM mutations are more common than we realize..

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9746003

Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Carbamazepine and vigabatrin are contraindicated in typical absence seizures. Of 18 consecutive referrals of children with resistant typical absences only, eight were erroneously treated with carbamazepine either as monotherapy or as an add-on. Vigabatrin was also used in the treatment of two children. Frequency of absences increased in four children treated with carbamazepine and two of these developed myoclonic jerks, which resolved on withdrawal of carbamazepine. Absences were aggravated in both cases where vigabatrin was added on to concurrent treatment. Optimal control of the absences was achieved with sodium valproate, lamotrigine, or ethosuximide alone or in combination.

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15609295

Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome. Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient.

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16288197

Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree. PURPOSE: Congenital microcoria is a rare autosomal dominant developmental disorder of the iris associated with myopia and juvenile open angle glaucoma. Linkage to the chromosomal locus 13q31-q32 has previously been reported in a large French family. In the current study, a three generation Asian Indian family with 15 congenital microcoria (pupils with a diameter <2 mm) affected members was studied for linkage to candidate microsatellite markers at the 13q31-q32 locus. METHODS: Twenty-four members of the family were clinically examined and genomic DNA was extracted. Microsatellite markers at 13q31-q32 were PCR amplified and run on an ABI Prism 310 genetic analyzer and genotyped with the GeneScan analysis. Two point and multipoint linkage analyses were performed using the MLINK and SUPERLINK programs. RESULTS: Peak two point LOD scores of 3.5, 4.7, and 5.3 were found co-incident with consecutive markers D13S154, DCT, and D13S1280. Multipoint analysis revealed a 4 cM region encompassing D13S1300 to D13S1280 where the LOD remains just over 6.0 Thus we confirm localization of the congenital microcoria locus to chromosomal locus 13q31-q32. In addition, eight individuals who had both microcoria and glaucoma were screened for glaucoma genes: myocilin (MYOC), optineurin (OPTN) and CYP1B1. Using direct sequencing a point mutation (144 G>A) resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five of the eight glaucoma patients, but not in unaffected family members and 100 unrelated controls. CONCLUSIONS: We have confirmed the localization of the congenital microcoria locus (MCOR) to 13q31-q32 in a large Asian Indian family and conclude that current information suggests this is a single locus disorder and genetically homogeneous. When combined with the initial linkage paper our haplotype and linkage data map the MCOR locus to a 6-7 cM region between D13S265 and D13S1280. The DCT locus, a member of the tyrosinase family involved in pigmentation, maps within this region. Data presented here supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma, although this observation is complicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), a mutation known to be associated with glaucoma in India. Fine mapping and candidate gene analysis continues with the hope that characterizing the micocoria gene will lead to a better understanding of microcoria and glaucoma causation. The relationship between microcoria, glaucoma, and the MYOC Q48H mutation in this family is discussed.

