Brizape/multiCorp_tokenized_split_LabelNorm_0404_dev

id stringlengths 7 37	tokens sequence	ner_tags sequence	texts stringlengths 0 39.2k	input_ids sequence	token_type_ids sequence	attention_mask sequence	labels sequence
22295085	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
15122711	[ "Alpers'", "syndrome", "is", "a", "fatal", "neurogenetic", "disorder", "first", "described", "more", "than", "70", "years", "ago.", "It", "is", "an", "autosomal", "recessive,", "developmental", "mitochondrial", "DNA", "depletion", "disorder", "characterized", "by", "deficiency", "in", "mitochondrial", "DNA", "polymerase", "gamma", "(POLG)", "catalytic", "activity,", "refractory", "seizures,", "neurodegeneration,", "and", "liver", "disease.", "In", "two", "unrelated", "pedigrees", "of", "Alpers'", "syndrome,", "each", "affected", "child", "was", "found", "to", "carry", "a", "homozygous", "mutation", "in", "exon", "17", "of", "the", "POLG", "locus", "that", "led", "to", "a", "Glu873Stop", " ", "mutation", "just", "upstream", "of", "the", "polymerase", "domain", "of", "the", "protein.", "In", "addition,", "each", "affected", "child", "was", "heterozygous", "for", "the", "G1681A", " ", "mutation", "in", "exon", "7", "that", "led", "to", "an", "Ala467Thr", " ", "substitution", "in", "POLG,", "within", "the", "linker", "region", "of", "the", "protein." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein.	[ 2, 14089, 2045, 11, 4741, 1977, 43, 11990, 3366, 14687, 2002, 4770, 2561, 2910, 2253, 2254, 3895, 2739, 11511, 18, 2176, 1977, 1925, 13027, 13992, 16, 5878, 4596, 2678, 6882, 4770, 4378, 2007, 6179, 1922, 4596, 2678, 6479, 7034, 12, 2492, 1029, 13, 6804, 2455, 16, 10923, 10060, 16, 14481, 16, 1930, 3568, 2573, 18, 1922, 2288, 10295, 22336, 1036, 1927, 14089, 2045, 11, 4741, 16, 2362, 4218, 2748, 1982, 2435, 1942, 9875, 43, 9419, 3979, 1922, 7049, 2752, 1927, 1920, 2492, 1029, 6730, 1988, 4866, 1942, 43, 9258, 8851, 1010, 2156, 2011, 3979, 6244, 7671, 1927, 1920, 6479, 3418, 1927, 1920, 2213, 18, 1922, 2459, 16, 2362, 4218, 2748, 1982, 9589, 1958, 1920, 8533, 6735, 6146, 3979, 1922, 7049, 27, 1988, 4866, 1942, 1925, 10527, 7772, 1027, 5856, 6636, 1922, 2492, 1029, 16, 2651, 1920, 11040, 3031, 1927, 1920, 2213, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
15937959	[ "Loss", "of", "heterozygosity", "(LOH)", "analysis", "was", "performed", "in", "epithelial", "ovarian", "cancers", "(EOC)", "to", "further", "characterize", "a", "previously", "identified", "candidate", "tumor", "suppressor", "gene", "(TSG)", "region", "encompassing", "D17S801", "at", "chromosomal", "region", "17q25.1.", "LOH", "of", "at", "least", "one", "informative", "marker", "was", "observed", "for", "100", "(71%)", "of", "140", "malignant", "EOC", "samples", "in", "an", "analysis", "of", "6", "polymorphic", "markers", "(cen-D17S1839-D17S785-D17S1817-D17S801-D17S751-D17S722-tel).", "The", "combined", "LOH", "analysis", "revealed", "a", "453", "kilobase", "(Kb)", "minimal", "region", "of", "deletion", "(MRD)", "bounded", "by", "D17S1817", "and", "D17S751.", "Human", "and", "mouse", "genome", "assemblies", "were", "used", "to", "resolve", "marker", "inconsistencies", "in", "the", "D17S1839-D17S722", "interval", "and", "identify", "candidates.", "The", "region", "contains", "32", "known", "and", "strongly", "predicted", "genes,", "9", "of", "which", "overlap", "the", "MRD.", "The", "reference", "genomic", "sequences", "share", "nearly", "identical", "gene", "structures", "and", "the", "organization", "of", "the", "region", "is", "highly", "collinear.", "Although,", "the", "region", "does", "not", "show", "any", "large", "internal", "duplications,", "a", "1.5", "Kb", "inverted", "duplicated", "sequence", "of", "87%", "nucleotide", "identity", "was", "observed", "in", "a", "13", "Kb", "region", "surrounding", "D17S801.", "Transcriptome", "analysis", "by", "Affymetrix", "GeneChip", "and", "reverse", "transcription", "(RT)-polymerase", "chain", "reaction", "(PCR)", "methods", "of", "3", "well", "characterized", "EOC", "cell", "lines", "and", "primary", "cultures", "of", "normal", "ovarian", "surface", "epithelial", "(NOSE)", "cells", "was", "performed", "with", "32", "candidates", "spanning", "D17S1839-D17S722", "interval.", "RT-PCR", "analysis", "of", "8", "known", "or", "strongly", "predicted", "genes", "residing", "in", "the", "MRD", "in", "10", "EOC", "samples,", "that", "exhibited", "LOH", "of", "the", "MRD,", "identified", "FLJ22341", "as", "a", "strong", "candidate", "TSG.", "The", "proximal", "repeat", "sequence", "of", "D17S801", "occurs", "8", "Kb", "upstream", "of", "the", "putative", "promoter", "region", "of", "FLJ22341.", "RT-PCR", "analysis", "of", "the", "EOC", "samples", "and", "cell", "lines", "identified", "DKFZP434P0316", "that", "maps", "proximal", "to", "the", "MRD,", "as", "a", "candidate.", "While", "Affymetrix", "technology", "was", "useful", "for", "initially", "eliminating", "less", "promising", "candidates,", "subsequent", "RT-PCR", "analysis", "of", "well-characterized", "EOC", "samples", "was", "essential", "to", "prioritize", "TSG", "candidates", "for", "further", "study." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Loss of heterozygosity (LOH) analysis was performed in epithelial ovarian cancers (EOC) to further characterize a previously identified candidate tumor suppressor gene (TSG) region encompassing D17S801 at chromosomal region 17q25.1. LOH of at least one informative marker was observed for 100 (71%) of 140 malignant EOC samples in an analysis of 6 polymorphic markers (cen-D17S1839-D17S785-D17S1817-D17S801-D17S751-D17S722-tel). The combined LOH analysis revealed a 453 kilobase (Kb) minimal region of deletion (MRD) bounded by D17S1817 and D17S751. Human and mouse genome assemblies were used to resolve marker inconsistencies in the D17S1839-D17S722 interval and identify candidates. The region contains 32 known and strongly predicted genes, 9 of which overlap the MRD. The reference genomic sequences share nearly identical gene structures and the organization of the region is highly collinear. Although, the region does not show any large internal duplications, a 1.5 Kb inverted duplicated sequence of 87% nucleotide identity was observed in a 13 Kb region surrounding D17S801. Transcriptome analysis by Affymetrix GeneChip and reverse transcription (RT)-polymerase chain reaction (PCR) methods of 3 well characterized EOC cell lines and primary cultures of normal ovarian surface epithelial (NOSE) cells was performed with 32 candidates spanning D17S1839-D17S722 interval. RT-PCR analysis of 8 known or strongly predicted genes residing in the MRD in 10 EOC samples, that exhibited LOH of the MRD, identified FLJ22341 as a strong candidate TSG. The proximal repeat sequence of D17S801 occurs 8 Kb upstream of the putative promoter region of FLJ22341. RT-PCR analysis of the EOC samples and cell lines identified DKFZP434P0316 that maps proximal to the MRD, as a candidate. While Affymetrix technology was useful for initially eliminating less promising candidates, subsequent RT-PCR analysis of well-characterized EOC samples was essential to prioritize TSG candidates for further study.	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17311329	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
