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21799811
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12752111
[ "The", "beta-globin", "gene", "mutations", "and", "the", "alpha-globin", "genes", "of", "620", "patients", "with", "the", "phenotype", "of", "severe", "to", "moderate", "thalassaemia", "from", "seven", "centres", "in", "Sri", "Lanka", "were", "analysed.", "Twenty-four", "beta-globin", "gene", "mutations", "were", "identified,", "three", "accounting", "for", "84.5%", "of", "the", "1240", "alleles", "studied:", "IVSI-5", "(G-->C)", " ", "56.2%;", "IVSI-1", "(G-->A)", " ", "15.2%;", "and", "haemoglobin", "E", "(", "codon", "(CD)26", "GAG-->GAA", ")", "13.1%.", "Three", "new", "mutations", "were", "found;", "a", "13-bp", "deletion", "removing", "the", "last", "nucleotide", "in", "CD6", "to", "CD10", "inclusively,", "IVSI-129", "(A-->C)", " ", "in", "the", "consensus", "splice", "site,", "and", "a", "frame", "shift,", "CD55", "(-A).", "The", "allele", "frequency", "of", "alpha+", "thalassaemia", "was", "6.5%", "and", "1.1%", "for", "-alpha3.7", "and", "-alpha4.2", "deletions", "respectively.", "Non-deletion", "alpha-thalassaemia", "was", "not", "observed.", "Triplicate", "or", "quadruplicate", "alpha-globin", "genes", "were", "unusually", "common.", "In", "1.5%", "of", "cases", "it", "was", "impossible", "to", "identify", "beta-thalassaemia", "alleles,", "but", "in", "Kurunegala", "detailed", "family", "studies", "led", "to", "an", "explanation", "for", "the", "severe", "thalassaemia", "phenotype", "in", "every", "case,", "including", "a", "previously", "unreported", "instance", "of", "homozygosity", "for", "a", "quadruplicated", "alpha-globin", "gene", "together", "with", "beta-thalassaemia", "trait.", "These", "findings", "have", "implications", "for", "the", "control", "of", "thalassaemia", "in", "high-frequency", "populations", "with", "complex", "ethnic", "histories." ]
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The beta-globin gene mutations and the alpha-globin genes of 620 patients with the phenotype of severe to moderate thalassaemia from seven centres in Sri Lanka were analysed. Twenty-four beta-globin gene mutations were identified, three accounting for 84.5% of the 1240 alleles studied: IVSI-5 (G-->C) 56.2%; IVSI-1 (G-->A) 15.2%; and haemoglobin E ( codon (CD)26 GAG-->GAA ) 13.1%. Three new mutations were found; a 13-bp deletion removing the last nucleotide in CD6 to CD10 inclusively, IVSI-129 (A-->C) in the consensus splice site, and a frame shift, CD55 (-A). The allele frequency of alpha+ thalassaemia was 6.5% and 1.1% for -alpha3.7 and -alpha4.2 deletions respectively. Non-deletion alpha-thalassaemia was not observed. Triplicate or quadruplicate alpha-globin genes were unusually common. In 1.5% of cases it was impossible to identify beta-thalassaemia alleles, but in Kurunegala detailed family studies led to an explanation for the severe thalassaemia phenotype in every case, including a previously unreported instance of homozygosity for a quadruplicated alpha-globin gene together with beta-thalassaemia trait. These findings have implications for the control of thalassaemia in high-frequency populations with complex ethnic histories.
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20086182
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21340161
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The aim of this study was to identify the genetic defect of a patient with dyshormonogenetic congenital hypothyroidisms (CH) with total iodide organification defect (TIOD). A male child diagnosed with CH during neonatal screening. Laboratory tests confirmed the permanent and severe CH with TIOD (99% perchlorate release). The coding sequence of TPO, DUOX2, and DUOXA2 genes and 2957 base pairs (bp) of the TPO promoter were sequenced. Molecular analysis of patient's DNA identified the heterozygous duplication GGCC ( c.1186_1187insGGCC ) in exon 8 of the TPO gene. No additional mutation was detected either in the TPO gene, TPO promoter, DUOX2 or DUOXA2 genes. We have described a patient with a clear TIOD causing severe goitrous CH due to a monoallelic TPO mutation. A plausible explanation for the association between an autosomal recessive disorder with a single TPO-mutated allele is the presence of monoallelic TPO expression.
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14576201
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21879313
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Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C.
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15607529
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19645056
[ "BACKGROUND:", "Children", "with", "22q11.2", "deletion", "syndrome", "(22q11.2DS)", "have", "a", "wide", "range", "of", "clinical", "features.", "TBX1", "has", "been", "proposed", "as", "a", "candidate", "gene", "for", "some", "of", "the", "features", "in", "this", "condition.", "Polymorphisms", "in", "the", "nondeleted", "TBX1,", "which", "may", "affect", "the", "function", "of", "the", "sole", "TBX1", "gene", "in", "individuals", "with", "the", "22q11.2DS,", "may", "be", "a", "key", "to", "understanding", "the", "phenotypic", "variability", "among", "individuals", "with", "a", "shared", "deletion.", "Comprehensive", "single", "nucleotide", "polymorphism", "(SNP)", "discovery", "by", "resequencing", "candidate", "genes", "can", "identify", "genetic", "variants", "that", "influence", "a", "given", "phenotype.", "The", "purpose", "of", "this", "study", "was", "to", "further", "characterize", "the", "sequence", "variability", "in", "TBX1", "by", "identifying", "all", "common", "SNPs", "in", "this", "gene.", "METHODS:", "We", "resequenced", "TBX1", "in", "29", "children", "with", "a", "documented", "22q11.2", "deletion", "and", "95", "nondeleted,", "healthy", "individuals.", "We", "estimated", "allele", "frequencies,", "performed", "tagSNP", "selection,", "and", "inferred", "haplotypes.", "We", "also", "compared", "SNP", "frequencies", "between", "22q11.2DS", "and", "control", "samples.", "RESULTS:", "We", "identified", "355", "biallelic", "markers", "among", "the", "190", "chromosomes", "resequenced", "in", "the", "control", "panel.", "The", "vast", "majority", "of", "the", "markers", "identified", "were", "SNPs", "(n", "=", "331),", "and", "the", "remainder", "indels", "(n", "=", "24).", "We", "did", "not", "identify", "SNPs", "or", "indels", "in", "the", "cis-", "regulatory", "element", "(FOX-binding", "site)", "upstream", "of", "TBX1.", "In", "children", "with", "22q11.2DS", "we", "detected", "187", "biallelic", "markers,", "six", "of", "which", "were", "indels.", "Four", "of", "the", "seven", "coding", "SNPs", "identified", "in", "the", "controls", "were", "identified", "in", "children", "with", "22q11.2DS.", "CONCLUSIONS:", "This", "comprehensive", "SNP", "discovery", "data", "can", "be", "used", "to", "select", "SNPs", "to", "genotype", "for", "future", "association", "studies", "assessing", "the", "role", "of", "TBX1", "and", "phenotypic", "variability", "in", "individuals", "with", "22q11.2DS." ]
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BACKGROUND: Children with 22q11.2 deletion syndrome (22q11.2DS) have a wide range of clinical features. TBX1 has been proposed as a candidate gene for some of the features in this condition. Polymorphisms in the nondeleted TBX1, which may affect the function of the sole TBX1 gene in individuals with the 22q11.2DS, may be a key to understanding the phenotypic variability among individuals with a shared deletion. Comprehensive single nucleotide polymorphism (SNP) discovery by resequencing candidate genes can identify genetic variants that influence a given phenotype. The purpose of this study was to further characterize the sequence variability in TBX1 by identifying all common SNPs in this gene. METHODS: We resequenced TBX1 in 29 children with a documented 22q11.2 deletion and 95 nondeleted, healthy individuals. We estimated allele frequencies, performed tagSNP selection, and inferred haplotypes. We also compared SNP frequencies between 22q11.2DS and control samples. RESULTS: We identified 355 biallelic markers among the 190 chromosomes resequenced in the control panel. The vast majority of the markers identified were SNPs (n = 331), and the remainder indels (n = 24). We did not identify SNPs or indels in the cis- regulatory element (FOX-binding site) upstream of TBX1. In children with 22q11.2DS we detected 187 biallelic markers, six of which were indels. Four of the seven coding SNPs identified in the controls were identified in children with 22q11.2DS. CONCLUSIONS: This comprehensive SNP discovery data can be used to select SNPs to genotype for future association studies assessing the role of TBX1 and phenotypic variability in individuals with 22q11.2DS.
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19129715
[ "Three", "novel", "IGFALS", "gene", "mutations", "resulting", "in", "total", "ALS", "and", "severe", "circulating", "IGF-I/IGFBP-3", "deficiency", "in", "children", "of", "different", "ethnic", "origins." ]
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Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins.