[ "Genetic", "homogeneity", "for", "inherited", "congenital", "microcoria", "loci", "in", "an", "Asian", "Indian", "pedigree", ".", "PURPOSE", ":", "Congenital", "microcoria", "is", "a", "rare", "autosomal", "dominant", "developmental", "disorder", "of", "the", "iris", "associated", "with", "myopia", "and", "juvenile", "open", "angle", "glaucoma", ".", "Linkage", "to", "the", "chromosomal", "locus", "13q31-q32", "has", "previously", "been", "reported", "in", "a", "large", "French", "family", ".", "In", "the", "current", "study", ",", "a", "three", "generation", "Asian", "Indian", "family", "with", "15", "congenital", "microcoria", "(", "pupils", "with", "a", "diameter", "<", "2", "mm", ")", "affected", "members", "was", "studied", "for", "linkage", "to", "candidate", "microsatellite", "markers", "at", "the", "13q31-q32", "locus", ".", "METHODS", ":", "Twenty-four", "members", "of", "the", "family", "were", "clinically", "examined", "and", "genomic", "DNA", "was", "extracted", ".", "Microsatellite", "markers", "at", "13q31-q32", "were", "PCR", "amplified", "and", "run", "on", "an", "ABI", "Prism", "310", "genetic", "analyzer", "and", "genotyped", "with", "the", "GeneScan", "analysis", ".", "Two", "point", "and", "multipoint", "linkage", "analyses", "were", "performed", "using", "the", "MLINK", "and", "SUPERLINK", "programs", ".", "RESULTS", ":", "Peak", "two", "point", "LOD", "scores", "of", "3.5", ",", "4.7", ",", "and", "5.3", "were", "found", "co-incident", "with", "consecutive", "markers", "D13S154", ",", "DCT", ",", "and", "D13S1280", ".", "Multipoint", "analysis", "revealed", "a", "4", "cM", "region", "encompassing", "D13S1300", "to", "D13S1280", "where", "the", "LOD", "remains", "just", "over", "6.0", "Thus", "we", "confirm", "localization", "of", "the", "congenital", "microcoria", "locus", "to", "chromosomal", "locus", "13q31-q32", ".", "In", "addition", ",", "eight", "individuals", "who", "had", "both", "microcoria", "and", "glaucoma", "were", "screened", "for", "glaucoma", "genes", ":", "myocilin", "(", "MYOC", ")", ",", "optineurin", "(", "OPTN", ")", "and", "CYP1B1", ".", "Using", "direct", "sequencing", "a", "point", "mutation", "(", "144", "G", ">", "A", ")", "resulting", "in", "a", "Q48H", "substitution", "in", "exon", "1", "of", "the", "MYOC", "gene", "was", "observed", "in", "five", "of", "the", "eight", "glaucoma", "patients", ",", "but", "not", "in", "unaffected", "family", "members", "and", "100", "unrelated", "controls", ".", "CONCLUSIONS", ":", "We", "have", "confirmed", "the", "localization", "of", "the", "congenital", "microcoria", "locus", "(", "MCOR", ")", "to", "13q31-q32", "in", "a", "large", "Asian", "Indian", "family", "and", "conclude", "that", "current", "information", "suggests", "this", "is", "a", "single", "locus", "disorder", "and", "genetically", "homogeneous", ".", "When", "combined", "with", "the", "initial", "linkage", "paper", "our", "haplotype", "and", "linkage", "data", "map", "the", "MCOR", "locus", "to", "a", "6-7", "cM", "region", "between", "D13S265", "and", "D13S1280", ".", "The", "DCT", "locus", ",", "a", "member", "of", "the", "tyrosinase", "family", "involved", "in", "pigmentation", ",", "maps", "within", "this", "region", ".", "Data", "presented", "here", "supports", "the", "hypothesis", "that", "congenital", "microcoria", "is", "a", "potential", "risk", "factor", "for", "glaucoma", ",", "although", "this", "observation", "is", "complicated", "by", "the", "partial", "segregation", "of", "MYOC", "Q48H", "(", "1q24.3-q25.2", ")", ",", "a", "mutation", "known", "to", "be", "associated", "with", "glaucoma", "in", "India", ".", "Fine", "mapping", "and", "candidate", "gene", "analysis", "continues", "with", "the", "hope", "that", "characterizing", "the", "micocoria", "gene", "will", "lead", "to", "a", "better", "understanding", "of", "microcoria", "and", "glaucoma", "causation", ".", "The", "relationship", "between", "microcoria", ",", "glaucoma", ",", "and", "the", "MYOC", "Q48H", "mutation", "in", "this", "family", "is", "discussed", "." ]

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17177139

A novel mutation (E333D) in the thyroid hormone beta receptor causing resistance to thyroid hormone syndrome. Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.

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17634480

Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. PURPOSE: The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer. PATIENTS AND METHODS: We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer. RESULTS: Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes. CONCLUSION: These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.

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15748645

Photochemoprevention of ultraviolet B signaling and photocarcinogenesis. Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.

[ "Photochemoprevention", "of", "ultraviolet", "B", "signaling", "and", "photocarcinogenesis", ".", "Exposure", "to", "solar", "radiation", ",", "particularly", "its", "ultraviolet", "(", "UV", ")", "B", "component", ",", "has", "a", "variety", "of", "harmful", "effects", "on", "human", "health", ".", "Some", "of", "these", "effects", "include", "sunburn", "cell", "formation", ",", "basal", "and", "squamous", "cell", "cancers", ",", "melanoma", ",", "cataracts", ",", "photoaging", "of", "the", "skin", ",", "and", "immune", "suppression", ".", "Amongst", "these", "various", "adverse", "effects", "of", "UV", "radiation", ",", "skin", "cancer", "is", "of", "the", "greatest", "concern", ".", "Over", "the", "years", ",", "changes", "in", "lifestyle", "has", "led", "to", "a", "significant", "increase", "in", "the", "amount", "of", "UV", "radiation", "that", "people", "receive", ",", "and", "this", "consequently", "has", "led", "to", "a", "surge", "in", "the", "incidence", "of", "skin", "cancer", ".", "The", "development", "of", "skin", "cancer", "is", "a", "complex", "multistage", "phenomenon", "involving", "three", "distinct", "stages", "exemplified", "by", "initiation", ",", "promotion", "and", "progression", "stages", ".", "Each", "of", "these", "stages", "is", "mediated", "via", "alterations", "in", "various", "cellular", ",", "biochemical", ",", "and", "molecular", "changes", ".", "Initiation", ",", "the", "first", "step", "in", "the", "carcinogenesis", "process", "is", "essentially", "an", "irreversible", "step", "in", "which", "genetic", "alterations", "occur", "in", "genes", "that", "ultimately", "leads", "to", "DNA", "modification", "and", "fixation", "of", "mutation", ".", "Tumor", "promotion", "is", "the", "essential", "process", "in", "cancer", "development", "involving", "clonal", "expansion", "of", "initiated", "cells", "giving", "rise", "to", "pre-malignant", "and", "then", "to", "malignant", "lesions", ",", "essentially", "by", "alterations", "in", "signal", "transduction", "pathways", ".", "Tumor", "progression", "involves", "the", "conversion", "of", "pre-malignant", "and", "malignant", "lesions", "into", "an", "invasive", "and", "potentially", "metastatic", "malignant", "tumor", ".", "All", "these", "processes", "for", "skin", "cancer", "development", "involve", "stimulation", "of", "DNA", "synthesis", ",", "DNA", "damage", "and", "proliferation", ",", "inflammation", ",", "immunosuppression", ",", "epidermal", "hyperplasia", ",", "cell", "cycle", "dysregulation", ",", "depletion", "of", "antioxidant", "defenses", ",", "impairment", "of", "signal", "transduction", "pathways", ",", "induction", "of", "cyclooxygenase", ",", "increase", "in", "prostaglandin", "synthesis", ",", "and", "induction", "of", "ornithine", "decarboxylase", ".", "Photochemoprevention", "has", "been", "appreciated", "as", "a", "viable", "approach", "to", "reduce", "the", "occurrence", "of", "skin", "cancer", "and", "in", "recent", "years", ",", "the", "use", "of", "agents", ",", "especially", "botanical", "antioxidants", ",", "present", "in", "the", "common", "diet", "and", "beverages", "consumed", "by", "human", "population", "have", "gained", "considerable", "attention", "as", "photochemopreventive", "agents", "for", "human", "use", ".", "Many", "such", "agents", "have", "also", "found", "a", "place", "in", "skin", "care", "products", ".", "Although", "this", "is", "more", "common", "in", "oriental", "countries", ",", "its", "popularity", "is", "significantly", "growing", "in", "western", "countries", ".", "In", "this", "article", ",", "we", "have", "summarized", "the", "available", "information", "of", "laboratory", "studies", "on", "UVB-mediated", "signaling", "that", "can", "be", "exploited", "as", "targets", "for", "photochemoprevention", ".", "We", "suggest", "that", "the", "use", "of", "skin", "care", "products", "supplemented", "with", "proven", "chemopreventive", "agents", "in", "conjunction", "with", "the", "use", "of", "sunscreens", "along", "with", "educational", "efforts", "may", "be", "an", "effective", "strategy", "for", "reducing", "UV-induced", "photodamage", "and", "skin", "cancer", "in", "humans", ".", "The", "mechanistic", "basis", "for", "the", "use", "of", "such", "products", "is", "discussed", "." ]