19370764	[ "Mucolipidosis", "type", "III", "(MLIII)", "is", "an", "autosomal", "recessive", "disorder", "affecting", "lysosomal", "hydrolase", "trafficking.", "In", "a", "study", "of", "10", "patients", "from", "seven", "families", "with", "a", "clinical", "phenotype", "and", "enzymatic", "diagnosis", "of", "MLIII,", "six", "novel", "GNPTG", "gene", "mutations", "were", "identified.", "These", "included", "missense", "(", "p.T286M", ")", "and", "nonsense", "(", "p.W111X", ")", "mutations", "and", "a", "transition", "in", "the", "obligate", "AG-dinucleotide", "of", "the", "intron", "8", "acceptor", "splice", "site", "(", "c.610-2A>G", ").", "Three", "microdeletions", "were", "also", "identified,", "two", "of", "which", "(", "c.611delG", " ", "and", "c.640_667del28", ")", "were", "located", "within", "the", "coding", "region", "whereas", "one", "(", "c.609+28_610-16del", ")", "was", "located", "entirely", "within", "intron", "8.", "RT-PCR", "analysis", "of", "the", "c.610-2A>G", " ", "transition", "demonstrated", "that", "the", "change", "altered", "splicing,", "leading", "to", "the", "production", "of", "two", "distinct", "aberrantly", "spliced", "forms,", "viz.", "the", "skipping", "of", "exon", "9", "(", "p.G204_K247del", ")", "or", "the", "retention", "of", "introns", "8", "and", "9", "(", "p.G204VfsX28", ").", "RT-PCR", "analysis,", "performed", "on", "a", "patient", "homozygous", "for", "the", "intronic", "deletion", "(", "c.609+28_610-16del", "),", "failed", "to", "detect", "any", "GNPTG", "RNA", "transcripts.", "To", "determine", "whether", "c.609+28_610-16del", " ", "allele-derived", "transcripts", "were", "subject", "to", "nonsense-mediated", "mRNA", "decay", "(NMD),", "patient", "fibroblasts", "were", "incubated", "with", "the", "protein", "synthesis", "inhibitor", "anisomycin.", "An", "RT-PCR", "fragment", "retaining", "43", "bp", "of", "intron", "8", "was", "consistently", "detected", "suggesting", "that", "the", "33-bp", "genomic", "deletion", "had", "elicited", "NMD.", "Quantitative", "real-time", "PCR", "and", "GNPTG", "western", "blot", "analysis", "confirmed", "that", "the", "homozygous", "microdeletion", "p.G204VfsX17", " ", "had", "elicited", "NMD", "resulting", "in", "failure", "to", "synthesize", "GNPTG", "protein.", "Analysis", "of", "the", "sequences", "surrounding", "the", "microdeletion", "breakpoints", "revealed", "either", "intrinsic", "repetitivity", "of", "the", "deleted", "region", "or", "short", "direct", "repeats", "adjacent", "to", "the", "breakpoint", "junctions.", "This", "is", "consistent", "with", "these", "repeats", "having", "mediated", "the", "microdeletions", "via", "replication", "slippage", "and", "supports", "the", "view", "that", "the", "mutational", "spectrum", "of", "the", "GNPTG", "gene", "is", "strongly", "influenced", "by", "the", "properties", "of", "the", "local", "DNA", "sequence", "environment." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense ( p.T286M ) and nonsense ( p.W111X ) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site ( c.610-2A>G ). Three microdeletions were also identified, two of which ( c.611delG and c.640_667del28 ) were located within the coding region whereas one ( c.609+28_610-16del ) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 ( p.G204_K247del ) or the retention of introns 8 and 9 ( p.G204VfsX28 ). RT-PCR analysis, performed on a patient homozygous for the intronic deletion ( c.609+28_610-16del ), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment.	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16575011	[ "PURPOSE:", "The", "purpose", "of", "this", "study", "was", "to", "analyze", "the", "value", "of", "germline", "and", "tumor", "thymidylate", "synthase", "(TS)", "genotyping", "as", "a", "prognostic", "marker", "in", "a", "series", "of", "colorectal", "cancer", "patients", "receiving", "adjuvant", "fluorouracil", "(FU)", "-based", "treatment.", "PATIENTS", "AND", "METHODS:", "One", "hundred", "twenty-nine", "colorectal", "cancer", "patients", "homogeneously", "treated", "with", "FU", "plus", "levamisole", "or", "leucovorin", "in", "the", "adjuvant", "setting", "were", "included.", "TS", "enhancer", "region,", "3R", "G", ">", "C", " ", "single", "nucleotide", "polymorphism", "(SNP),", "and", "TS", "1494del6", " ", "polymorphisms", "were", "assessed", "in", "both", "fresh-frozen", "normal", "mucosa", "and", "tumor.", "Mutational", "analyses", "of", "TS", "and", "allelic", "imbalances", "were", "studied", "in", "all", "primary", "tumors", "and", "in", "18", "additional", "metachronic", "metastases.", "TS", "protein", "immunostaining", "was", "assessed", "in", "an", "expanded", "series", "of", "214", "tumors.", "Multivariate", "Cox", "models", "were", "adjusted", "for", "stage,", "differentiation,", "and", "location.", "RESULTS:", "Tumor", "genotyping", "(frequency", "of", "allelic", "loss,", "26%)", "showed", "that", "the", "3R/3R", "genotype", "was", "associated", "with", "a", "better", "outcome", "(hazard", "ratio", "[HR]", "=", "0.38;", "95%", "CI,", "0.16", "to", "0.93;", "P", "=", ".020", "for", "the", "recessive", "model).", "3R", "G", ">", "C", " ", "SNP", "genotyping", "did", "not", "add", "prognostic", "information.", "Tumor", "TS", "1494del6", " ", "allele", "(frequency", "of", "allelic", "loss,", "36%)", "was", "protective", "(for", "each", "allele", "with", "the", "deletion,", "based", "on", "an", "additive", "model,", "HR", "=", "0.42;", "95%", "CI,", "0.22", "to", "0.82;", "P", "=", ".0034).", "Both", "polymorphisms", "were", "in", "strong", "linkage", "disequilibrium", "(D'", "=", "0.71,", "P", "<", ".001),", "and", "the", "3R/-6", "base", "pair", "(bp)", "haplotype", "showed", "a", "significant", "overall", "survival", "benefit", "compared", "with", "the", "most", "prevalent", "haplotype", "2R/+6bp", "(HR", "=", "0.42;", "95%", "CI,", "0.20", "to", "0.85;", "P", "=", ".017).", "No", "TS", "point", "mutation", "was", "detected", "in", "primary", "tumors", "or", "metastases.", "TS", "protein", "immunostaining", "was", "not", "associated", "with", "survival", "or", "any", "of", "the", "genotypes", "analyzed.", "CONCLUSION:", "Tumor", "TS", "1494del6", " ", "genotype", "may", "be", "a", "prognostic", "factor", "in", "FU-based", "adjuvant", "treatment", "of", "colorectal", "cancer", "patients." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	PURPOSE: The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. PATIENTS AND METHODS: One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. RESULTS: Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/-6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. CONCLUSION: Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.	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18426832	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
20352162	[ "4G/5G", "polymorphism", "and", "haplotypes", "of", "SERPINE1", "in", "atherosclerotic", "diseases", "of", "coronary", "arteries." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	4G/5G polymorphism and haplotypes of SERPINE1 in atherosclerotic diseases of coronary arteries.	[ 2, 18385, 19, 19950, 8218, 1930, 12149, 1927, 27453, 2053, 1009, 1922, 13450, 3902, 1927, 5846, 9345, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
20529581	[ "BACKGROUND:", "Leukocyte", "adhesion", "deficiency", "type", "1", "(LAD-1)", "is", "a", "rare,", "autosomal", "recessive", "inherited", "immunodeficiency", "disease", "characterized", "by", "recurrent", "severe", "bacterial", "infection,", "impaired", "pus", "formation,", "poor", "wound", "healing,", "associated", "with", "the", "mutation", "in", "the", "CD18", "gene", "responsible", "for", "the", "ability", "of", "the", "leucocytes", "to", "migrate", "from", "the", "blood", "stream", "towards", "the", "site", "of", "inflammation.", "Correct", "and", "early", "diagnosis", "of", "LAD-1", "is", "vital", "to", "the", "success", "of", "treatment", "and", "prevention", "of", "aggressive", "infections.", "The", "purpose", "of", "this", "study", "was", "to", "collect", "the", "clinical", "findings", "of", "the", "disease", "and", "to", "identify", "the", "genetic", "entity.", "METHODS:", "CD18", "expression", "in", "the", "peripheral", "blood", "leukocytes", "from", "the", "patient,", "his", "parents", "and", "normal", "control", "was", "measured", "with", "flow", "cytometry.", "The", "entire", "coding", "regions", "of", "the", "CD18", "gene", "were", "screened", "with", "direct", "sequencing", "genomic", "DNA.", "RESULTS:", "CD18", "expression", "level", "on", "this", "patient's", "leukocyte", "surface", "was", "significantly", "decreased,", "with", "normal", "level", "in", "control", "group,", "his", "father", "and", "mother.", "Gene", "analysis", "revealed", "that", "this", "patient", "had", "a", "homozygous", "c.899A", ">", "T", " ", "missense", "mutation", "in", "exon", "8", "of", "CD18", "gene,", "causing", "the", "substitution", "of", "Asp", "to", "Val", "at", "the", "300", "amino", "acid.", "His", "parents", "were", "both", "heterozygous", "carriers", "while", "no", "such", "mutation", "was", "found", "in", "50", "normal", "controls.", "CONCLUSION:", "This", "study", "disclosed", "a", "novel", "point", "mutation", "Asp", "300", "Val", " ", "located", "in", "a", "highly", "conserved", "region", "(HCR)", "of", "CD18", "and", "confirmed", "the", "heterogeneity", "of", "the", "mutations", "causing", "LAD-1,", "indicating", "it", "was", "quite", "beneficial", "to", "establish", "correct", "and", "early", "diagnosis", "in", "children", "with", "severe", "LAD-1." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation. Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections. The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity. METHODS: CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry. The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA. RESULTS: CD18 expression level on this patient's leukocyte surface was significantly decreased, with normal level in control group, his father and mother. Gene analysis revealed that this patient had a homozygous c.899A > T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid. His parents were both heterozygous carriers while no such mutation was found in 50 normal controls. CONCLUSION: This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region (HCR) of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1.	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21695597	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
17175380	[ "We", "examined", "chromosome", "3", "in", "32", "childhood", "acute", "lymphoblastic", "leukemia", "(ALL)", "bone", "marrow", "samples.", "Using", "interphase", "multipoint", "FISH", "(mp-FISH),", "which", "was", "developed", "by", "our", "group,", "with", "42", "chromosome", "3-specific", "probes,", "we", "detected", "clonal", "chromosome", "3", "aberrations", "in", "4", "T-cell", "ALL", "(T-ALL)", "cases.", "Four", "out", "of", "seven", "T-ALL", "cases", "carried", "3q", "trisomies.", "One", "T-ALL", "case", "carried", "either", "trisomy", "3", "(in", "15%", "of", "the", "cells)", "or", "a", "23-megabase", "(Mb)", "3p13", "approximately", "p12", "deletion", "in", "a", "different", "subpopulation", "of", "cells", "of", "32%.", "Another", "T-ALL", "case", "had", "either", "3q", "trisomy", "in", "11%", "or", "a", "12-Mb", "3p12", "approximately", "p13", "deletion", "in", "19%", "of", "the", "cells.", "The", "deletions", "were", "overlapping.", "In", "both", "cases,", "the", "majority", "of", "the", "bone", "marrow", "cells", "(47", "and", "70%,", "respectively)", "were", "normal", "chromosome", "3", "disomics.", "The", "interstitial", "deletions", "detected", "harbor", "a", "known", "homozygous", "deletion", "region", "between", "72.6", "and", "78.8", "Mb,", "which", "has", "been", "described", "in", "lung", "and", "breast", "tumors", "and", "contains", "the", "DUTT1/ROBO1", "tumor", "suppressor", "gene.", "These", "deletions", "detected", "by", "mp-FISH", "would", "have", "remained", "unnoticed", "by", "conventional", "cytogenetics", "and", "multiplex", "FISH,", "as", "well", "as", "by", "current", "methods", "based", "on", "total", "tumor", "DNA", "analysis", "such", "as", "comparative", "genomic", "hybridization", "(CGH),", "array", "CGH,", "and", "loss", "of", "heterozygosity", "(LOH)." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	We examined chromosome 3 in 32 childhood acute lymphoblastic leukemia (ALL) bone marrow samples. Using interphase multipoint FISH (mp-FISH), which was developed by our group, with 42 chromosome 3-specific probes, we detected clonal chromosome 3 aberrations in 4 T-cell ALL (T-ALL) cases. Four out of seven T-ALL cases carried 3q trisomies. One T-ALL case carried either trisomy 3 (in 15% of the cells) or a 23-megabase (Mb) 3p13 approximately p12 deletion in a different subpopulation of cells of 32%. Another T-ALL case had either 3q trisomy in 11% or a 12-Mb 3p12 approximately p13 deletion in 19% of the cells. The deletions were overlapping. In both cases, the majority of the bone marrow cells (47 and 70%, respectively) were normal chromosome 3 disomics. The interstitial deletions detected harbor a known homozygous deletion region between 72.6 and 78.8 Mb, which has been described in lung and breast tumors and contains the DUTT1/ROBO1 tumor suppressor gene. These deletions detected by mp-FISH would have remained unnoticed by conventional cytogenetics and multiplex FISH, as well as by current methods based on total tumor DNA analysis such as comparative genomic hybridization (CGH), array CGH, and loss of heterozygosity (LOH).	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15282322	[ "Deletion", "of", "mouse", "rad9", "causes", "abnormal", "cellular", "responses", "to", "DNA", "damage,", "genomic", "instability,", "and", "embryonic", "lethality." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Deletion of mouse rad9 causes abnormal cellular responses to DNA damage, genomic instability, and embryonic lethality.	[ 2, 5541, 1927, 3321, 4226, 1026, 5092, 4552, 3689, 3387, 1942, 2678, 4293, 16, 4935, 9557, 16, 1930, 7231, 15400, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
18813858	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
22295085	[ "Genetic", "and", "epigenetic", "alterations", "of", "the", "NF2", "gene", "in", "sporadic", "vestibular", "schwannomas." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas.	[ 2, 3299, 1930, 8542, 5996, 1927, 1920, 4651, 1028, 2359, 1922, 13088, 15752, 16511, 4956, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
16796766	[ "Genomic", "characterization", "of", "five", "deletions", "in", "the", "LDL", "receptor", "gene", "in", "Danish", "Familial", "Hypercholesterolemic", "subjects." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Genomic characterization of five deletions in the LDL receptor gene in Danish Familial Hypercholesterolemic subjects.	[ 2, 4935, 7285, 1927, 3628, 10550, 1922, 1920, 8017, 3148, 2359, 1922, 18247, 11444, 19284, 4197, 3297, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
19101703	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
17392687	[ "PURPOSE:", "betaB2-crystallin", "is", "one", "of", "the", "most", "abundant", "proteins", "of", "the", "adult", "ocular", "lens", "of", "mammals", "although", "it", "is", "expressed", "at", "lower", "levels", "in", "several", "extralenticular", "locations.", "While", "mutations", "in", "betaB2-crystallin", "are", "known", "to", "result", "in", "lens", "opacities,", "alterations", "in", "tissues", "besides", "the", "lens", "have", "not", "been", "previously", "investigated", "in", "these", "mutants.", "Since", "we", "found", "mice", "harboring", "the", "Crybb2Phil", "mutation", "bred", "poorly,", "here", "we", "assess", "the", "contribution", "of", "betaB2-crystallin", "to", "mouse", "fertility", "and", "determine", "the", "expression", "pattern", "of", "betaB2-crystallin", "in", "the", "testis.", "METHODS:", "The", "expression", "pattern", "of", "betaB2-crystallin", "in", "the", "testis", "was", "analyzed", "by", "rt-PCR,", "western", "blotting,", "and", "immunohistochemistry.", "The", "fecundity", "of", "wildtype", "and", "Crybb2Phil", "mice", "was", "analyzed", "by", "quantitative", "fertility", "testing.", "The", "morphology", "of", "testes", "and", "ovaries", "was", "assessed", "by", "hematoxylin", "and", "eosin", "staining.", "RESULTS:", "In", "the", "mouse", "testis,", "betaB2-crystallin", "mRNA", "is", "found", "at", "low", "levels", "at", "birth,", "but", "its", "expression", "upregulates", "in", "this", "tissue", "as", "the", "testis", "is", "primed", "to", "initiate", "spermatogenesis.", "Western", "blotting", "detected", "betaB2-crystallin", "protein", "in", "sperm", "obtained", "from", "mice,", "cattle,", "and", "humans", "while", "immunolocalization", "detected", "this", "protein", "in", "developing", "sperm", "from", "the", "spermatocyte", "stage", "onward.", "Male", "and", "female", "mice", "homozygous", "for", "a", "12", "nucleotide", "inframe", "deletion", "mutation", "in", "betaB2-crystallin", "are", "subfertile", "when", "analyzed", "on", "a", "Swiss", "Webster", "derived", "background", "due", "to", "defects", "in", "egg", "and", "sperm", "production.", "However,", "mice", "harboring", "the", "same", "mutation", "on", "the", "C57Bl/6", "genetic", "background", "did", "not", "exhibit", "any", "defects", "in", "reproductive", "function.", "CONCLUSIONS:", "betaB2-crystallin", "is", "expressed", "in", "developing", "and", "mature", "sperm", "and", "mice", "of", "both", "sexes", "harboring", "the", "Philly", "mutation", "in", "the", "betaB2-crystallin", "gene", "are", "subfertile", "when", "analyzed", "on", "a", "Swiss", "Webster", "genetic", "background.", "While", "these", "data", "are", "suggestive", "of", "a", "role", "for", "betaB2-crystallin", "in", "fertility,", "definitive", "determination", "of", "this", "will", "await", "the", "creation", "of", "a", "betaB2-crystallin", "null", "mouse." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	PURPOSE: betaB2-crystallin is one of the most abundant proteins of the adult ocular lens of mammals although it is expressed at lower levels in several extralenticular locations. While mutations in betaB2-crystallin are known to result in lens opacities, alterations in tissues besides the lens have not been previously investigated in these mutants. Since we found mice harboring the Crybb2Phil mutation bred poorly, here we assess the contribution of betaB2-crystallin to mouse fertility and determine the expression pattern of betaB2-crystallin in the testis. METHODS: The expression pattern of betaB2-crystallin in the testis was analyzed by rt-PCR, western blotting, and immunohistochemistry. The fecundity of wildtype and Crybb2Phil mice was analyzed by quantitative fertility testing. The morphology of testes and ovaries was assessed by hematoxylin and eosin staining. RESULTS: In the mouse testis, betaB2-crystallin mRNA is found at low levels at birth, but its expression upregulates in this tissue as the testis is primed to initiate spermatogenesis. Western blotting detected betaB2-crystallin protein in sperm obtained from mice, cattle, and humans while immunolocalization detected this protein in developing sperm from the spermatocyte stage onward. Male and female mice homozygous for a 12 nucleotide inframe deletion mutation in betaB2-crystallin are subfertile when analyzed on a Swiss Webster derived background due to defects in egg and sperm production. However, mice harboring the same mutation on the C57Bl/6 genetic background did not exhibit any defects in reproductive function. CONCLUSIONS: betaB2-crystallin is expressed in developing and mature sperm and mice of both sexes harboring the Philly mutation in the betaB2-crystallin gene are subfertile when analyzed on a Swiss Webster genetic background. While these data are suggestive of a role for betaB2-crystallin in fertility, definitive determination of this will await the creation of a betaB2-crystallin null mouse.	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21059483	[ "Classic", "galactosemia", "is", "an", "autosomal", "recessive", "disorder", "of", "galactose", "metabolism", "manifesting", "in", "the", "first", "weeks", "of", "life", "following", "exposure", "to", "a", "milk-based", "diet.", "Despite", "the", "benefit", "of", "avoidance", "of", "lactose,", "many", "patients", "suffer", "from", "long-term", "complications", "including", "neurological", "deficits", "and", "ovarian", "failure.", "To", "date,", "over", "230", "mutations", "have", "been", "described", "in", "the", "GALT", "gene", "resulting", "in", "galactosemia.", "Recently,", "an", "unusual", "mutation", "was", "characterized", "causing", "a", "5.5", "kb", "deletion,", "with", "a", "relatively", "high", "carrier", "rate", "in", "subjects", "of", "Ashkenazi", "Jewish", "(AJ)", "descent.", "The", "aim", "of", "this", "study", "was", "to", "estimate", "the", "carrier", "frequency", "of", "this", "mutation", "in", "the", "AJ", "population", "in", "Israel.", "For", "this", "purpose", "we", "developed", "a", "high-throughput", "methodology", "to", "genotype", "both", "normal", "and", "deleted", "alleles", "using", "a", "chip-based", "matrix-assisted", "laser", "desorption-time-of-flight", "(MALDI-TOF)", "mass", "spectrometer", "and", "Multiplex", "PCR.", "DNA", "samples", "of", "760", "anonymous", "AJ", "subjects", "were", "submitted", "for", "analysis,", "subsequently", "detecting", "six", "individuals", "heterozygous", "for", "the", "GALT", "deletion", "mutation,", "giving", "a", "carrier", "frequency", "of", "1", "in", "127", "(0.79%).", "Based", "on", "these", "results,", "we", "suggest", "that", "the", "method", "described", "here", "provides", "a", "basis", "for", "genetic", "screening", "and", "prenatal", "counseling", "and", "can", "potentially", "reduce", "the", "morbidity", "and", "mortality", "associated", "with", "delayed", "diagnosis", "of", "galactosemia", "in", "this", "patient", "population." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Classic galactosemia is an autosomal recessive disorder of galactose metabolism manifesting in the first weeks of life following exposure to a milk-based diet. Despite the benefit of avoidance of lactose, many patients suffer from long-term complications including neurological deficits and ovarian failure. To date, over 230 mutations have been described in the GALT gene resulting in galactosemia. Recently, an unusual mutation was characterized causing a 5.5 kb deletion, with a relatively high carrier rate in subjects of Ashkenazi Jewish (AJ) descent. The aim of this study was to estimate the carrier frequency of this mutation in the AJ population in Israel. For this purpose we developed a high-throughput methodology to genotype both normal and deleted alleles using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer and Multiplex PCR. DNA samples of 760 anonymous AJ subjects were submitted for analysis, subsequently detecting six individuals heterozygous for the GALT deletion mutation, giving a carrier frequency of 1 in 127 (0.79%). Based on these results, we suggest that the method described here provides a basis for genetic screening and prenatal counseling and can potentially reduce the morbidity and mortality associated with delayed diagnosis of galactosemia in this patient population.	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16628674	[ "A", "novel", "multidrug-resistance", "protein", "2", "gene", "mutation", "identifies", "a", "subgroup", "of", "patients", "with", "primary", "biliary", "cirrhosis", "and", "pruritus." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus.	[ 2, 43, 4008, 16398, 17, 3554, 2213, 22, 2359, 3979, 14133, 43, 6200, 1927, 2132, 1956, 3065, 13210, 11260, 1930, 27496, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
15353880	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
12820697	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