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18050247
[ "OBJECTIVE:", "Childhood-onset", "systemic", "lupus", "erythematosus", "(SLE)", "presents", "a", "unique", "subgroup", "of", "patients", "for", "genetic", "study.", "The", "present", "study", "was", "undertaken", "to", "identify", "susceptibility", "genes", "contributing", "to", "SLE,", "using", "a", "novel", "candidate", "gene", "pathway", "microarray", "platform", "to", "investigate", "gene", "expression", "in", "patients", "with", "childhood-onset", "SLE", "and", "both", "of", "their", "parents.", "METHODS:", "Utilizing", "bioinformatic", "tools,", "a", "platform", "of", "9,412", "single-nucleotide", "polymorphisms", "(SNPs)", "from", "1,204", "genes", "was", "designed", "and", "validated.", "Molecular", "inversion", "probes", "and", "high-throughput", "SNP", "technologies", "were", "used", "for", "assay", "development.", "Seven", "hundred", "fifty", "three", "subjects,", "corresponding", "to", "251", "full", "trios", "of", "childhood-onset", "SLE", "families,", "were", "genotyped", "and", "analyzed", "using", "transmission", "disequilibrium", "testing", "(TDT)", "and", "multitest", "corrections.", "RESULTS:", "Family-based", "TDT", "showed", "a", "significant", "association", "of", "SLE", "with", "a", "N673S", " ", "polymorphism", "in", "the", "P-selectin", "gene", "(SELP)", "(P", "=", "5.74", "x", "10(-6))", "and", "a", "C203S", " ", "polymorphism", "in", "the", "interleukin-1", "receptor-associated", "kinase", "1", "gene", "(IRAK1)", "(P", "=", "9.58", "x", "10(-6)).", "These", "2", "SNPs", "had", "a", "false", "discovery", "rate", "for", "multitest", "correction", "of", "<0.05,", "and", "therefore", "a", ">95%", "probability", "of", "being", "considered", "as", "proven.", "Furthermore,", "7", "additional", "SNPs", "showed", "q", "values", "of", "<0.5,", "suggesting", "association", "with", "SLE", "and", "providing", "a", "direction", "for", "followup", "studies.", "These", "additional", "genes", "notably", "included", "TNFRSF6", "(Fas)", "and", "IRF5,", "supporting", "previous", "findings", "of", "their", "association", "with", "SLE", "pathogenesis.", "CONCLUSION:", "SELP", "and", "IRAK1", "were", "identified", "as", "novel", "SLE-associated", "genes", "with", "a", "high", "degree", "of", "significance,", "suggesting", "new", "directions", "in", "understanding", "the", "pathogenesis", "of", "SLE.", "The", "overall", "design", "and", "results", "of", "this", "study", "demonstrate", "that", "the", "candidate", "gene", "pathway", "microarray", "platform", "used", "provides", "a", "novel", "and", "powerful", "approach", "that", "is", "generally", "applicable", "in", "identifying", "genetic", "foundations", "of", "complex", "diseases." ]
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OBJECTIVE: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. METHODS: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. RESULTS: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. CONCLUSION: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.
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[ "NRAMP1", "genetic", "polymorphisms", "as", "a", "risk", "factor", "of", "tuberculous", "pleurisy." ]
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NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy.
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20523265
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Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population.
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21163864
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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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16152606
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Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies.
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22295085
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BACKGROUND: Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior. METHODOLOGY/PRINCIPAL FINDINGS: NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study. CONCLUSIONS/SIGNIFICANCE: The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth.
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19804530
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Reducing amplicon sizes has become a major strategy for analyzing degraded DNA typical of forensic samples. However, amplicon sizes in current mini-short tandem repeat-polymerase chain reaction (PCR) and mini-sequencing assays are still not suitable for analysis of severely degraded DNA. In this study, we present a multiplex typing method that couples ligase detection reaction with PCR that can be used to identify single nucleotide polymorphisms and small-scale insertion/deletions in a sample of severely fragmented DNA. This method adopts thermostable ligation for allele discrimination and subsequent PCR for signal enhancement. In this study, four polymorphic loci were used to assess the ability of this technique to discriminate alleles in an artificially degraded sample of DNA with fragment sizes <100 bp. Our results showed clear allelic discrimination of single or multiple loci, suggesting that this method might aid in the analysis of extremely degraded samples in which allelic drop out of larger fragments is observed.
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19309272
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A simple multiplex real-time PCR methodology for the SMN1 gene copy number quantification.
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21799811
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Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis.
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18050247
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Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform.
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12631337
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22016685
[ "Factor", "XI", "(FXI)", "deficiency", "is", "a", "rare", "autosomal", "recessive", "coagulation", "disorder", "most", "commonly", "found", "in", "Ashkenazi", "and", "Iraqi", "Jews,", "but", "it", "is", "also", "found", "in", "other", "ethnic", "groups.", "It", "is", "a", "trauma", "or", "surgery-related", "bleeding", "disorder,", "but", "spontaneous", "bleeding", "is", "rarely", "seen.", "The", "clinical", "manifestation", "of", "bleeding", "in", "FXI", "deficiency", "cases", "is", "variable", "and", "seems", "to", "poorly", "correlate", "with", "plasma", "FXI", "levels.", "The", "molecular", "pathology", "of", "FXI", "deficiency", "is", "mutation", "in", "the", "F11", "gene", "on", "the", "chromosome", "band", "4q35.", "We", "report", "a", "novel", "mutation", "of", "the", "F11", "gene", "in", "an", "18-year-old", "asymptomatic", "Korean", "woman", "with", "mild", "FXI", "deficiency.", "Pre-operative", "laboratory", "screen", "tests", "for", "lipoma", "on", "her", "back", "revealed", "slightly", "prolonged", "activated", "partial", "thromboplastin", "time", "(45.2", "sec;", "reference", "range,", "23.2-39.4", "sec).", "Her", "FXI", "activity", "(35%)", "was", "slightly", "lower", "than", "the", "normal", "FXI", "activity", "(reference", "range,", "50-150%).", "Direct", "sequence", "analysis", "of", "the", "F11", "gene", "revealed", "a", "heterozygous", "A", "to", "G", "substitution", "in", "nucleotide", "1517", "(", "c.1517A>G", ")", "of", "exon", "13,", "resulting", "in", "the", "substitution", "of", "aspartic", "acid", "with", "glycine", "in", "codon", "506", "(", "p.Asp506Gly", ").", "To", "the", "best", "of", "our", "knowledge,", "the", "Asp506Gly", " ", "is", "a", "novel", "missense", "mutation,", "and", "this", "is", "the", "first", "genetically", "confirmed", "case", "of", "mild", "FXI", "deficiency", "in", "Korea." ]
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Factor XI (FXI) deficiency is a rare autosomal recessive coagulation disorder most commonly found in Ashkenazi and Iraqi Jews, but it is also found in other ethnic groups. It is a trauma or surgery-related bleeding disorder, but spontaneous bleeding is rarely seen. The clinical manifestation of bleeding in FXI deficiency cases is variable and seems to poorly correlate with plasma FXI levels. The molecular pathology of FXI deficiency is mutation in the F11 gene on the chromosome band 4q35. We report a novel mutation of the F11 gene in an 18-year-old asymptomatic Korean woman with mild FXI deficiency. Pre-operative laboratory screen tests for lipoma on her back revealed slightly prolonged activated partial thromboplastin time (45.2 sec; reference range, 23.2-39.4 sec). Her FXI activity (35%) was slightly lower than the normal FXI activity (reference range, 50-150%). Direct sequence analysis of the F11 gene revealed a heterozygous A to G substitution in nucleotide 1517 ( c.1517A>G ) of exon 13, resulting in the substitution of aspartic acid with glycine in codon 506 ( p.Asp506Gly ). To the best of our knowledge, the Asp506Gly is a novel missense mutation, and this is the first genetically confirmed case of mild FXI deficiency in Korea.
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21790735
[ "A", "large", "heterozygous", "deletion", "including", "the", "entire", "C1", "inhibitor", "gene", "in", "a", "sporadic", "case", "of", "hereditary", "angio-oedema." ]
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A large heterozygous deletion including the entire C1 inhibitor gene in a sporadic case of hereditary angio-oedema.