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16543197

A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis. PURPOSE: To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. MATERIALS AND METHODS: The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. RESULTS: All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. CONCLUSION: Although hyperopia has been associated with LCA, it is typically moderate and variable between patients with the same mutation. In addition, some CRB1 mutations can be associated with either RP or LCA. We have shown that hyperopia and LCA are linked to the mutant CRB1 gene itself and are not dependent on unlinked modifiers.

[ "A", "G1103R", "mutation", "in", "CRB1", "is", "co-inherited", "with", "high", "hyperopia", "and", "Leber", "congenital", "amaurosis", ".", "PURPOSE", ":", "To", "identify", "the", "genetic", "basis", "of", "recessive", "inheritance", "of", "high", "hyperopia", "and", "Leber", "congenital", "amaurosis", "(", "LCA", ")", "in", "a", "family", "of", "Middle", "Eastern", "origin", ".", "MATERIALS", "AND", "METHODS", ":", "The", "patients", "were", "examined", "using", "standard", "ophthalmic", "techniques", ".", "DNA", "samples", "were", "obtained", "and", "genetic", "linkage", "was", "carried", "out", "using", "polymorphic", "markers", "flanking", "the", "known", "genes", "and", "loci", "for", "LCA", ".", "Exons", "were", "amplified", "and", "sequenced", ".", "RESULTS", ":", "All", "four", "members", "of", "this", "family", "affected", "by", "LCA", "showed", "high", "to", "extreme", "hyperopia", ",", "with", "average", "spherical", "refractive", "errors", "ranging", "from", "+5.00", "to", "+10.00", ".", "Linkage", "was", "obtained", "to", "1q31.3", "with", "a", "maximal", "LOD", "score", "of", "5.20", "and", "a", "mutation", "found", "in", "exon", "9", "of", "the", "CRB1", "gene", ",", "causing", "a", "G1103R", "substitution", "at", "a", "highly", "conserved", "site", "in", "the", "protein", ".", "CRB1", "is", "a", "vertebrate", "homolog", "of", "the", "Drosophila", "crumbs", "gene", ",", "which", "is", "required", "for", "photoreceptor", "morphogenesis", ",", "and", "has", "been", "associated", "with", "either", "retinitis", "pigmentosa", "(", "RP", ")", "or", "LCA", ".", "This", "sequence", "variant", "has", "previously", "been", "reported", "as", "a", "compound", "heterozygote", "in", "one", "sporadic", "LCA", "patient", ".", "CONCLUSION", ":", "Although", "hyperopia", "has", "been", "associated", "with", "LCA", ",", "it", "is", "typically", "moderate", "and", "variable", "between", "patients", "with", "the", "same", "mutation", ".", "In", "addition", ",", "some", "CRB1", "mutations", "can", "be", "associated", "with", "either", "RP", "or", "LCA", ".", "We", "have", "shown", "that", "hyperopia", "and", "LCA", "are", "linked", "to", "the", "mutant", "CRB1", "gene", "itself", "and", "are", "not", "dependent", "on", "unlinked", "modifiers", "." ]