19542096	[ "Arthrogryposis", "multiplex", "congenita", "(AMC)", "is", "a", "group", "of", "disorders", "characterized", "by", "congenital", "joint", "contractures", "caused", "by", "reduced", "fetal", "movements.", "AMC", "has", "an", "incidence", "of", "1", "in", "3000", "newborns", "and", "is", "genetically", "heterogeneous.", "We", "describe", "an", "autosomal", "recessive", "form", "of", "myogenic", "AMC", "in", "a", "large", "consanguineous", "family.", "The", "disease", "is", "characterized", "by", "bilateral", "clubfoot,", "decreased", "fetal", "movements,", "delay", "in", "motor", "milestones,", "then", "progressive", "motor", "decline", "after", "the", "first", "decade.", "Genome-wide", "linkage", "analysis", "revealed", "a", "single", "locus", "on", "chromosome", "6q25", "with", "Z(max)", "=", "3.55", "at", "theta", "=", "0.0", "and", "homozygosity", "of", "the", "polymorphic", "markers", "at", "this", "locus", "in", "patients.", "Homozygous", "A", "to", "G", "nucleotide", "substitution", "of", "the", "conserved", "AG", "splice", "acceptor", "site", "at", "the", "junction", "of", "intron", "136", "and", "exon", "137", "of", "the", "SYNE-1", "gene", "was", "found", "in", "patients.", "This", "mutation", "results", "in", "an", "aberrant", "retention", "of", "intron", "136", "of", "SYNE-1", "RNA", "leading", "to", "premature", "stop", "codons", "and", "the", "lack", "of", "the", "C-terminal", "transmembrane", "domain", "KASH", "of", "nesprin-1,", "the", "SYNE-1", "gene", "product.", "Mice", "lacking", "the", "KASH", "domain", "of", "nesprin-1", "display", "a", "myopathic", "phenotype", "similar", "to", "that", "observed", "in", "patients.", "Altogether,", "these", "data", "strongly", "suggest", "that", "the", "splice", "site", "mutation", "of", "SYNE-1", "gene", "found", "in", "the", "family", "is", "responsible", "for", "AMC.", "Recent", "reports", "have", "shown", "that", "mutations", "of", "the", "SYNE-1", "gene", "might", "be", "responsible", "for", "autosomal", "recessive", "adult", "onset", "cerebellar", "ataxia.", "These", "data", "indicate", "that", "mutations", "of", "nesprin-1", "which", "interacts", "with", "lamin", "A/C", "may", "lead", "to", "at", "least", "two", "distinct", "human", "disease", "phenotypes,", "myopathic", "or", "neurological,", "a", "feature", "similar", "to", "that", "found", "in", "laminopathies." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Arthrogryposis multiplex congenita (AMC) is a group of disorders characterized by congenital joint contractures caused by reduced fetal movements. AMC has an incidence of 1 in 3000 newborns and is genetically heterogeneous. We describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterized by bilateral clubfoot, decreased fetal movements, delay in motor milestones, then progressive motor decline after the first decade. Genome-wide linkage analysis revealed a single locus on chromosome 6q25 with Z(max) = 3.55 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Homozygous A to G nucleotide substitution of the conserved AG splice acceptor site at the junction of intron 136 and exon 137 of the SYNE-1 gene was found in patients. This mutation results in an aberrant retention of intron 136 of SYNE-1 RNA leading to premature stop codons and the lack of the C-terminal transmembrane domain KASH of nesprin-1, the SYNE-1 gene product. Mice lacking the KASH domain of nesprin-1 display a myopathic phenotype similar to that observed in patients. Altogether, these data strongly suggest that the splice site mutation of SYNE-1 gene found in the family is responsible for AMC. Recent reports have shown that mutations of the SYNE-1 gene might be responsible for autosomal recessive adult onset cerebellar ataxia. These data indicate that mutations of nesprin-1 which interacts with lamin A/C may lead to at least two distinct human disease phenotypes, myopathic or neurological, a feature similar to that found in laminopathies.	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20126413	[ "U87MG", "decoded:", "the", "genomic", "sequence", "of", "a", "cytogenetically", "aberrant", "human", "cancer", "cell", "line." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line.	[ 2, 18617, 9759, 2344, 21564, 30, 1920, 4935, 3244, 1927, 43, 18486, 2169, 9801, 2616, 2539, 2024, 2823, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
19435819	[ "High-resolution", "genomic", "copy", "number", "profiling", "of", "glioblastoma", "multiforme", "by", "single", "nucleotide", "polymorphism", "DNA", "microarray." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray.	[ 2, 2149, 17, 4885, 4935, 6983, 2529, 10156, 1927, 14224, 15453, 2076, 1021, 2007, 2957, 5489, 8218, 2678, 7850, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
19521089	[ "Parkinson's", "disease", "(PD)", "is", "a", "neurodegenerative", "disorder", "causing", "muscular", "rigidity,", "resting", "tremor", "and", "bradykinesia.", "We", "conducted", "an", "association", "study", "assessing", "how", "PD", "risk", "in", "Italy", "was", "influenced", "by", "the", "serotonin", "transporter", "gene", "(SLC6A4)", "polymorphic", "region", "5-HTTLPR,", "consisting", "of", "an", "insertion/deletion", "(long", "allele-L/short", "allele-S)", "of", "43", "bp", "in", "the", "SLC6A4", "promoter", "region.", "The", "SLC6A4", "promoter", "single", "nucleotide", "polymorphism", "rs25531", "(", "A-->G", ")", "was", "evaluated", "too.", "We", "collected", "837", "independent", "subjects", "(393", "PD,", "444", "controls).", "An", "association", "between", "the", "5-HTTLPR", "polymorphism", "and", "risk", "of", "PD", "(S/S", "genotype", "OR", "[95%", "CI]:", "1.7[1.2-2.5],", "p", "=", "0.002)", "was", "found.", "The", "rs25531", " ", "and", "the", "haplotype", "5-HTTLPR/", "rs25531", " ", "did", "not", "associate", "with", "risk", "of", "PD.", "Our", "data", "indicate", "that", "the", "5-HTTLPR", "polymorphic", "element", "within", "the", "SLC6A4", "promoter", "may", "govern", "the", "genetic", "risk", "of", "PD", "in", "Italians." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Parkinson's disease (PD) is a neurodegenerative disorder causing muscular rigidity, resting tremor and bradykinesia. We conducted an association study assessing how PD risk in Italy was influenced by the serotonin transporter gene (SLC6A4) polymorphic region 5-HTTLPR, consisting of an insertion/deletion (long allele-L/short allele-S) of 43 bp in the SLC6A4 promoter region. The SLC6A4 promoter single nucleotide polymorphism rs25531 ( A-->G ) was evaluated too. We collected 837 independent subjects (393 PD, 444 controls). An association between the 5-HTTLPR polymorphism and risk of PD (S/S genotype OR [95% CI]: 1.7[1.2-2.5], p = 0.002) was found. The rs25531 and the haplotype 5-HTTLPR/ rs25531 did not associate with risk of PD. Our data indicate that the 5-HTTLPR polymorphic element within the SLC6A4 promoter may govern the genetic risk of PD in Italians.	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19218574	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
15316799	[ "Apolipoprotein", "D", "(apoD)", "is", "a", "lipoprotein-associated", "glycoprotein,", "structurally", "unrelated", "to", "apoE,", "that", "transports", "small", "hydrophobic", "ligands", "including", "cholesterol", "and", "sterols.", "Levels", "are", "increased", "in", "the", "hippocampus", "and", "CSF", "of", "Alzheimer's", "disease", "(AD)", "patients.", "We", "tested", "whether", "variation", "in", "the", "APOD", "gene", "affects", "AD", "risk.", "Four", "single", "nucleotide", "polymorphisms", "(SNPs)", "were", "investigated", "(in", "map", "order):", "exon", "2,", "15T-->C", " ", "encodes", "an", "amino", "acid", "substitution", "Phe-->Ser", "at", "codon", "15", ";", "intron", "2,", "-352G-->A", ";", "intron", "3,", "+45C-->T", ";", "intron", "4,", "+718C-->T", ",", "determined", "by", "SNaPshot", "assay.", "SNP", "frequencies", "for", "394", "eastern", "Finnish", "AD", "patients", "were", "compared", "with", "those", "found", "for", "470", "control", "subjects,", "dividing", "subjects", "also", "into", "early-onset", "AD", "(EOAD;", "<", "or", "=", "65", "years)", "and", "late-onset", "AD", "(LOAD;", ">65", "years)", "groups.", "The", "-352G", "allele", "was", "associated", "with", "a", "significant", "3-fold", "increase", "in", "the", "risk", "of", "EOAD", "(OR:", "2.7;", "95%", "CI:", "1.1-6.5).", "The", "-352G", "containing", "haplotypes", "were", "more", "common", "for", "EOAD", "cases", "(TGCC:", "0.48", "vs", "0.41;", "TGCT:", "0.08", "vs", "0.01", "(p", "=", "0.002).", "In", "the", "Grade-of-membership", "analysis,", "APOD", "genotype", "frequencies", "at", "each", "SNP", "site", "and", "disease", "status", "were", "used", "to", "construct", "two", "latent", "groups:", "the", "affected", "group", "carried", "-352", "as", "GG", "or", "GA", "and", "+45", "CC,", "was", "often", "women", "and", "enriched", "in", "APOE", "epsilon4.", "Each", "method", "suggested", "that", "the", "-352G", "allele", "frequency", "is", "higher", "for", "EOAD", "in", "the", "eastern", "Finnish", "population." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 0, 1, 2, 2, 0, 1, 2, 2, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein, structurally unrelated to apoE, that transports small hydrophobic ligands including cholesterol and sterols. Levels are increased in the hippocampus and CSF of Alzheimer's disease (AD) patients. We tested whether variation in the APOD gene affects AD risk. Four single nucleotide polymorphisms (SNPs) were investigated (in map order): exon 2, 15T-->C encodes an amino acid substitution Phe-->Ser at codon 15 ; intron 2, -352G-->A ; intron 3, +45C-->T ; intron 4, +718C-->T , determined by SNaPshot assay. SNP frequencies for 394 eastern Finnish AD patients were compared with those found for 470 control subjects, dividing subjects also into early-onset AD (EOAD; < or = 65 years) and late-onset AD (LOAD; >65 years) groups. The -352G allele was associated with a significant 3-fold increase in the risk of EOAD (OR: 2.7; 95% CI: 1.1-6.5). The -352G containing haplotypes were more common for EOAD cases (TGCC: 0.48 vs 0.41; TGCT: 0.08 vs 0.01 (p = 0.002). In the Grade-of-membership analysis, APOD genotype frequencies at each SNP site and disease status were used to construct two latent groups: the affected group carried -352 as GG or GA and +45 CC, was often women and enriched in APOE epsilon4. Each method suggested that the -352G allele frequency is higher for EOAD in the eastern Finnish population.	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20693575	[ "BACKGROUND:", "HCN", "channels", "activate", "the", "pacemaker", "current", "I(f),", "which", "is", "thought", "to", "contribute", "significantly", "to", "generation", "and", "regulation", "of", "heart", "rhythm.", "HCN4", "represents", "the", "dominant", "isotype", "in", "the", "sinoatrial", "node", "and", "binding", "of", "cAMP", "was", "suggested", "to", "be", "necessary", "for", "autonomic", "heart", "rate", "regulation.", "METHODS", "AND", "RESULTS:", "In", "a", "candidate", "gene", "approach,", "a", "heterozygous", "insertion", "of", "13", "nucleotides", "in", "exon", "6", "of", "the", "HCN4", "gene", "leading", "to", "a", "truncated", "cyclic", "nucleotide-binding", "domain", "was", "identified", "in", "a", "45-year-old", "woman", "with", "sinus", "bradycardia.", "Biophysical", "properties", "determined", "by", "whole-cell", "patch-clamp", "recording", "of", "HEK293", "cells", "demonstrated", "that", "mutant", "subunits", "(HCN4-695X)", "were", "insensitive", "to", "cAMP.", "Heteromeric", "channels", "composed", "of", "wild-type", "and", "mutant", "subunits", "failed", "to", "respond", "to", "cAMP-like", "homomeric", "mutant", "channels,", "indicating", "a", "dominant-negative", "suppression", "of", "cAMP-induced", "channel", "activation", "by", "mutant", "subunits.", "Pedigree", "analysis", "identified", "7", "additional", "living", "carriers", "showing", "similar", "clinical", "phenotypes,", "that", "is,", "sinus", "node", "dysfunction", "with", "mean", "resting", "heart", "rate", "of", "45.9", " ", "4.6", "bpm", "(n=8)", "compared", "with", "66.5", " ", "9.1", "bpm", "of", "unaffected", "relatives", "(n=6;", "P<0.01).", "Clinical", "evaluation", "revealed", "no", "ischemic", "or", "structural", "heart", "disease", "in", "any", "family", "member.", "Importantly,", "mutant", "carriers", "exhibited", "normal", "heart", "rate", "variance", "and", "full", "ability", "to", "accelerate", "heart", "rate", "under", "physical", "activity", "or", "pharmacological", "stimulation.", "Moreover,", "mutant", "carriers", "displayed", "distinctive", "sinus", "arrhythmias", "and", "premature", "beats", "linked", "to", "adrenergic", "stress.", "CONCLUSIONS:", "In", "humans,", "cAMP", "responsiveness", "of", "I(f)", "determines", "basal", "heart", "rate", "but", "is", "not", "critical", "for", "maximum", "heart", "rate,", "heart", "rate", "variability,", "or", "chronotropic", "competence.", "Furthermore,", "cAMP-activated", "I(f)", "may", "stabilize", "heart", "rhythm", "during", "chronotropic", "response." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	BACKGROUND: HCN channels activate the pacemaker current I(f), which is thought to contribute significantly to generation and regulation of heart rhythm. HCN4 represents the dominant isotype in the sinoatrial node and binding of cAMP was suggested to be necessary for autonomic heart rate regulation. METHODS AND RESULTS: In a candidate gene approach, a heterozygous insertion of 13 nucleotides in exon 6 of the HCN4 gene leading to a truncated cyclic nucleotide-binding domain was identified in a 45-year-old woman with sinus bradycardia. Biophysical properties determined by whole-cell patch-clamp recording of HEK293 cells demonstrated that mutant subunits (HCN4-695X) were insensitive to cAMP. Heteromeric channels composed of wild-type and mutant subunits failed to respond to cAMP-like homomeric mutant channels, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. Pedigree analysis identified 7 additional living carriers showing similar clinical phenotypes, that is, sinus node dysfunction with mean resting heart rate of 45.9 4.6 bpm (n=8) compared with 66.5 9.1 bpm of unaffected relatives (n=6; P<0.01). Clinical evaluation revealed no ischemic or structural heart disease in any family member. Importantly, mutant carriers exhibited normal heart rate variance and full ability to accelerate heart rate under physical activity or pharmacological stimulation. Moreover, mutant carriers displayed distinctive sinus arrhythmias and premature beats linked to adrenergic stress. CONCLUSIONS: In humans, cAMP responsiveness of I(f) determines basal heart rate but is not critical for maximum heart rate, heart rate variability, or chronotropic competence. Furthermore, cAMP-activated I(f) may stabilize heart rhythm during chronotropic response.	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18046082	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
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17175380	[ "Multipoint", "interphase", "FISH", "in", "childhood", "T-acute", "lymphoblastic", "leukemia", "detects", "subpopulations", "that", "carry", "different", "chromosome", "3", "aberrations." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations.	[ 2, 20677, 4418, 21376, 5724, 1922, 7238, 62, 17, 3939, 24403, 8111, 19998, 14349, 1988, 9875, 2413, 5597, 23, 16303, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
21790735	[ "C1", "inhibitor", "(C1-INH)", "deficiency", "[hereditary", "or", "acquired", "angio-oedema", "(HAE", "or", "AAE)]", "is", "characterized", "by", "recurring", "episodes", "of", "subcutaneous", "or", "submucosal", "oedema.", "Many", "different", "mutations", "in", "the", "C1-INH", "gene", "have", "been", "identified", "as", "a", "cause", "of", "HAE.", "We", "investigated", "the", "molecular", "basis", "of", "the", "disease", "in", "a", "Japanese", "woman", "with", "sporadic", "HAE.", "Direct", "sequencing", "of", "genomic", "DNA", "revealed", "no", "point", "mutation", "in", "the", "C1-INH", "gene.", "Quantitative", "real-time", "PCR", "showed", "that", "the", "copy", "number", "of", "the", "C1-INH", "gene", "in", "the", "patient", "was", "half", "that", "of", "a", "healthy", "control.", "Furthermore,", "we", "identified", "a", "650-kbp", "deletion", "on", "the", "chromosome,", "which", "included", "the", "C1-INH", "gene.", "We", "evaluated", "the", "correlation", "between", "the", "patient's", "attacks", "and", "her", "coagulation", "activity.", "The", "levels", "of", "D-dimer", "were", "high", "during", "the", "angio-oedema", "attacks,", "and", "often", "exceeded", "the", "normal", "range", "even", "during", "remission,", "thus", "the", "level", "of", "D-dimer", "reflected", "the", "activity", "of", "HAE", "in", "this", "patient." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	C1 inhibitor (C1-INH) deficiency [hereditary or acquired angio-oedema (HAE or AAE)] is characterized by recurring episodes of subcutaneous or submucosal oedema. Many different mutations in the C1-INH gene have been identified as a cause of HAE. We investigated the molecular basis of the disease in a Japanese woman with sporadic HAE. Direct sequencing of genomic DNA revealed no point mutation in the C1-INH gene. Quantitative real-time PCR showed that the copy number of the C1-INH gene in the patient was half that of a healthy control. Furthermore, we identified a 650-kbp deletion on the chromosome, which included the C1-INH gene. We evaluated the correlation between the patient's attacks and her coagulation activity. The levels of D-dimer were high during the angio-oedema attacks, and often exceeded the normal range even during remission, thus the level of D-dimer reflected the activity of HAE in this patient.	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17868390	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