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19664890
[ "BACKGROUND:", "The", "majority", "of", "spinal", "muscular", "atrophy", "(SMA)", "patients", "showed", "homozygous", "deletion", "or", "other", "mutations", "of", "SMN1.", "However,", "the", "genetic", "etiology", "of", "a", "significant", "number", "of", "SMA", "patients", "has", "not", "been", "clarified.", "Recently,", "mutation", "in", "the", "gene", "underlying", "cat", "SMA,", "limb", "expression", "1", "(LIX1),", "has", "been", "reported.", "Similarity", "in", "clinical", "and", "pathological", "features", "of", "cat", "and", "human", "SMA", "may", "give", "an", "insight", "into", "possible", "similarity", "of", "the", "genetic", "etiology.", "PATIENTS", "AND", "METHODS:", "In", "this", "study,", "we", "screened", "for", "a", "mutation", "in", "LIX1", "using", "direct", "DNA", "sequencing", "in", "our", "SMA", "and/or", "SMA-like", "patients", "who", "retained", "SMN1.", "A", "total", "of", "33", "patients", "were", "enrolled", "in", "this", "study,", "of", "which", "22", "were", "Japanese", "and", "11", "were", "Malaysians.", "All", "these", "patients", "possessed", "at", "least", "two", "copies", "of", "SMN1.", "RESULTS:", "We", "did", "not", "identify", "any", "pathogenic", "mutations", "in", "the", "coding", "regions", "or", "splice", "sites", "of", "LIX1", "in", "the", "patients.", "In", "addition,", "we", "described", "a", "polymorphism", "within", "LIX1", "intron", "3,", "c.387+107A>T", ".", "We", "found", "that", "A-allele", "is", "significantly", "more", "frequent", "in", "SMA", "patients", "compared", "to", "normal", "individuals.", "CONCLUSION:", "Molecular", "genetic", "analysis", "of", "our", "SMA", "and/or", "SMA-like", "patients", "suggests", "that", "LIX1", "is", "not", "associated", "with", "the", "development", "of", "their", "disorders.", "However,", "the", "number", "of", "patients", "analyzed", "in", "this", "study", "was", "very", "limited,", "and", "a", "larger", "study", "with", "bigger", "sample", "size", "is", "needed", "to", "confirm", "this", "result." ]
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BACKGROUND: The majority of spinal muscular atrophy (SMA) patients showed homozygous deletion or other mutations of SMN1. However, the genetic etiology of a significant number of SMA patients has not been clarified. Recently, mutation in the gene underlying cat SMA, limb expression 1 (LIX1), has been reported. Similarity in clinical and pathological features of cat and human SMA may give an insight into possible similarity of the genetic etiology. PATIENTS AND METHODS: In this study, we screened for a mutation in LIX1 using direct DNA sequencing in our SMA and/or SMA-like patients who retained SMN1. A total of 33 patients were enrolled in this study, of which 22 were Japanese and 11 were Malaysians. All these patients possessed at least two copies of SMN1. RESULTS: We did not identify any pathogenic mutations in the coding regions or splice sites of LIX1 in the patients. In addition, we described a polymorphism within LIX1 intron 3, c.387+107A>T . We found that A-allele is significantly more frequent in SMA patients compared to normal individuals. CONCLUSION: Molecular genetic analysis of our SMA and/or SMA-like patients suggests that LIX1 is not associated with the development of their disorders. However, the number of patients analyzed in this study was very limited, and a larger study with bigger sample size is needed to confirm this result.
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22042570
[ "PURPOSE:", "To", "report", "three", "types", "of", "heterozygous", "mutations", "in", "the", "OPA1", "gene", "in", "five", "patients", "from", "three", "families", "with", "autosomal", "dominant", "optic", "atrophy", "(ADOA,", "MIM#165500).", "METHODS:", "DNA", "was", "extracted", "from", "the", "leukocytes", "of", "the", "peripheral", "blood.", "For", "mtDNA,", "mutations", "were", "examined", "at", "positions", "11778,", "3460", "and", "14484.", "For", "the", "OPA1", "gene,", "the", "exons", "were", "amplified", "by", "PCR", "and", "mutations", "were", "detected", "by", "restriction", "enzymes", "or", "the", "dye", "terminator", "method.", "RESULTS:", "We", "detected", "three", "types", "of", "OPA1", "mutation", "but", "no", "mtDNA", "mutations.", "In", "the", "OPA1", "gene,", "heterozygous", "frameshift", "mutations", "from", "codon", "903", "due", "to", "a", "four-base", "pair", "deletion", "in", "exon", "27", "were", "detected", "in", "three", "patients", "from", "one", "family", "(", "c.2708_2711delTTAG", ",", "p.V903GfsX905", ").", "A", "heterozygous", "mutation", "due", "to", "a", "three-base", "pair", "deletion", "in", "exon", "17,", "leading", "to", "a", "one-amino", "acid", "deletion", "(", "c.1618_1620delACT", ",", "p.T540del", "),", "and", "a", "heterozygous", "mutation", "due", "to", "a", "one-base", "substitution", "in", "exon", "11,", "leading", "to", "a", "stop", "codon", "(", "c.1084G>T", ",", "p.E362X", "),", "were", "detected", "in", "sporadic", "cases.", "CONCLUSION:", "OPA1", "mutations", "existed", "in", "three", "Japanese", "families", "with", "ADOA.", "After", "a", "detailed", "clinical", "assessment", "of", "the", "proband,", "the", "screening", "of", "the", "OPA1", "gene", "may", "be", "helpful", "for", "precise", "diagnosis", "of", "ADOA,", "provided", "the", "relevant", "information", "of", "the", "family", "members", "is", "limited." ]
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PURPOSE: To report three types of heterozygous mutations in the OPA1 gene in five patients from three families with autosomal dominant optic atrophy (ADOA, MIM#165500). METHODS: DNA was extracted from the leukocytes of the peripheral blood. For mtDNA, mutations were examined at positions 11778, 3460 and 14484. For the OPA1 gene, the exons were amplified by PCR and mutations were detected by restriction enzymes or the dye terminator method. RESULTS: We detected three types of OPA1 mutation but no mtDNA mutations. In the OPA1 gene, heterozygous frameshift mutations from codon 903 due to a four-base pair deletion in exon 27 were detected in three patients from one family ( c.2708_2711delTTAG , p.V903GfsX905 ). A heterozygous mutation due to a three-base pair deletion in exon 17, leading to a one-amino acid deletion ( c.1618_1620delACT , p.T540del ), and a heterozygous mutation due to a one-base substitution in exon 11, leading to a stop codon ( c.1084G>T , p.E362X ), were detected in sporadic cases. CONCLUSION: OPA1 mutations existed in three Japanese families with ADOA. After a detailed clinical assessment of the proband, the screening of the OPA1 gene may be helpful for precise diagnosis of ADOA, provided the relevant information of the family members is limited.
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19394258
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17050029
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16843501
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20728296
[ "A", "patient", "with", "a", "large", "deletion", "of", "the", "distal", "part", "of", "the", "long", "arm", "of", "chromosome", "13", "showed", "severe", "psychomotor", "retardation,", "a", "characteristic", "face,", "nystagmus,", "retinopathy,", "cystic", "kidney", "disease,", "and", "brain", "malformation", "with", "molar", "tooth", "sign", "and", "cerebellar", "vermis", "hypoplasia,", "a", "phenotype", "typical", "of", "Arima", "syndrome.", "This", "patient", "also", "had", "bilateral", "retinoblastoma.", "Fluorescent", "in", "situ", "hybridization", "and", "single-nucleotide-polymorphism", "genotyping", "microarray", "demonstrated", "an", "interstitial", "deletion", "of", "54", "Mbp,", "ranging", "from", "13q14.13", "to", "13q32.3", "and", "involving", "the", "RB1", "gene.", "This", "patient", "is", "the", "first", "case", "of", "Arima", "syndrome,", "or", "a", "Joubert", "syndrome-related", "disorder,", "that", "showed", "linkage", "to", "chromosome", "13q." ]
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A patient with a large deletion of the distal part of the long arm of chromosome 13 showed severe psychomotor retardation, a characteristic face, nystagmus, retinopathy, cystic kidney disease, and brain malformation with molar tooth sign and cerebellar vermis hypoplasia, a phenotype typical of Arima syndrome. This patient also had bilateral retinoblastoma. Fluorescent in situ hybridization and single-nucleotide-polymorphism genotyping microarray demonstrated an interstitial deletion of 54 Mbp, ranging from 13q14.13 to 13q32.3 and involving the RB1 gene. This patient is the first case of Arima syndrome, or a Joubert syndrome-related disorder, that showed linkage to chromosome 13q.
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16911351
[ "OBJECTIVES:", "Dystonia", "is", "a", "common", "movement", "disorder.", "The", "purpose", "of", "this", "study", "is", "to", "examine", "the", "relative", "distribution", "of", "the", "primary", "dystonia", "subtypes", "and", "identify", "mutation", "(s)", "in", "the", "DYT1", "gene", "in", "Indian", "patients.", "MATERIALS", "AND", "METHODS:", "Primary", "dystonia", "patients", "(n", "=", "178)", "and", "controls", "(n", "=", "63),", "lacking", "any", "symptoms", "of", "the", "disease,", "were", "recruited", "for", "the", "study", "from", "eastern", "India.", "The", "nucleotide", "variants", "in", "the", "DYT1", "gene", "were", "identified", "by", "carrying", "out", "polymerase", "chain", "reaction,", "single", "stranded", "conformation", "polymorphism,", "and", "DNA", "sequencing.", "RESULTS:", "Unlike", "other", "reports,", "pain", "and/or", "tremor", "was", "more", "common", "in", "our", "sporadic", "patients", "than", "in", "familial", "cases.", "Three", "reported", "and", "two", "novel", "changes", "were", "identified", "in", "this", "gene.", "The", "homozygous", "genotype", "(G,G)", "for", "a", "missense", "variant", "(", "c.646G", ">", "C", ";", "Asp216His", ")", "was", "significantly", "over-represented", "in", "the", "patients", "compared", "with", "controls", "(P", "<", "0.05).", "However,", "the", "commonly", "reported", "3", "bp", "deletion", "(", "904-906delGAG", ")", "was", "not", "detected.", "CONCLUSION:", "Our", "results", "suggest", "that", "the", "DYT1", "gene", "might", "have", "a", "limited", "role", "in", "causation", "of", "dystonia", "in", "the", "Indian", "population." ]
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OBJECTIVES: Dystonia is a common movement disorder. The purpose of this study is to examine the relative distribution of the primary dystonia subtypes and identify mutation (s) in the DYT1 gene in Indian patients. MATERIALS AND METHODS: Primary dystonia patients (n = 178) and controls (n = 63), lacking any symptoms of the disease, were recruited for the study from eastern India. The nucleotide variants in the DYT1 gene were identified by carrying out polymerase chain reaction, single stranded conformation polymorphism, and DNA sequencing. RESULTS: Unlike other reports, pain and/or tremor was more common in our sporadic patients than in familial cases. Three reported and two novel changes were identified in this gene. The homozygous genotype (G,G) for a missense variant ( c.646G > C ; Asp216His ) was significantly over-represented in the patients compared with controls (P < 0.05). However, the commonly reported 3 bp deletion ( 904-906delGAG ) was not detected. CONCLUSION: Our results suggest that the DYT1 gene might have a limited role in causation of dystonia in the Indian population.