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20477932

Cocaine causes memory and learning impairments in rats: involvement of nuclear factor kappa B and oxidative stress, and prevention by topiramate. Different mechanisms have been suggested for cocaine toxicity including an increase in oxidative stress but the association between oxidative status in the brain and cocaine induced-behaviour is poorly understood. Nuclear factor kappa B (NFkappaB) is a sensor of oxidative stress and participates in memory formation that could be involved in drug toxicity and addiction mechanisms. Therefore NFkappaB activity, oxidative stress, neuronal nitric oxide synthase (nNOS) activity, spatial learning and memory as well as the effect of topiramate, a previously proposed therapy for cocaine addiction, were evaluated in an experimental model of cocaine administration in rats. NFkappaB activity was decreased in the frontal cortex of cocaine treated rats, as well as GSH concentration and glutathione peroxidase activity in the hippocampus, whereas nNOS activity in the hippocampus was increased. Memory retrieval of experiences acquired prior to cocaine administration was impaired and negatively correlated with NFkappaB activity in the frontal cortex. In contrast, learning of new tasks was enhanced and correlated with the increase of nNOS activity and the decrease of glutathione peroxidase. These results provide evidence for a possible mechanistic role of oxidative and nitrosative stress and NFkappaB in the alterations induced by cocaine. Topiramate prevented all the alterations observed, showing novel neuroprotective properties.

[ "Cocaine", "causes", "memory", "and", "learning", "impairments", "in", "rats", ":", "involvement", "of", "nuclear", "factor", "kappa", "B", "and", "oxidative", "stress", ",", "and", "prevention", "by", "topiramate", ".", "Different", "mechanisms", "have", "been", "suggested", "for", "cocaine", "toxicity", "including", "an", "increase", "in", "oxidative", "stress", "but", "the", "association", "between", "oxidative", "status", "in", "the", "brain", "and", "cocaine", "induced-behaviour", "is", "poorly", "understood", ".", "Nuclear", "factor", "kappa", "B", "(", "NFkappaB", ")", "is", "a", "sensor", "of", "oxidative", "stress", "and", "participates", "in", "memory", "formation", "that", "could", "be", "involved", "in", "drug", "toxicity", "and", "addiction", "mechanisms", ".", "Therefore", "NFkappaB", "activity", ",", "oxidative", "stress", ",", "neuronal", "nitric", "oxide", "synthase", "(", "nNOS", ")", "activity", ",", "spatial", "learning", "and", "memory", "as", "well", "as", "the", "effect", "of", "topiramate", ",", "a", "previously", "proposed", "therapy", "for", "cocaine", "addiction", ",", "were", "evaluated", "in", "an", "experimental", "model", "of", "cocaine", "administration", "in", "rats", ".", "NFkappaB", "activity", "was", "decreased", "in", "the", "frontal", "cortex", "of", "cocaine", "treated", "rats", ",", "as", "well", "as", "GSH", "concentration", "and", "glutathione", "peroxidase", "activity", "in", "the", "hippocampus", ",", "whereas", "nNOS", "activity", "in", "the", "hippocampus", "was", "increased", ".", "Memory", "retrieval", "of", "experiences", "acquired", "prior", "to", "cocaine", "administration", "was", "impaired", "and", "negatively", "correlated", "with", "NFkappaB", "activity", "in", "the", "frontal", "cortex", ".", "In", "contrast", ",", "learning", "of", "new", "tasks", "was", "enhanced", "and", "correlated", "with", "the", "increase", "of", "nNOS", "activity", "and", "the", "decrease", "of", "glutathione", "peroxidase", ".", "These", "results", "provide", "evidence", "for", "a", "possible", "mechanistic", "role", "of", "oxidative", "and", "nitrosative", "stress", "and", "NFkappaB", "in", "the", "alterations", "induced", "by", "cocaine", ".", "Topiramate", "prevented", "all", "the", "alterations", "observed", ",", "showing", "novel", "neuroprotective", "properties", "." ]

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28348168

FGFR2 is required for airway basal cell self-renewal and terminal differentiation. Airway stem cells slowly self-renew and produce differentiated progeny to maintain homeostasis throughout the lifespan of an individual. Mutations in the molecular regulators of these processes may drive cancer or degenerative disease, but are also potential therapeutic targets. Conditionally deleting one copy of FGF receptor 2 (FGFR2) in adult mouse airway basal cells results in self-renewal and differentiation phenotypes. We show that FGFR2 signalling correlates with maintenance of expression of a key transcription factor for basal cell self-renewal and differentiation: SOX2. This heterozygous phenotype illustrates that subtle changes in receptor tyrosine kinase signalling can have significant effects, perhaps providing an explanation for the numerous changes seen in cancer.