22125978	[ "OBJECTIVE:", "To", "identify", "the", "disease", "causing", "gene", "in", "a", "four", "generation", "consanguineous", "family", "in", "which", "eleven", "family", "members", "were", "suffering", "from", "Woolly", "hair/hypotrichosis", "phenotype.", "METHODS:", "Linkage", "analysis", "was", "carried", "out", "to", "identify", "the", "disease-causing", "gene", "in", "this", "family.", "Genomic", "DNA", "of", "all", "the", "available", "family", "members", "was", "genotyped", "for", "the", "microsatellite", "markers", "for", "all", "the", "known", "woolly", "hair/hypotrichosis", "loci.Automated", "DNA", "sequencing", "of", "the", "candidate", "gene", "was", "performed", "to", "identify", "the", "disease-causing", "mutation.", "RESULTS:", "By", "using", "homozygosity", "linkage", "analysis", "we", "have", "mapped", "the", "family", "on", "chromosome", "3q27.3", "with", "a", "two", "point", "LOD", "score", "of", "4.04,", "Mutation", "screening", "of", "the", "LIPH", "gene", "revealed", "a", "homozygous", "c.659_660delTA", " ", "deletion", "mutation", "segregating", "with", "the", "disease", "phenotype.", "CONCLUSION:", "The", "results", "indicate", "that", "the", "c.659_660delTA", " ", "mutation", "in", "the", "LIPH", "gene", "cause", "autosomal", "recessive", "WH/hypotrichosis", "phenotype", "in", "this", "family.", "This", "mutation", "has", "been", "reported", "in", "several", "Pakistani", "and", "Guyanese", "families", "suggesting", "a", "founder", "mutation", "in", "the", "LIPH", "gene", "in", "Indo-Pak", "sub-continent." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	OBJECTIVE: To identify the disease causing gene in a four generation consanguineous family in which eleven family members were suffering from Woolly hair/hypotrichosis phenotype. METHODS: Linkage analysis was carried out to identify the disease-causing gene in this family. Genomic DNA of all the available family members was genotyped for the microsatellite markers for all the known woolly hair/hypotrichosis loci.Automated DNA sequencing of the candidate gene was performed to identify the disease-causing mutation. RESULTS: By using homozygosity linkage analysis we have mapped the family on chromosome 3q27.3 with a two point LOD score of 4.04, Mutation screening of the LIPH gene revealed a homozygous c.659_660delTA deletion mutation segregating with the disease phenotype. CONCLUSION: The results indicate that the c.659_660delTA mutation in the LIPH gene cause autosomal recessive WH/hypotrichosis phenotype in this family. This mutation has been reported in several Pakistani and Guyanese families suggesting a founder mutation in the LIPH gene in Indo-Pak sub-continent.	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14722925	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
16989765	[ "A", "novel", "His158Arg", " ", "mutation", "in", "TIMP3", "causes", "a", "late-onset", "form", "of", "Sorsby", "fundus", "dystrophy." ]	[ 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy.	[ 2, 43, 4008, 4167, 22633, 2419, 3979, 1922, 18300, 1010, 5092, 43, 5058, 17, 4727, 2386, 1927, 6548, 1036, 4864, 18862, 19321, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
18391980	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
18164595	[ "Mutations", "in", "the", "hairless", "gene", "underlie", "APL", "in", "three", "families", "of", "Pakistani", "origin." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Mutations in the hairless gene underlie APL in three families of Pakistani origin.	[ 2, 3527, 1922, 1920, 7018, 5427, 2359, 14150, 18373, 1922, 2559, 5767, 1927, 21493, 1033, 4853, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
21182502	[ "A", "novel", "homozygous", "splice", "site", "mutation", "in", "COL7A1", "in", "a", "Chinese", "patient", "with", "severe", "recessive", "dystrophic", "epidermolysis", "bullosa", "and", "squamous", "cell", "carcinoma." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	A novel homozygous splice site mutation in COL7A1 in a Chinese patient with severe recessive dystrophic epidermolysis bullosa and squamous cell carcinoma.	[ 2, 43, 4008, 9419, 10708, 3200, 3979, 1922, 2503, 13827, 1009, 1922, 43, 7185, 2774, 1956, 4010, 13992, 29851, 12135, 6892, 14267, 5360, 1930, 10364, 2024, 5373, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
19664890	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
20143913	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
16614502	[ "Insertion/deletion", "polymorphism", "of", "angiotensin", "converting", "enzyme", "gene", "in", "Kawasaki", "disease." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Insertion/deletion polymorphism of angiotensin converting enzyme gene in Kawasaki disease.	[ 2, 7413, 19, 5541, 8218, 1927, 10814, 15025, 4113, 2359, 1922, 22131, 29299, 2573, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
16311014	[ "This", "study", "demonstrates", "an", "array-based", "platform", "to", "genotype", "simultaneously", "single", "nucleotide", "polymorphisms", "(SNPs)", "and", "some", "short", "insertions/deletions", "(indels)", "by", "the", "integration", "of", "the", "universal", "tag/anti-tag", "(TAT)", "system,", "liquid-phase", "primer", "extension", "(LIPEX),", "and", "a", "novel", "two-color", "detection", "strategy", "on", "an", "array", "format", "(TATLIPEXA).", "The", "TAT", "system", "permits", "a", "universal", "chip", "to", "be", "used", "for", "many", "applications,", "and", "the", "LIPEX", "simplifies", "the", "sample", "preparation", "but", "improves", "the", "sensitivity", "significantly.", "More", "importantly,", "all", "SNPs", "and", "some", "short", "indels", "can", "be", "interrogated", "in", "a", "single", "reaction", "with", "only", "two", "fluorescent", "ddNTPs.", "The", "concept", "of", "TATLIPEXA", "is", "demonstrated", "for", "nine", "SNPs", "(eight", "point", "mutations", "and", "one", "single-base", "insertion),", "and", "genotypes", "obtained", "show", "a", "remarkable", "concordance", "rate", "of", "100%", "with", "both", "DNA", "sequencing", "and", "restriction", "fragment", "length", "polymorphism.", "Moreover,", "TATLIPEXA", "is", "able", "to", "provide", "quantitative", "information", "on", "allele", "frequency", "in", "pooled", "DNA", "samples,", "which", "could", "serve", "as", "a", "rapid", "screening", "tool", "for", "SNPs", "associated", "with", "diseases." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	This study demonstrates an array-based platform to genotype simultaneously single nucleotide polymorphisms (SNPs) and some short insertions/deletions (indels) by the integration of the universal tag/anti-tag (TAT) system, liquid-phase primer extension (LIPEX), and a novel two-color detection strategy on an array format (TATLIPEXA). The TAT system permits a universal chip to be used for many applications, and the LIPEX simplifies the sample preparation but improves the sensitivity significantly. More importantly, all SNPs and some short indels can be interrogated in a single reaction with only two fluorescent ddNTPs. The concept of TATLIPEXA is demonstrated for nine SNPs (eight point mutations and one single-base insertion), and genotypes obtained show a remarkable concordance rate of 100% with both DNA sequencing and restriction fragment length polymorphism. Moreover, TATLIPEXA is able to provide quantitative information on allele frequency in pooled DNA samples, which could serve as a rapid screening tool for SNPs associated with diseases.	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15623763	[ "TGFBI", "gene", "mutations", "causing", "lattice", "and", "granular", "corneal", "dystrophies", "in", "Indian", "patients." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients.	[ 2, 5525, 3821, 2359, 3527, 7538, 13018, 1930, 16284, 9990, 10612, 2789, 2062, 1922, 10733, 2132, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