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Recently, molecular testing for GJB2 mutations has become the standard of care for the diagnosis of patients with non syndromic hearing impairment of unknown cause. The aims of this study are to determine the association between GJB2 mutation and GJB6 and to report the variation of mutations in deaf students who have heterozygous GJB2. This retrospective study was conducted at Universiti Kebangsaan Malaysia Medical Center (UKMMC). Data was collected from previous files and records from Tissue Engineering and Human Genetic Research Group Laboratory. Approval from Ethical Committee was obtained prior to the study. A total of 138 students have been screened in previous studies in UKMMC for the presence of GJB2 mutations as a cause for hearing loss. Thirty four of the 138 subjects have GJB2 mutations; 2 showed homozygous mutations whereas another 32 were heterozygous for GJB2 gene mutation. Only 31 DNA samples of students presented with sensorineural hearing loss with heterozygous mutation in GJB2 gene were included in this study. The sequencing results obtained were analyzed. The degree of hearing loss of those students with association between GJB2 mutation and GJB6 mutation will be discussed. Five out of 31 subjects (16.2%) have mutations in their GJB6 gene, suggesting a digenic inheritance of GJB2/GJB6 mutation. In total, four novel mutations were identified; E137D (n=1), R32Q (n=1), E101K (n=1) and Y156H (n=1) and one mutation deletion; 366delT (n=1). All students with association GJB2 mutation and GJB6 showed severe to profound hearing loss in both ears. Interestingly this study not detected the large deletion of 342 kb in GJB6 gene suggesting that the mutation is very rare in this region compared to certain parts of the world.
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12701064
[ "Mutations", "in", "the", "CYP17", "gene", "impair", "steroid", "biosynthesis", "in", "the", "adrenals", "and", "gonads", "and", "often", "cause", "17alpha-hydroxylase/17,20-lyase", "deficiency,", "leading", "to", "amenorrhea,", "sexual", "infantilism,", "and", "hypokalemic", "low", "aldosterone", "hypertension.", "Several", "CYP17", "mutations", "resulting", "in", "17alpha-hydroxylase/17,20-lyase", "deficiency", "have", "been", "reported", "previously.", "In", "the", "present", "study,", "we", "found", "a", "novel", "CYP17", "mutation", "from", "the", "molecular", "analysis", "of", "a", "Korean", "patient", "with", "primary", "amenorrhea", "with", "a", "46,XX", "karyotype,", "and", "hypokalemic", "hypertension.", "We", "sequenced", "all", "8", "exons", "of", "the", "CYP17", "gene", "that", "were", "amplified", "from", "patient's", "genomic", "DNA", "using", "polymerase", "chain", "reaction", "(PCR)", "and", "found", "a", "compound", "heterozygous", "mutation", "in", "the", "CYP17", "structural", "gene;", "a", "1-base", "deletion", "and", "a", "1-base", "transversion", "(TAC-->AA)", "at", "codon", "329", ",", "leading", "to", "the", "production", "of", "a", "truncated", "protein", "(1-417", "amino", "acids),", "and", "a", "3-base", "deletion", "(TCC,", "either", "350-351", "or", "351-352", "codon)", "in", "the", "other", "allele.", "Restriction", "enzyme", "digestion", "analysis", "of", "patient's", "and", "parental", "DNA", "showed", "that", "the", "1-base", "deletion", "and", "the", "3-base", "deletion", "are", "inherited", "from", "mother", "and", "father,", "respectively.", "Here", "we", "conclude", "that", "these", "novel", "compound", "heterozygous", "mutations", "might", "account", "for", "the", "patient's", "clinical", "manifestations", "of", "17alpha-hydroxylase/17,20-lyase", "deficiency." ]
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Mutations in the CYP17 gene impair steroid biosynthesis in the adrenals and gonads and often cause 17alpha-hydroxylase/17,20-lyase deficiency, leading to amenorrhea, sexual infantilism, and hypokalemic low aldosterone hypertension. Several CYP17 mutations resulting in 17alpha-hydroxylase/17,20-lyase deficiency have been reported previously. In the present study, we found a novel CYP17 mutation from the molecular analysis of a Korean patient with primary amenorrhea with a 46,XX karyotype, and hypokalemic hypertension. We sequenced all 8 exons of the CYP17 gene that were amplified from patient's genomic DNA using polymerase chain reaction (PCR) and found a compound heterozygous mutation in the CYP17 structural gene; a 1-base deletion and a 1-base transversion (TAC-->AA) at codon 329 , leading to the production of a truncated protein (1-417 amino acids), and a 3-base deletion (TCC, either 350-351 or 351-352 codon) in the other allele. Restriction enzyme digestion analysis of patient's and parental DNA showed that the 1-base deletion and the 3-base deletion are inherited from mother and father, respectively. Here we conclude that these novel compound heterozygous mutations might account for the patient's clinical manifestations of 17alpha-hydroxylase/17,20-lyase deficiency.
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18385794
[ "Identification", "of", "novel", "mutations", "and", "sequence", "variants", "in", "the", "SOX2", "and", "CHX10", "genes", "in", "patients", "with", "anophthalmia/microphthalmia." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia.
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16321363
[ "Congenital", "disorder", "of", "glycosylation", "Ic", "due", "to", "a", "de", "novo", "deletion", "and", "an", "hALG-6", "mutation." ]
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Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation.
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22125978
[ "Identification", "of", "LIPH", "gene", "mutation", "in", "a", "consanguineous", "family", "segregating", "the", "woolly", "hair/hypotrichosis", "phenotype." ]
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Identification of LIPH gene mutation in a consanguineous family segregating the woolly hair/hypotrichosis phenotype.
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19592582
[]
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14673473
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19958188
[]
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17185385
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17356395
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15135245
[ "ApolipoproteinB", "100", "(apoB-100)", "is", "an", "important", "component", "of", "atherogenic", "lipoproteins", "such", "as", "LDL", "and", "serves", "as", "a", "ligand", "for", "the", "LDL-receptor.", "Familial", "defective", "apolipoproteinB", "100", "(FDB)", "is", "caused", "by", "a", "R3500Q", " ", "mutation", "of", "the", "apoB", "gene", "and", "results", "in", "decreased", "binding", "of", "LDL", "to", "the", "LDL-receptor.", "So", "far", "FDB", "is", "the", "most", "frequent", "and", "best", "studied", "alteration", "of", "apoB-100.", "Apart", "from", "this,", "three", "other", "apoB", "mutations,", "R3500W", ",", "R3531C", " ", "and", "R3480W", ",", "affecting", "binding", "to", "the", "LDL-receptor", "are", "known", "to", "date.", "We", "screened", "the", "apoB", "gene", "segment", "of", "codons", "3448-3561", "by", "denaturing", "gradient", "gel", "electrophoresis", "(DGGE)", "analysis", "in", "a", "total", "of", "853", "consecutively", "sampled", "German", "patients", "undergoing", "diagnostic", "coronary", "angiography", "for", "suspected", "CAD.", "By", "this,", "a", "new", "single", "base", "mutation", "was", "detected", "and", "confirmed", "by", "DNA", "sequencing.", "The", "mutation,", "CAC(3543)TAC", " ", "results", "in", "a", "His3543Tyr", " ", "substitution", "in", "apoB-100", "(", "H3543Y", ").", "The", "prevalence", "of", "heterozygotes", "for", "H3543Y", " ", "in", "the", "study", "population", "was", "0.47%", "compared", "to", "0.12%", "for", "the", "known", "Arg", "3500", "Gln", " ", "(", "R3500Q", ")", "mutation.", "In", "conclusion,", "the", "new", "mutation", "is", "four", "times", "more", "frequent", "than", "\"classical\"", "FDB", "and", "thus", "appears", "to", "be", "the", "most", "common", "apoB", "mutation", "in", "Germany." ]
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ApolipoproteinB 100 (apoB-100) is an important component of atherogenic lipoproteins such as LDL and serves as a ligand for the LDL-receptor. Familial defective apolipoproteinB 100 (FDB) is caused by a R3500Q mutation of the apoB gene and results in decreased binding of LDL to the LDL-receptor. So far FDB is the most frequent and best studied alteration of apoB-100. Apart from this, three other apoB mutations, R3500W , R3531C and R3480W , affecting binding to the LDL-receptor are known to date. We screened the apoB gene segment of codons 3448-3561 by denaturing gradient gel electrophoresis (DGGE) analysis in a total of 853 consecutively sampled German patients undergoing diagnostic coronary angiography for suspected CAD. By this, a new single base mutation was detected and confirmed by DNA sequencing. The mutation, CAC(3543)TAC results in a His3543Tyr substitution in apoB-100 ( H3543Y ). The prevalence of heterozygotes for H3543Y in the study population was 0.47% compared to 0.12% for the known Arg 3500 Gln ( R3500Q ) mutation. In conclusion, the new mutation is four times more frequent than "classical" FDB and thus appears to be the most common apoB mutation in Germany.