[ "FGFR2", "is", "required", "for", "airway", "basal", "cell", "self-renewal", "and", "terminal", "differentiation", ".", "Airway", "stem", "cells", "slowly", "self-renew", "and", "produce", "differentiated", "progeny", "to", "maintain", "homeostasis", "throughout", "the", "lifespan", "of", "an", "individual", ".", "Mutations", "in", "the", "molecular", "regulators", "of", "these", "processes", "may", "drive", "cancer", "or", "degenerative", "disease", ",", "but", "are", "also", "potential", "therapeutic", "targets", ".", "Conditionally", "deleting", "one", "copy", "of", "FGF", "receptor", "2", "(", "FGFR2", ")", "in", "adult", "mouse", "airway", "basal", "cells", "results", "in", "self-renewal", "and", "differentiation", "phenotypes", ".", "We", "show", "that", "FGFR2", "signalling", "correlates", "with", "maintenance", "of", "expression", "of", "a", "key", "transcription", "factor", "for", "basal", "cell", "self-renewal", "and", "differentiation", ":", "SOX2", ".", "This", "heterozygous", "phenotype", "illustrates", "that", "subtle", "changes", "in", "receptor", "tyrosine", "kinase", "signalling", "can", "have", "significant", "effects", ",", "perhaps", "providing", "an", "explanation", "for", "the", "numerous", "changes", "seen", "in", "cancer", "." ]

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16418600

Genetic investigation of the TSPYL1 gene in sudden infant death syndrome. BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.

[ "Genetic", "investigation", "of", "the", "TSPYL1", "gene", "in", "sudden", "infant", "death", "syndrome", ".", "BACKGROUND", ":", "Sudden", "infant", "death", "syndrome", "(", "SIDS", ")", "constitutes", "the", "most", "frequent", "cause", "of", "death", "in", "the", "postperinatal", "period", "in", "Germany", ".", "Recently", ",", "a", "lethal", "phenotype", "characterized", "by", "sudden", "infant", "death", "with", "dysgenesis", "of", "the", "testes", "syndrome", "(", "SIDDT", ")", "was", "identified", "to", "be", "caused", "by", "loss", "of", "function", "mutations", "in", "the", "TSPYL1", "gene", ".", "PURPOSE", ":", "The", "study", "'s", "purpose", "was", "to", "reveal", "a", "possible", "role", "of", "TSPYL1", "in", "SIDS", ".", "METHODS", ":", "DNA", "samples", "of", "126", "SIDS", "cases", "and", "261", "controls", "were", "investigated", ".", "RESULTS", ":", "We", "found", "five", "sequence", "variations", ",", "each", "of", "them", "causing", "an", "amino", "acid", "substitution", ".", "No", "Hardy", "Weinberg", "disequilibrium", "and", "no", "significant", "difference", "in", "allele", "frequencies", "between", "patients", "and", "controls", "were", "observed", "for", "any", "variation", ".", "In", "one", "female", "patient", "a", "p.F366L", "amino", "acid", "polymorphism", "was", "found", "heterozygous", ",", "which", "could", "not", "be", "displayed", "in", "controls", ".", "A", "pathogenic", "implication", "of", "this", "substitution", ",", "which", "is", "conserved", "in", "primates", "and", "rodents", ",", "can", "not", "be", "ruled", "out", "completely", ".", "Because", "SIDDT", "is", "the", "result", "of", "homozygous", "TSPYL1", "mutations", ",", "this", "heterozygous", "exchange", "can", "not", "solely", "explain", "the", "sudden", "death", "in", "this", "child", ".", "The", "reported", "mutation", "associated", "with", "SIDDT", "(", "457_458insG", ")", "was", "not", "detectable", "in", "our", "cohort", ".", "CONCLUSION", ":", "No", "association", "of", "sequence", "variations", "in", "the", "TSPYL1", "gene", "and", "SIDS", "has", "been", "found", "in", "a", "German", "cohort", ".", "Genetic", "analysis", "of", "TSPYL1", "seems", "to", "be", "of", "limited", "significance", "in", "the", "differential", "diagnosis", "of", "SIDS", "without", "dysgenesis", "of", "the", "testes", "." ]

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16904497

Cauda equina syndrome after epidural steroid injection: a case report. OBJECTIVE: Conventional treatment methods of lumbusacral radiculopathy are physical therapy, epidural steroid injections, oral medications, and spinal manipulative therapy. Cauda equina syndrome is a rare complication of epidural anesthesia. The following case is a report of cauda equina syndrome possibly caused by epidural injection of triamcinolone and bupivacaine. CLINICAL FEATURES: A 50-year-old woman with low back and right leg pain was scheduled for epidural steroid injection. INTERVENTION AND OUTCOME: An 18-gauge Touhy needle was inserted until loss of resistance occurred at the L4-5 level. Spread of the contrast medium within the epidural space was determined by radiographic imaging. After verifying the epidural space, bupivacaine and triamcinolone diacetate were injected. After the injection, there was a reduction in radicular symptoms. Three hours later, she complained of perineal numbness and lower extremity weakness. The neurologic evaluation revealed loss of sensation in the saddle area and medial aspect of her right leg. There was a decrease in the perception of pinprick test. Deep-tendon reflexes were decreased especially in the right leg. She was unable to urinate. The patient's symptoms improved slightly over the next few hours. She had a gradual return of motor function and ability of feeling Foley catheter. All of the symptoms were completely resolved over the next 8 hours. CONCLUSION: Complications associated with epidural steroid injections are rare. Clinical examination and continued vigilance for neurologic deterioration after epidural steroid injections is important.

[ "Cauda", "equina", "syndrome", "after", "epidural", "steroid", "injection", ":", "a", "case", "report", ".", "OBJECTIVE", ":", "Conventional", "treatment", "methods", "of", "lumbusacral", "radiculopathy", "are", "physical", "therapy", ",", "epidural", "steroid", "injections", ",", "oral", "medications", ",", "and", "spinal", "manipulative", "therapy", ".", "Cauda", "equina", "syndrome", "is", "a", "rare", "complication", "of", "epidural", "anesthesia", ".", "The", "following", "case", "is", "a", "report", "of", "cauda", "equina", "syndrome", "possibly", "caused", "by", "epidural", "injection", "of", "triamcinolone", "and", "bupivacaine", ".", "CLINICAL", "FEATURES", ":", "A", "50-year-old", "woman", "with", "low", "back", "and", "right", "leg", "pain", "was", "scheduled", "for", "epidural", "steroid", "injection", ".", "INTERVENTION", "AND", "OUTCOME", ":", "An", "18-gauge", "Touhy", "needle", "was", "inserted", "until", "loss", "of", "resistance", "occurred", "at", "the", "L4-5", "level", ".", "Spread", "of", "the", "contrast", "medium", "within", "the", "epidural", "space", "was", "determined", "by", "radiographic", "imaging", ".", "After", "verifying", "the", "epidural", "space", ",", "bupivacaine", "and", "triamcinolone", "diacetate", "were", "injected", ".", "After", "the", "injection", ",", "there", "was", "a", "reduction", "in", "radicular", "symptoms", ".", "Three", "hours", "later", ",", "she", "complained", "of", "perineal", "numbness", "and", "lower", "extremity", "weakness", ".", "The", "neurologic", "evaluation", "revealed", "loss", "of", "sensation", "in", "the", "saddle", "area", "and", "medial", "aspect", "of", "her", "right", "leg", ".", "There", "was", "a", "decrease", "in", "the", "perception", "of", "pinprick", "test", ".", "Deep-tendon", "reflexes", "were", "decreased", "especially", "in", "the", "right", "leg", ".", "She", "was", "unable", "to", "urinate", ".", "The", "patient", "'s", "symptoms", "improved", "slightly", "over", "the", "next", "few", "hours", ".", "She", "had", "a", "gradual", "return", "of", "motor", "function", "and", "ability", "of", "feeling", "Foley", "catheter", ".", "All", "of", "the", "symptoms", "were", "completely", "resolved", "over", "the", "next", "8", "hours", ".", "CONCLUSION", ":", "Complications", "associated", "with", "epidural", "steroid", "injections", "are", "rare", ".", "Clinical", "examination", "and", "continued", "vigilance", "for", "neurologic", "deterioration", "after", "epidural", "steroid", "injections", "is", "important", "." ]

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17083016

Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease. BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.

[ "Genetic", "polymorphism", "of", "the", "binding", "domain", "of", "surfactant", "protein-A2", "increases", "susceptibility", "to", "meningococcal", "disease", ".", "BACKGROUND", ":", "Meningococcal", "disease", "occurs", "after", "colonization", "of", "the", "nasopharynx", "with", "Neisseria", "meningitidis", ".", "Surfactant", "protein", "(", "SP", ")", "-A", "and", "SP-D", "are", "pattern-recognition", "molecules", "of", "the", "respiratory", "tract", "that", "activate", "inflammatory", "and", "phagocytic", "defences", "after", "binding", "to", "microbial", "sugars", ".", "Variation", "in", "the", "genes", "of", "the", "surfactant", "proteins", "affects", "the", "expression", "and", "function", "of", "these", "molecules", ".", "METHODS", ":", "Allele", "frequencies", "of", "SP-A1", ",", "SP-A2", ",", "and", "SP-D", "were", "determined", "by", "polymerase", "chain", "reaction", "in", "303", "patients", "with", "microbiologically", "proven", "meningococcal", "disease", ",", "including", "18", "patients", "who", "died", ",", "and", "222", "healthy", "control", "subjects", ".", "RESULTS", ":", "Homozygosity", "of", "allele", "1A1", "of", "SP-A2", "increased", "the", "risk", "of", "meningococcal", "disease", "(", "odds", "ratio", "[", "OR", "]", ",", "7.4", ";", "95", "%", "confidence", "interval", "[", "CI", "]", ",", "1.3-42.4", ")", ";", "carriage", "of", "1A5", "reduced", "the", "risk", "(", "OR", ",", "0.3", ";", "95", "%", "CI", ",", "0.1-0.97", ")", ".", "An", "analysis", "of", "the", "multiple", "single-nucleotide", "polymorphisms", "in", "SP-A", "demonstrated", "that", "homozygosity", "for", "alleles", "encoding", "lysine", "(", "in", "1A1", ")", "rather", "than", "glutamine", "(", "in", "1A5", ")", "at", "amino", "acid", "223", "in", "the", "carbohydrate", "recognition", "domain", "was", "associated", "with", "an", "increased", "risk", "of", "meningococcal", "disease", "(", "OR", ",", "6.7", ";", "95", "%", "CI", ",", "1.4-31.5", ")", ".", "Carriage", "of", "alleles", "encoding", "lysine", "at", "residue", "223", "was", "found", "in", "61", "%", "of", "patients", "who", "died", ",", "compared", "with", "35", "%", "of", "those", "who", "survived", "(", "OR", "adjusted", "for", "age", ",", "2.9", ";", "95", "%", "CI", ",", "1.1-7.7", ")", ".", "Genetic", "variation", "of", "SP-A1", "and", "SP-D", "was", "not", "associated", "with", "meningococcal", "disease", ".", "CONCLUSIONS", ":", "Gene", "polymorphism", "resulting", "in", "the", "substitution", "of", "glutamine", "with", "lysine", "at", "residue", "223", "in", "the", "carbohydrate", "recognition", "domain", "of", "SP-A2", "increases", "susceptibility", "to", "meningococcal", "disease", ",", "as", "well", "as", "the", "risk", "of", "death", "." ]