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Molecular diagnosis of 46,XY DSD and identification of a novel 8 nucleotide deletion in exon 1 of the SRD5A2 gene.
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12832681
[ "Epidemiology", "of", "tuberculosis", "on", "Gran", "Canaria:", "a", "4", "year", "population", "study", "using", "traditional", "and", "molecular", "approaches." ]
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Epidemiology of tuberculosis on Gran Canaria: a 4 year population study using traditional and molecular approaches.
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19218574
[ "Phosphatidylinositol", "3-kinase", "p85alpha", "regulatory", "subunit", "gene", "Met326Ile", " ", "polymorphism", "in", "women", "with", "polycystic", "ovary", "syndrome." ]
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Phosphatidylinositol 3-kinase p85alpha regulatory subunit gene Met326Ile polymorphism in women with polycystic ovary syndrome.
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16840830
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21976953
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Identification of a novel FBN1 gene mutation in a Chinese family with Marfan syndrome.
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17250667
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21533187
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Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
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14979495
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17426470
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21943124
[ "A", "deletion", "of", "FGFR2", "creating", "a", "chimeric", "IIIb/IIIc", "exon", "in", "a", "child", "with", "Apert", "syndrome." ]
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A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome.
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15200408
[ "Lack", "of", "major", "involvement", "of", "human", "uroplakin", "genes", "in", "vesicoureteral", "reflux:", "implications", "for", "disease", "heterogeneity." ]
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Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity.
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22106692
[]
[]
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16601880
[ "Genetic", "heterogeneity", "of", "the", "GLDC", "gene", "in", "28", "unrelated", "patients", "with", "glycine", "encephalopathy." ]
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Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy.
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19918264
[ "FGFR4", "Gly388Arg", " ", "polymorphism", "and", "prostate", "cancer", "risk", "in", "Scottish", "men." ]
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FGFR4 Gly388Arg polymorphism and prostate cancer risk in Scottish men.
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20005218
[]
[]
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18457324
[ "Genetic", "polymorphisms", "in", "the", "carbonyl", "reductase", "3", "gene", "CBR3", "and", "the", "NAD(P)H:quinone", "oxidoreductase", "1", "gene", "NQO1", "in", "patients", "who", "developed", "anthracycline-related", "congestive", "heart", "failure", "after", "childhood", "cancer." ]
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Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer.
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17221831
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15018851
[ "BACKGROUND:", "Long-term", "anti-cytomegalovirus", "(CMV)", "treatments", "in", "immunocompromised", "patients", "are", "hampered", "by", "resistance", "to", "antiviral", "drugs.", "Longitudinal", "changes", "in", "the", "resistance", "genotype", "may", "depend", "on", "changes", "in", "selective", "pressure", "and", "the", "complexity", "of", "CMV", "isolates.", "OBJECTIVE:", "To", "evaluate", "longitudinal", "changes", "in", "the", "CMV", "resistance", "genotype", "and", "phenotype", "along", "with", "strain-specific", "variability", "in", "a", "patient", "with", "non-Hodgkin's", "lymphoma", "in", "whom", "successive", "anti-CMV", "treatments", "failed.", "STUDY", "DESIGN:", "The", "resistance", "phenotype", "and", "genotype", "of", "seven", "CMV", "isolates", "collected", "from", "one", "patient", "during", "a", "2-year", "follow-up", "period", "were", "retrospectively", "analysed.", "In", "parallel,", "we", "used", "glycoprotein", "B", "(gB)", "genotyping,", "and", "a-", "and", "UL10-13-sequence", "analysis", "to", "study", "CMV", "interstrain", "variability.", "RESULTS:", "The", "patient", "was", "infected", "by", "at", "least", "three", "CMV", "strains", "plus", "variants", "of", "the", "parental", "strains.", "Resistance", "to", "ganciclovir,", "cidofovir", "and", "foscarnet", "was", "successively", "detected", "during", "the", "follow-up", "period.", "UL97", "protein", "kinase", "changes", "responsible", "for", "resistance", "to", "ganciclovir", "were", "initially", "detected", "at", "residues", "591", "and", "592,", "and", "then", "at", "position", "594.", "Decreased", "sensitivity", "to", "foscarnet", "coincided", "with", "the", "appearance", "of", "amino", "acid", "substitution", "N495K", " ", "in", "DNA", "polymerase,", "whereas", "cross-resistance", "to", "ganciclovir", "and", "cidofovir", "was", "due", "to", "the", "L501I", " ", "substitution.", "CONCLUSIONS:", "The", "CMV", "isolates", "obtained", "from", "our", "patient", "were", "complex", "mixtures", "of", "strains.", "Changes", "in", "resistance", "genotypes", "depended", "on", "resistance", "selective", "pressure", "and", "were", "not", "linked", "to", "interstrain", "variation." ]
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BACKGROUND: Long-term anti-cytomegalovirus (CMV) treatments in immunocompromised patients are hampered by resistance to antiviral drugs. Longitudinal changes in the resistance genotype may depend on changes in selective pressure and the complexity of CMV isolates. OBJECTIVE: To evaluate longitudinal changes in the CMV resistance genotype and phenotype along with strain-specific variability in a patient with non-Hodgkin's lymphoma in whom successive anti-CMV treatments failed. STUDY DESIGN: The resistance phenotype and genotype of seven CMV isolates collected from one patient during a 2-year follow-up period were retrospectively analysed. In parallel, we used glycoprotein B (gB) genotyping, and a- and UL10-13-sequence analysis to study CMV interstrain variability. RESULTS: The patient was infected by at least three CMV strains plus variants of the parental strains. Resistance to ganciclovir, cidofovir and foscarnet was successively detected during the follow-up period. UL97 protein kinase changes responsible for resistance to ganciclovir were initially detected at residues 591 and 592, and then at position 594. Decreased sensitivity to foscarnet coincided with the appearance of amino acid substitution N495K in DNA polymerase, whereas cross-resistance to ganciclovir and cidofovir was due to the L501I substitution. CONCLUSIONS: The CMV isolates obtained from our patient were complex mixtures of strains. Changes in resistance genotypes depended on resistance selective pressure and were not linked to interstrain variation.
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22042570
[ "OPA1", "mutations", "in", "Japanese", "patients", "suspected", "to", "have", "autosomal", "dominant", "optic", "atrophy." ]
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OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy.
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17003923
[ "Gene", "polymorphisms", "implicated", "in", "influencing", "susceptibility", "to", "venous", "and", "arterial", "thromboembolism:", "frequency", "distribution", "in", "a", "healthy", "German", "population." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population.
[ 2, 2359, 8321, 6835, 1922, 11623, 6461, 1942, 8562, 1930, 6624, 23821, 30, 3528, 3282, 1922, 43, 4097, 12194, 2973, 18, 3 ]
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17910065
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19918264
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Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan.
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14623461
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Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.
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19012332
[ "Somatic", "TP53", "mutation", "mosaicism", "in", "a", "patient", "with", "Li-Fraumeni", "syndrome." ]
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Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome.
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22048266
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Trisomy of the 21{st} chromosome leads to an over dosage of several regulatory genes in Down syndrome (DS). Though allelic and genotypic combinations formed between genes are interesting, till date, this particular area has never been explored in DS. In the present investigation four SNPs in two transcription factors, Single minded 2 (SIM2) and V-ets erythroblastosis virus E26 oncogene homolog2 (ETS2), located in the 21{st} chromosome were genotyped to understand their role in DS. Genomic DNA of eastern Indian probands with DS (N=132), their parents (N=209) and ethnically matched controls (N=149) was subjected to PCR-based analyses of functionally important SNPs followed by statistical analyses. ETS2 rs461155 showed high heterozygosity in DS. Significantly lower frequency of SIM2 C-G haplotype ( rs2073601 - rs2073416 ) was noticed in individuals with DS (P value =0.01669) and their fathers (P value=0.01185). Significantly lower frequency of the A-C-C-G with higher frequency of A-C-A-G haplotypes was also noticed in subjects with DS (P value =0.02089 and 0.00588 respectively). Data obtained indicate that the rs2073601 'A' allele, responsible for nonsynonymous substitution of leucine to methionine, may have some role in DS in this population.
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17221831
[ "Alzheimer's", "disease", "(AD)", "is", "a", "polygenic", "and", "multifactorial", "complex", "disease,", "whose", "etiopathology", "is", "still", "unclear,", "however", "several", "genetic", "factors", "have", "shown", "to", "increase", "the", "risk", "of", "developing", "the", "disease.", "Purine", "nucleotides", "and", "nucleosides", "play", "an", "important", "role", "in", "the", "brain.", "Besides", "their", "role", "in", "neurotransmission", "and", "neuromodulation,", "they", "are", "involved", "in", "trophic", "factor", "release,", "apoptosis,", "and", "inflammatory", "responses.", "These", "mediators", "may", "also", "have", "a", "pivotal", "role", "in", "the", "control", "of", "neurodegenerative", "processes", "associated", "with", "AD.", "In", "this", "report", "the", "distribution", "of", "the", "exonic", "G/A", " ", "single", "nucleotide", "polymorphism", "(SNP)", "in", "purine", "nucleoside", "phosphorylase", "(PNP)", "gene,", "resulting", "in", "the", "amino", "acid", "substitution", "serine", "to", "glycine", "at", "position", "51", "(", "G51S", "),", "was", "investigated", "in", "a", "large", "population", "of", "AD", "patients", "(n=321)", "and", "non-demented", "control", "(n=208).", "The", "PNP", "polymorphism", "distribution", "was", "not", "different", "between", "patients", "and", "controls.", "The", "polymorphism", "distribution", "was", "also", "analyzed", "in", "AD", "patients", "stratified", "according", "to", "differential", "progressive", "rate", "of", "cognitive", "decline", "during", "a", "2-year", "follow-up.", "An", "increased", "representation", "of", "the", "PNP", "AA", "genotype", "was", "observed", "in", "AD", "patients", "with", "fast", "cognitive", "deterioration", "in", "comparison", "with", "that", "from", "patients", "with", "slow", "deterioration", "rate.", "Our", "findings", "suggest", "that", "the", "G51S", " ", "PNP", "polymorphism", "is", "associated", "with", "a", "faster", "rate", "of", "cognitive", "decline", "in", "AD", "patients,", "highlighting", "the", "important", "role", "of", "purine", "metabolism", "in", "the", "progression", "of", "this", "neurodegenerative", "disorder." ]
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Alzheimer's disease (AD) is a polygenic and multifactorial complex disease, whose etiopathology is still unclear, however several genetic factors have shown to increase the risk of developing the disease. Purine nucleotides and nucleosides play an important role in the brain. Besides their role in neurotransmission and neuromodulation, they are involved in trophic factor release, apoptosis, and inflammatory responses. These mediators may also have a pivotal role in the control of neurodegenerative processes associated with AD. In this report the distribution of the exonic G/A single nucleotide polymorphism (SNP) in purine nucleoside phosphorylase (PNP) gene, resulting in the amino acid substitution serine to glycine at position 51 ( G51S ), was investigated in a large population of AD patients (n=321) and non-demented control (n=208). The PNP polymorphism distribution was not different between patients and controls. The polymorphism distribution was also analyzed in AD patients stratified according to differential progressive rate of cognitive decline during a 2-year follow-up. An increased representation of the PNP AA genotype was observed in AD patients with fast cognitive deterioration in comparison with that from patients with slow deterioration rate. Our findings suggest that the G51S PNP polymorphism is associated with a faster rate of cognitive decline in AD patients, highlighting the important role of purine metabolism in the progression of this neurodegenerative disorder.
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16911351
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12832681
[ "BACKGROUND:", "In", "recent", "years", "several", "population", "based", "studies", "using", "restriction", "fragment", "length", "polymorphism", "(RFLP)", "analysis", "have", "shown", "a", "higher", "rate", "of", "recent", "transmission", "of", "tuberculosis", "than", "previously", "thought.", "This", "study", "was", "undertaken", "to", "determine", "the", "transmission", "patterns", "of", "tuberculosis", "and", "the", "potential", "causes", "of", "recent", "transmission", "on", "the", "island", "of", "Gran", "Canaria", "(Spain).", "METHODS:", "The", "strains", "of", "all", "patients", "diagnosed", "with", "tuberculosis", "confirmed", "by", "culture", "between", "1", "January", "1993", "and", "31", "December", "1996", "were", "typed", "by", "RFLP", "using", "the", "insertion", "sequence", "IS6110.", "A", "cluster", "was", "defined", "as", "two", "or", "more", "isolates", "with", "an", "identical", "RFLP", "pattern.", "Epidemiological", "linkage", "through", "contact", "tracing", "was", "investigated.", "RESULTS:", "Of", "the", "total", "of", "719", "patients,", "153", "(21.3%)", "were", "excluded", "because", "there", "was", "inadequate", "bacterial", "DNA", "for", "genotyping", "(n=129)", "or", "the", "isolates", "of", "Mycobacterium", "tuberculosis", "had", "less", "than", "five", "copies", "of", "IS6110", "(n=24).", "The", "isolates", "from", "409", "patients", "(72.3%)", "were", "grouped", "into", "78", "different", "clusters", "with", "an", "estimated", "58.5%", "of", "the", "cases", "being", "due", "to", "recent", "transmission.", "Young", "age", "was", "the", "only", "significant", "predictor", "of", "clustering.", "Only", "in", "147", "(35.9%)", "of", "the", "409", "patients", "belonging", "to", "a", "cluster", "could", "an", "epidemiological", "link", "be", "found.", "111", "patients", "(19.6%)", "were", "identified", "as", "having", "had", "previous", "contact", "with", "a", "tuberculosis", "patient", "and", "81", "of", "them", "(72.9%)", "belonged", "to", "a", "cluster.", "The", "three", "largest", "clusters", "included", "75,", "49", "and", "20", "patients,", "respectively.", "CONCLUSION:", "Recent", "transmission", "is", "frequent", "among", "patients", "with", "tuberculosis", "on", "Gran", "Canaria", "and", "could", "be", "associated", "with", "certain", "aspects", "of", "control", "measures.", "Some", "of", "the", "clusters", "described", "in", "the", "study", "could", "be", "due", "to", "the", "prevalence", "of", "particular", "strains", "of", "M", "tuberculosis", "on", "the", "island." ]
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BACKGROUND: In recent years several population based studies using restriction fragment length polymorphism (RFLP) analysis have shown a higher rate of recent transmission of tuberculosis than previously thought. This study was undertaken to determine the transmission patterns of tuberculosis and the potential causes of recent transmission on the island of Gran Canaria (Spain). METHODS: The strains of all patients diagnosed with tuberculosis confirmed by culture between 1 January 1993 and 31 December 1996 were typed by RFLP using the insertion sequence IS6110. A cluster was defined as two or more isolates with an identical RFLP pattern. Epidemiological linkage through contact tracing was investigated. RESULTS: Of the total of 719 patients, 153 (21.3%) were excluded because there was inadequate bacterial DNA for genotyping (n=129) or the isolates of Mycobacterium tuberculosis had less than five copies of IS6110 (n=24). The isolates from 409 patients (72.3%) were grouped into 78 different clusters with an estimated 58.5% of the cases being due to recent transmission. Young age was the only significant predictor of clustering. Only in 147 (35.9%) of the 409 patients belonging to a cluster could an epidemiological link be found. 111 patients (19.6%) were identified as having had previous contact with a tuberculosis patient and 81 of them (72.9%) belonged to a cluster. The three largest clusters included 75, 49 and 20 patients, respectively. CONCLUSION: Recent transmission is frequent among patients with tuberculosis on Gran Canaria and could be associated with certain aspects of control measures. Some of the clusters described in the study could be due to the prevalence of particular strains of M tuberculosis on the island.
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Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11b-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension.
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16575011
[ "Tumor", "thymidylate", "synthase", "1494del6", " ", "genotype", "as", "a", "prognostic", "factor", "in", "colorectal", "cancer", "patients", "receiving", "fluorouracil-based", "adjuvant", "treatment." ]
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Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment.