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17910065

A novel missense mutation in the paired domain of human PAX9 causes oligodontia. PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype.

[ "A", "novel", "missense", "mutation", "in", "the", "paired", "domain", "of", "human", "PAX9", "causes", "oligodontia", ".", "PAX9", "and", "MSX1", "are", "transcription", "factors", "that", "play", "essential", "roles", "in", "craniofacial", "and", "limb", "development", ".", "In", "humans", ",", "mutations", "in", "both", "genes", "are", "associated", "with", "nonsyndromic", "and", "syndromic", "oligodontia", ",", "respectively", ".", "We", "screened", "one", "family", "with", "nonsyndromic", "oligodontia", "for", "mutations", "in", "PAX9", "and", "MSX1", ".", "Single", "stranded", "conformational", "polymorphism", "(", "SSCP", ")", "analysis", "and", "sequencing", "revealed", "a", "novel", "heterozygous", "C139T", "transition", "in", "PAX9", "in", "the", "affected", "members", "of", "the", "family", ".", "There", "were", "no", "mutations", "detected", "in", "the", "entire", "coding", "sequence", "of", "MSX1", ".", "The", "C139T", "mutation", ",", "predicted", "to", "result", "in", "the", "substitution", "of", "an", "arginine", "by", "a", "tryptophan", "(", "R47W", ")", "in", "the", "N-terminal", "subdomain", ",", "affected", "conserved", "residues", "in", "the", "PAX9", "paired", "domain", ".", "To", "elucidate", "the", "pathogenic", "mechanism", "producing", "oligodontia", "phenotype", "caused", "by", "this", "mutation", ",", "we", "analyzed", "the", "binding", "of", "wild-type", "and", "mutant", "PAX9", "paired", "domain", "protein", "to", "double-stranded", "DNA", "targets", ".", "The", "R47W", "mutation", "dramatically", "reduced", "DNA", "binding", "suggesting", "that", "the", "mutant", "protein", "with", "consequent", "haploinsufficiency", "results", "in", "a", "clinical", "phenotype", "." ]

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20846357

A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome. BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. AIM: To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. RESULTS: The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). CONCLUSIONS: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.

[ "A", "novel", "mutation", "in", "the", "connexin", "26", "gene", "(", "GJB2", ")", "in", "a", "child", "with", "clinical", "and", "histological", "features", "of", "keratitis-ichthyosis-deafness", "(", "KID", ")", "syndrome", ".", "BACKGROUND", ":", "Keratitis-ichthyosis-deafness", "(", "KID", ")", "syndrome", "is", "a", "rare", "congenital", "ectodermal", "disorder", ",", "caused", "by", "heterozygous", "missense", "mutation", "in", "GJB2", ",", "encoding", "the", "gap", "junction", "protein", "connexin", "26", ".", "The", "commonest", "mutation", "is", "the", "p.Asp50Asn", "mutation", ",", "and", "only", "a", "few", "other", "mutations", "have", "been", "described", "to", "date", ".", "AIM", ":", "To", "report", "the", "fatal", "clinical", "course", "and", "characterize", "the", "genetic", "background", "of", "a", "premature", "male", "neonate", "with", "the", "clinical", "and", "histological", "features", "of", "KID", "syndrome", ".", "METHODS", ":", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "and", "used", "for", "PCR", "amplification", "of", "the", "GJB2", "gene", ".", "Direct", "sequencing", "was", "used", "for", "mutation", "analysis", ".", "RESULTS", ":", "The", "clinical", "features", "included", "hearing", "impairment", ",", "ichthyosiform", "erythroderma", "with", "hyperkeratotic", "plaques", ",", "palmoplantar", "keratoderma", ",", "alopecia", "of", "the", "scalp", "and", "eyelashes", ",", "and", "a", "thick", "vernix", "caseosa-like", "covering", "of", "the", "scalp", ".", "On", "histological", "analysis", ",", "features", "characteristic", "of", "KID", "syndrome", ",", "such", "as", "acanthosis", "and", "papillomatosis", "of", "the", "epidermis", "with", "basket-weave", "hyperkeratosis", ",", "were", "seen", ".", "The", "skin", "symptoms", "were", "treated", "successfully", "with", "acitretin", "0.5", "mg/kg", ".", "The", "boy", "developed", "intraventricular", "and", "intracerebral", "haemorrhage", ",", "leading", "to", "hydrocephalus", ".", "His", "condition", "was", "further", "complicated", "by", "septicaemia", "and", "meningitis", "caused", "by", "infection", "with", "extended-spectrum", "beta-lactamase-producing", "Klebsiella", "pneumoniae", ".", "Severe", "respiratory", "failure", "followed", ",", "and", "the", "child", "died", "at", "46", "weeks", "of", "gestational", "age", "(", "13", "weeks", "postnatally", ")", ".", "Sequencing", "of", "the", "GJB2", "gene", "showed", "that", "the", "child", "was", "heterozygous", "for", "a", "novel", "nucleotide", "change", ",", "c.263C", ">", "T", ",", "in", "exon", "2", ",", "leading", "to", "a", "substitution", "of", "alanine", "for", "valine", "at", "position", "88", "(", "p.Ala88Val", ")", ".", "CONCLUSIONS", ":", "This", "study", "has", "identified", "a", "new", "heterozygous", "de", "novo", "mutation", "in", "the", "Cx26", "gene", "(", "c.263C", ">", "T", ";", "p.Ala88Val", ")", "leading", "to", "KID", "syndrome", "." ]