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19110214
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21904390
[ "PURPOSE:", "Aniridia", "(AN)", "is", "a", "rare", "congenital", "panocular", "disorder", "caused", "by", "the", "mutations", "of", "the", "paired", "box", "homeotic", "gene", "6(PAX6)", "gene.", "The", "PAX6gene", "is", "also", "involved", "in", "other", "anterior", "segment", "malformations", "including", "Peters", "anomaly.", "We", "studied", "the", "PAX6gene", "mutations", "in", "a", "cohort", "of", "affected", "individuals", "with", "different", "clinical", "phenotype", "including", "AN,", "coloboma", "of", "iris", "and", "choroid,", "or", "anterior", "segment", "malformations.", "PATIENTS", "AND", "METHODS:", "Six", "unrelated", "families", "and", "10", "sporadic", "patients", "were", "examined", "clinically.", "After", "informed", "consent", "was", "obtained,", "genomic", "DNA", "was", "extracted", "from", "the", "venous", "blood", "of", "all", "participants.", "Mutation", "screening", "of", "all", "exons", "of", "the", "PAX6gene", "was", "performed", "by", "direct", "sequencing", "of", "PCR-amplified", "DNA", "fragments.", "Multiplex", "ligation-dependent", "probe", "amplification", "(MLPA)", "was", "performed", "to", "detect", "large", "deletions.", "RESULTS:", "By", "clinical", "examination,", "the", "patients", "and", "the", "pedigrees", "were", "divided", "into", "the", "following", "three", "groups:", "AN,", "coloboma", "of", "iris", "and", "choroids,", "and", "the", "anterior", "segment", "malformations", "including", "peters", "anomaly.", "Sequencing", "of", "the", "PAX6gene,", "three", "intragenic", "mutations", "including", "a", "novel", "heterozygous", "splicing-site", "mutations", "c.357-3C>G", " ", "(", "p.Ser119fsX", ")", "were", "identified", "in", "the", "patients", "of", "the", "AN", "group.", "A", "novel", "missense", "mutation", "c.643T>C", " ", "(", "p.S216P", ")", "was", "detected", "in", "the", "anterior", "segment", "malformation", "group.", "The", "mutation", "p.S216P", " ", "located", "in", "the", "homeodomain", "region", "of", "the", "PAX6", "caused", "the", "phenotype", "of", "Peters", "anomaly", "in", "family", "A6", "with", "different", "expressing.", "Through", "MLPA", "analysis,", "a", "large", "deletion", "including", "the", "whole", "PAX6gene", "and", "DKFZ", "p686k1684gene", "was", "detected", "in", "one", "sporadic", "patient", "from", "the", "AN", "group.", "Neither", "intragenic", "mutation", "nor", "large", "deletion", "was", "identified", "in", "the", "group", "with", "coloboma", "of", "iris", "and", "choroid.", "CONCLUSION:", "Our", "findings", "further", "confirmed", "that", "different", "kind", "of", "mutations", "might", "cause", "different", "ocular", "phenotype,", "and", "clearly", "clinical", "phenotype", "classification", "might", "increase", "the", "mutation", "detection", "rate", "of", "the", "PAX6gene." ]
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PURPOSE: Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6(PAX6) gene. The PAX6gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations. PATIENTS AND METHODS: Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. RESULTS: By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C>G ( p.Ser119fsX ) were identified in the patients of the AN group. A novel missense mutation c.643T>C ( p.S216P ) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6gene and DKFZ p686k1684gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid. CONCLUSION: Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6gene.
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22303603
[]
[]
[ 2, 3 ]
[ 0, 0 ]
[ 1, 1 ]
[ -100, -100 ]
21159032
[ "Alpha2B-adrenergic", "receptor", "insertion/deletion", "polymorphism", "in", "women", "with", "spontaneous", "recurrent", "abortions." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Alpha2B-adrenergic receptor insertion/deletion polymorphism in women with spontaneous recurrent abortions.
[ 2, 4595, 9385, 17, 13672, 3148, 7413, 19, 5541, 8218, 1922, 3089, 1956, 6242, 7457, 30379, 18, 3 ]
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[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
18790087
[ "Is", "the", "European", "spatial", "distribution", "of", "the", "HIV-1-resistant", "CCR5-", "Delta32", " ", "allele", "formed", "by", "a", "breakdown", "of", "the", "pathocenosis", "due", "to", "the", "historical", "Roman", "expansion?" ]
[ 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 ]
Is the European spatial distribution of the HIV-1-resistant CCR5- Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?
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19473658
[ "Marked", "high", "density", "lipoprotein", "deficiency", "due", "to", "apolipoprotein", "A-I", "Tomioka", "(codon", "138", "deletion)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion).
[ 2, 4961, 2149, 3824, 9694, 6179, 2810, 1942, 18747, 43, 17, 51, 5970, 3940, 7640, 12, 8905, 12830, 5541, 13, 18, 3 ]
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21771880
[]
[]
[ 2, 3 ]
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21182502
[ "BACKGROUND:", "Recessive", "dystrophic", "epidermolysis", "bullosa", "(RDEB)", "is", "an", "inherited", "blistering", "skin", "disorder", "caused", "by", "mutations", "in", "COL7A1", "gene", "encoding", "type", "VII", "collagen,", "the", "major", "component", "of", "anchoring", "fibrils", "in", "the", "dermo-epidermal", "junction.", "The", "development", "of", "cutaneous", "squamous", "cell", "carcinoma", "(SCC)", "is", "one", "of", "the", "most", "serious", "complications", "of", "this", "disease.", "We", "report", "herein", "a", "Chinese", "patient", "with", "the", "severe", "generalized", "subtype", "of", "RDEB", "(RDEB-sev", "gen)", "complicated", "by", "SCC.", "METHODS:", "Skin", "biopsies", "were", "examined", "for", "histology,", "basement", "membrane", "ultrastructure,", "and", "type", "VII", "collagen", "expression.", "Genomic", "DNA", "was", "extracted", "from", "the", "peripheral", "blood", "samples", "and", "subjected", "to", "polymerase", "chain", "reaction", "amplification", "and", "direct", "automated", "DNA", "sequencing.", "RESULTS:", "Histopathological", "examination", "of", "the", "patient's", "skin", "revealed", "an", "undetectable", "expression", "of", "type", "VII", "collagen", "polypeptides", "in", "the", "basement", "membrane", "zone.", "Mutation", "analysis", "identified", "a", "novel", "splice", "site", "mutation", "in", "intron", "64", "(", "IVS64+5g->a", ")", "of", "COL7A1", "gene,", "which", "resulted", "in", "an", "in-frame", "deletion", "of", "exon", "64", "in", "both", "alleles.", "CONCLUSIONS:", "This", "report", "contributes", "to", "the", "expanding", "database", "of", "COL7A1", "mutations", "and", "emphasizes", "the", "need", "to", "elucidate", "the", "underlying", "genetic", "mechanisms", "associated", "with", "the", "increased", "incidence", "of", "SCC", "in", "RDEB", "patients." ]
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BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disorder caused by mutations in COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils in the dermo-epidermal junction. The development of cutaneous squamous cell carcinoma (SCC) is one of the most serious complications of this disease. We report herein a Chinese patient with the severe generalized subtype of RDEB (RDEB-sev gen) complicated by SCC. METHODS: Skin biopsies were examined for histology, basement membrane ultrastructure, and type VII collagen expression. Genomic DNA was extracted from the peripheral blood samples and subjected to polymerase chain reaction amplification and direct automated DNA sequencing. RESULTS: Histopathological examination of the patient's skin revealed an undetectable expression of type VII collagen polypeptides in the basement membrane zone. Mutation analysis identified a novel splice site mutation in intron 64 ( IVS64+5g->a ) of COL7A1 gene, which resulted in an in-frame deletion of exon 64 in both alleles. CONCLUSIONS: This report contributes to the expanding database of COL7A1 mutations and emphasizes the need to elucidate the underlying genetic mechanisms associated with the increased incidence of SCC in RDEB patients.
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16167150
[ "Genetic", "variation", "in", "UCP2", "(uncoupling", "protein-2)", "is", "associated", "with", "energy", "metabolism", "in", "Pima", "Indians." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians.
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21533187
[ "Loss-of-function", "mutations", "in", "PTPN11", "cause", "metachondromatosis,", "but", "not", "Ollier", "disease", "or", "Maffucci", "syndrome." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.
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17372760
[]
[]
[ 2, 3 ]
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19144556
[ "Identification", "of", "newly", "polymorphic", "intron", "40", "markers", "of", "the", "von", "Willebrand", "factor", "gene", "in", "a", "Japanese", "population." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Identification of newly polymorphic intron 40 markers of the von Willebrand factor gene in a Japanese population.
[ 2, 4824, 1927, 7471, 14240, 10444, 3040, 4432, 1927, 1920, 14147, 30067, 2991, 2359, 1922, 43, 10405, 2973, 18, 3 ]
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16418600
[ "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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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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17002658
[ "Severe", "prothrombin", "deficiency", "caused", "by", "prothrombin-Edmonton", "(", "R-4Q", ")", "combined", "with", "a", "previously", "undetected", "deletion." ]
[ 0, 0, 0, 0, 0, 0, 0, 3, 0, 0, 0, 0, 0, 0, 0 ]
Severe prothrombin deficiency caused by prothrombin-Edmonton ( R-4Q ) combined with a previously undetected deletion.
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20534762
[]
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17959715
[]
[]
[ 2, 3 ]
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15148206
[]
[]
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15198485
[]
[]
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12701064
[]
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21684788
[ "Sj", " ", "gren-Larsson", "syndrome", "(SLS)", "is", "an", "autosomal", "recessive", "disorder", "characterized", "by", "ichthyosis,", "mental", "retardation,", "spasticity", "and", "mutations", "in", "the", "ALDH3A2", "gene", "for", "fatty", "aldehyde", "dehydrogenase,", "an", "enzyme", "that", "catalyzes", "the", "oxidation", "of", "fatty", "aldehyde", "to", "fatty", "acid.", "More", "than", "70", "mutations", "have", "been", "identified", "in", "SLS", "patients,", "including", "small", "deletions", "or", "insertions,", "missense", "mutations,", "splicing", "defects", "and", "complex", "nucleotide", "changes.", "We", "now", "describe", "2", "SLS", "patients", "whose", "disease", "is", "caused", "by", "large", "contiguous", "gene", "deletions", "of", "the", "ALDH3A2", "locus", "on", "17p11.2.", "The", "deletions", "were", "defined", "using", "long", "distance", "inverse", "PCR", "and", "microarray-based", "comparative", "genomic", "hybridization.", "A", "24-year-old", "SLS", "female", "was", "homozygous", "for", "a", "352-kb", "deletion", "involving", "ALDH3A2", "and", "4", "contiguous", "genes", "including", "ALDH3A1,", "which", "codes", "for", "the", "major", "soluble", "protein", "in", "cornea.", "Although", "lacking", "corneal", "disease,", "she", "showed", "severe", "symptoms", "of", "SLS", "with", "uncommon", "deterioration", "in", "oral", "motor", "function", "and", "loss", "of", "ambulation.", "The", "other", "19-month-old", "female", "patient", "was", "a", "compound", "heterozygote", "for", "a", "1.44-Mb", "contiguous", "gene", "deletion", "and", "a", "missense", "mutation", "(", "c.407C>T", ",", "P136L", ")", "in", "ALDH3A2.", "These", "studies", "suggest", "that", "large", "gene", "deletions", "may", "account", "for", "up", "to", "5%", "of", "the", "mutant", "alleles", "in", "SLS.", "Geneticists", "should", "consider", "the", "possibility", "of", "compound", "heterozygosity", "for", "large", "deletions", "in", "patients", "with", "SLS", "and", "other", "inborn", "errors", "of", "metabolism,", "which", "has", "implications", "for", "carrier", "testing", "and", "prenatal", "diagnosis." ]
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Sj gren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation ( c.407C>T , P136L ) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.
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19766614
[ "A", "novel", "insertion", "mutation", "in", "the", "SEDL", "gene", "results", "in", "X-linked", "spondyloepiphyseal", "dysplasia", "tarda", "in", "a", "large", "Chinese", "pedigree." ]
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A novel insertion mutation in the SEDL gene results in X-linked spondyloepiphyseal dysplasia tarda in a large Chinese pedigree.
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18439317
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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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21042587
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20086182
[ "The", "six-nucleotide", "deletion/insertion", "variant", "in", "the", "CASP8", "promoter", "region", "is", "inversely", "associated", "with", "risk", "of", "squamous", "cell", "carcinoma", "of", "the", "head", "and", "neck." ]
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The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck.
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12968672
[ "A", "Cdx-2", "binding", "site", "polymorphism", "(G", "to", "A)", "in", "the", "promoter", "region", "of", "the", "human", "vitamin", "D", "receptor", "gene", "was", "reported.", "In", "an", "ecological", "study", "in", "eight", "ethnic", "groups", "and", "an", "association", "study", "in", "2848", "elderly", "whites,", "we", "found", "the", "A-allele", "to", "be", "associated", "with", "decreased", "fracture", "risk.", "Our", "findings", "expand", "previous", "similar", "findings", "in", "a", "Japanese", "study", "to", "whites", "and", "show", "a", "relationship", "with", "fracture", "risk", "of", "this", "functional", "polymorphism.", "INTRODUCTION:", "A", "single", "nucleotide", "polymorphism", "(SNP)", "within", "a", "binding", "site", "of", "the", "intestinal-specific", "transcription", "factor", "Cdx-2", "in", "the", "promoter", "region", "of", "the", "human", "vitamin", "D", "receptor", "(VDR)", "gene", "was", "previously", "reported.", "It", "was", "found", "to", "modulate", "the", "transcription", "of", "the", "hVDR", "gene", "and", "to", "be", "associated", "with", "decreased", "bone", "mineral", "density", "in", "a", "small", "group", "of", "postmenopausal", "Japanese", "women.", "In", "this", "study,", "we", "investigated", "the", "relationship", "between", "the", "VDR", "Cdx-2", "genotype", "and", "risk", "of", "fracture.", "METHODS:", "We", "first", "determined", "the", "location", "of", "this", "SNP", "in", "the", "VDR", "gene", "by", "sequencing", "analysis,", "and", "we", "developed", "an", "allele-specific", "multiplex", "polymerase", "chain", "reaction", "test", "to", "determine", "the", "Cdx-2", "genotype.", "We", "then", "performed", "an", "ecological", "study", "in", "eight", "ethnic", "groups", "and", "an", "association", "analysis", "in", "a", "large", "epidemiological", "cohort", "of", "2848", "Dutch", "white", "men", "and", "women,", ">", "or", "=", "55", "years", "old.", "RESULTS", "AND", "CONCLUSIONS:", "The", "location", "of", "the", "G", "to", "A", "substitution", "was", "found", "in", "the", "promoter", "region", "of", "exon", "le", "(le-G-1739A)", "of", "the", "VDR", "gene.", "By", "comparing", "the", "frequency", "of", "the", "A-allele", "in", "eight", "different", "ethnic", "groups,", "we", "observed", "a", "negative", "correlation", "between", "prevalence", "of", "the", "A-allele", "and", "published", "hip", "fracture", "incidence", "rates", "in", "these", "ethnic", "groups", "(p", "=", "0.006", "for", "men", "and", "p", "=", "0.02", "for", "women),", "suggesting", "a", "protective", "effect", "of", "this", "allele", "on", "fracture", "risk.", "Subsequently,", "in", "the", "association", "study,", "the", "A-allele", "(population", "frequency", "19%)", "was", "observed", "to", "have", "a", "protective", "effect", "on", "occurrence", "of", "osteoporotic", "fractures,", "especially", "for", "nonvertebral", "fracture", "in", "women", "(relative", "risk", "of", "AA", "versus", "GG", "genotype", "is", "0.2;", "95%", "CI,", "0.05-0.8).", "This", "effect", "remained", "after", "adjustment", "for", "age,", "weight,", "and", "bone", "mineral", "density.", "We", "conclude", "that", "the", "A-allele", "of", "the", "VDR", "Cdx-2", "polymorphism", "is", "present", "in", "whites,", "albeit", "at", "low", "frequency,", "and", "show", "a", "protective", "effect", "of", "this", "allele", "on", "risk", "of", "fracture." ]
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A Cdx-2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptor gene was reported. In an ecological study in eight ethnic groups and an association study in 2848 elderly whites, we found the A-allele to be associated with decreased fracture risk. Our findings expand previous similar findings in a Japanese study to whites and show a relationship with fracture risk of this functional polymorphism. INTRODUCTION: A single nucleotide polymorphism (SNP) within a binding site of the intestinal-specific transcription factor Cdx-2 in the promoter region of the human vitamin D receptor (VDR) gene was previously reported. It was found to modulate the transcription of the hVDR gene and to be associated with decreased bone mineral density in a small group of postmenopausal Japanese women. In this study, we investigated the relationship between the VDR Cdx-2 genotype and risk of fracture. METHODS: We first determined the location of this SNP in the VDR gene by sequencing analysis, and we developed an allele-specific multiplex polymerase chain reaction test to determine the Cdx-2 genotype. We then performed an ecological study in eight ethnic groups and an association analysis in a large epidemiological cohort of 2848 Dutch white men and women, > or = 55 years old. RESULTS AND CONCLUSIONS: The location of the G to A substitution was found in the promoter region of exon le (le-G-1739A) of the VDR gene. By comparing the frequency of the A-allele in eight different ethnic groups, we observed a negative correlation between prevalence of the A-allele and published hip fracture incidence rates in these ethnic groups (p = 0.006 for men and p = 0.02 for women), suggesting a protective effect of this allele on fracture risk. Subsequently, in the association study, the A-allele (population frequency 19%) was observed to have a protective effect on occurrence of osteoporotic fractures, especially for nonvertebral fracture in women (relative risk of AA versus GG genotype is 0.2; 95% CI, 0.05-0.8). This effect remained after adjustment for age, weight, and bone mineral density. We conclude that the A-allele of the VDR Cdx-2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture.
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12809638
[ "We", "describe", "three", "novel", "mutations", "in", "the", "human", "arylsulfatase", "A", "gene", "in", "three", "patients", "with", "MLD,", "an", "autosomal", "recessive", "lysosomal", "storage", "disorder.", "An", "insertion,", "2590_2591insCCCC", " ", "in", "exon", "8", "and", "a", "deletion,", "752_758delGCCGGCC", ",", "in", "exon", "3", "will", "both", "result", "in", "frameshifts.", "A", "mutation", "in", "exon", "8,", "2566T-->C", ",", "results", "in", "a", "missense", "mutation", "C488R", ",", "disrupting", "an", "unusual", "cysteine-knot", "at", "the", "C-terminal", "end", "of", "the", "protein.", "All", "three", "mutations", "are", "heterozygous", "with", "previously", "documented", "mutations.", "A", "previously", "reported", "mutation,", "R84Q", " ", "was", "identified", "on", "a", "pseudodeficiency", "allele.", "These", "mutations", "are", "part", "of", "a", "heterogeneous", "spectrum", "of", "mutations", "found", "in", "a", "collection", "of", "DNA", "samples", "from", "MLD", "patients", "from", "across", "Canada", "and", "the", "USA." ]
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We describe three novel mutations in the human arylsulfatase A gene in three patients with MLD, an autosomal recessive lysosomal storage disorder. An insertion, 2590_2591insCCCC in exon 8 and a deletion, 752_758delGCCGGCC , in exon 3 will both result in frameshifts. A mutation in exon 8, 2566T-->C , results in a missense mutation C488R , disrupting an unusual cysteine-knot at the C-terminal end of the protein. All three mutations are heterozygous with previously documented mutations. A previously reported mutation, R84Q was identified on a pseudodeficiency allele. These mutations are part of a heterogeneous spectrum of mutations found in a collection of DNA samples from MLD patients from across Canada and the USA.
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