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26115410

Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps. BACKGROUND: Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer. OBJECTIVES: This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure. DISCUSSION: Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects. CONCLUSIONS: Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes.

[ "Mechanisms", "Underlying", "Latent", "Disease", "Risk", "Associated", "with", "Early-Life", "Arsenic", "Exposure", ":", "Current", "Research", "Trends", "and", "Scientific", "Gaps", ".", "BACKGROUND", ":", "Millions", "of", "individuals", "worldwide", ",", "particularly", "those", "living", "in", "rural", "and", "developing", "areas", ",", "are", "exposed", "to", "harmful", "levels", "of", "inorganic", "arsenic", "(", "iAs", ")", "in", "their", "drinking", "water", ".", "Inorganic", "As", "exposure", "during", "key", "developmental", "periods", "is", "associated", "with", "a", "variety", "of", "adverse", "health", "effects", "including", "those", "that", "are", "evident", "in", "adulthood", ".", "There", "is", "considerable", "interest", "in", "identifying", "the", "molecular", "mechanisms", "that", "relate", "early-life", "iAs", "exposure", "to", "the", "development", "of", "these", "latent", "diseases", ",", "particularly", "in", "relationship", "to", "cancer", ".", "OBJECTIVES", ":", "This", "work", "summarizes", "research", "on", "the", "molecular", "mechanisms", "that", "underlie", "the", "increased", "risk", "of", "cancer", "development", "in", "adulthood", "that", "is", "associated", "with", "early-life", "iAs", "exposure", ".", "DISCUSSION", ":", "Epigenetic", "reprogramming", "that", "imparts", "functional", "changes", "in", "gene", "expression", ",", "the", "development", "of", "cancer", "stem", "cells", ",", "and", "immunomodulation", "are", "plausible", "underlying", "mechanisms", "by", "which", "early-life", "iAs", "exposure", "elicits", "latent", "carcinogenic", "effects", ".", "CONCLUSIONS", ":", "Evidence", "is", "mounting", "that", "relates", "early-life", "iAs", "exposure", "and", "cancer", "development", "later", "in", "life", ".", "Future", "research", "should", "include", "animal", "studies", "that", "address", "mechanistic", "hypotheses", "and", "studies", "of", "human", "populations", "that", "integrate", "early-life", "exposure", ",", "molecular", "alterations", ",", "and", "latent", "disease", "outcomes", "." ]

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15807692

Identification of novel type VII collagen gene mutations resulting in severe recessive dystrophic epidermolysis bullosa. In this work, we studied the proband in a small nuclear family of Chinese and Dutch/German descent and identified two novel mutations in the type VII collagen gene leading to recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens variant (HS-RDEB). The maternal mutation is a single base pair deletion of a cytosine nucleotide in exon 26, designated 3472delC, resulting in a frameshift and a premature termination codon (PTC) within the same exon, 7 bp downstream of the site of the mutation. The paternal mutation is a G-->A transition located at the 5' donor splice site within intron 51, designated IVS51 + 1G-->A. This mutation leads to the activation of a cryptic splice site, 32 bp downstream of the mutation site and to subsequent aberrant out-of-frame splicing, resulting in two alternative mRNA transcripts and a downstream PTC. To our knowledge, these two mutations have not been previously reported. These findings extend the body of evidence for compound heterozygous mutations leading to HS-RDEB and provide the basis for prenatal diagnosis in this family.

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16157158

A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study. Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.

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17192049

Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer. CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer.

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New_BioRED_Model

Dataset Card for "New_BioRED_Model"