18827003	[ "A", "novel", "point", "mutation", "in", "the", "amino", "terminal", "domain", "of", "the", "human", "glucocorticoid", "receptor", "(hGR)", "gene", "enhancing", "hGR-mediated", "gene", "expression." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression.	[ 2, 43, 4008, 3575, 3979, 1922, 1920, 3835, 4262, 3418, 1927, 1920, 2616, 14469, 3148, 12, 7175, 1005, 13, 2359, 9221, 7175, 1005, 17, 3434, 2359, 2294, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
20086182	[ "Caspase", "8", "(CASP8)", "is", "an", "apoptosis-related", "cysteine", "peptidase", "involved", "in", "the", "death", "receptor", "pathway", "and", "likely", "in", "the", "mitochondrial", "pathway.", "A", "CASP8", "promoter", "region", "six-nucleotide", "deletion/insertion", "(", "-652", "6N", "ins/del", ")", "variant", "and", "a", "coding", "region", "D302H", " ", "polymorphism", "are", "reportedly", "important", "in", "cancer", "development,", "but", "no", "reported", "study", "has", "assessed", "the", "associations", "of", "these", "genetic", "variations", "with", "risk", "of", "head", "and", "neck", "cancer.", "In", "a", "hospital-based", "study", "of", "non-Hispanic", "whites,", "we", "genotyped", "CASP8", "-652", "6N", "del", " ", "and", "302H", "variants", "in", "1,023", "patients", "with", "squamous", "cell", "carcinoma", "of", "the", "head", "and", "neck", "(SCCHN)", "and", "1,052", "cancer-free", "controls.", "Crude", "and", "adjusted", "odds", "ratios", "(OR)", "and", "95%", "confidence", "intervals", "(CI)", "were", "estimated", "using", "unconditional", "logistic", "regression", "models.", "The", "CASP8", "-652", "6N", "del", " ", "variant", "genotypes", "or", "haplotypes", "were", "inversely", "associated", "with", "SCCHN", "risk", "(adjusted", "OR,", "0.70;", "95%", "CI,", "0.57-0.85", "for", "the", "ins/del", "+", "del/del", "genotypes", "compared", "with", "the", "ins/ins", "genotype;", "adjusted", "OR,", "0.73;", "95%", "CI,", "0.55-0.97", "for", "the", "del-D", "haplotype", "compared", "with", "the", "ins-D", "haplotype).", "Furthermore,", "the", "number", "of", "the", "CASP8", "-652", "6N", "del", " ", "(but", "not", "302H)", "variant", "allele", "tended", "to", "correlate", "with", "increased", "levels", "of", "camptothecin-induced", "p53-mediated", "apoptosis", "in", "T", "lymphocytes", "from", "170", "cancer-free", "controls.", "We", "concluded", "that", "the", "CASP8", "-652", "6N", "del", " ", "variant", "allele", "may", "contribute", "to", "the", "risk", "of", "developing", "SCCHN", "in", "non-Hispanic", "white", "populations.", "Further", "validation", "by", "population-based", "case-control", "studies", "and", "rigorous", "mechanistic", "studies", "is", "warranted." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion ( -652 6N ins/del ) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted.	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22125978	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
20949073	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
15607529	[ "Inactivating", "mutations", "in", "the", "LH", "receptor", "are", "the", "predominant", "cause", "for", "male", "pseudohermaphroditism", "in", "subjects", "with", "Leydig", "cell", "hypoplasia", "(LCH).", "The", "severity", "of", "the", "mutations,", "correlates", "with", "residual", "receptor", "activities.", "Here,", "we", "detail", "the", "clinical", "presentation", "of", "one", "subject", "with", "complete", "male", "pseudohermaphroditism", "and", "LCH.", "We", "identify", "within", "the", "proband", "and", "her", "similarly", "afflicted", "sibling", "a", "homozygous", "T", "to", "G", "transversion", "at", "nucleotide", "1836", "in", "exon", "11", "of", "the", "LH/CGR", "gene.", "This", "causes", "conversion", "of", "a", "tyrosine", "codon", "into", "a", "stop", "codon", "at", "codon", "612", "in", "the", "seventh", "transmembrane", "domain,", "resulting", "in", "a", "truncated", "receptor", "that", "lacks", "a", "cytoplasmic", "tail.", "In", "vitro,", "in", "contrast", "to", "cells", "expressing", "a", "normal", "LHR,", "cells", "transfected", "with", "the", "mutant", "cDNA", "exhibit", "neither", "surface", "binding", "of", "radiolabeled", "hCG", "nor", "cAMP", "generation.", "In", "vitro", "expression", "under", "the", "control", "of", "the", "LHR", "signal", "peptide", "of", "either", "a", "wild", "type", "or", "mutant", "LHR-GFP", "fusion", "protein", "shows", "no", "differences", "in", "receptor", "cellular", "localization.", "In", "conclusion,", "the", "in", "vitro", "studies", "suggest", "that", "residues", "in", "the", "seventh", "transmembrane", "domain", "and", "cytoplasmic", "tail", "are", "important", "for", "receptor", "binding", "and", "activation", "without", "playing", "a", "major", "role", "in", "receptor", "cellular", "trafficking." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Inactivating mutations in the LH receptor are the predominant cause for male pseudohermaphroditism in subjects with Leydig cell hypoplasia (LCH). The severity of the mutations, correlates with residual receptor activities. Here, we detail the clinical presentation of one subject with complete male pseudohermaphroditism and LCH. We identify within the proband and her similarly afflicted sibling a homozygous T to G transversion at nucleotide 1836 in exon 11 of the LH/CGR gene. This causes conversion of a tyrosine codon into a stop codon at codon 612 in the seventh transmembrane domain, resulting in a truncated receptor that lacks a cytoplasmic tail. In vitro, in contrast to cells expressing a normal LHR, cells transfected with the mutant cDNA exhibit neither surface binding of radiolabeled hCG nor cAMP generation. In vitro expression under the control of the LHR signal peptide of either a wild type or mutant LHR-GFP fusion protein shows no differences in receptor cellular localization. In conclusion, the in vitro studies suggest that residues in the seventh transmembrane domain and cytoplasmic tail are important for receptor binding and activation without playing a major role in receptor cellular trafficking.	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12809638	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
14709355	[ "Familial", "HDL", "deficiency", "(FHD)", "is", "a", "rare", "autosomal", "dominant", "lipoprotein", "disorder.", "We", "describe", "a", "novel", "genetic", "variant", "of", "the", "apolipoprotein", "A-I", "(apoA-I)", "gene", "resulting", "in", "FHD.", "The", "proband", "is", "a", "51-year-old", "woman", "who", "was", "hospitalized", "due", "to", "severe", "heart", "failure.", "Her", "plasma", "HDL-cholesterol", "(C)", "and", "apoA-I", "concentrations", "were", "0.08mmol/l", "and", "1mg/dl,", "respectively.", "She", "exhibited", "corneal", "opacities", "and", "planar", "xanthomas", "on", "eyelids", "and", "elbows.", "Coronary", "angiography", "demonstrated", "extensive", "obstructions", "in", "two", "major", "vessels.", "Genomic", "DNA", "sequencing", "of", "the", "patient's", "apoA-I", "gene", "revealed", "a", "homozygosity", "for", "a", "GC", "deletion", "between", "5", "GC", "repeats", "in", "exon", "4,", "creating", "a", "frameshift", "and", "a", "stop", "codon", "at", "residue", "178.", "We", "designated", "this", "mutation", "as", "apoA-I", "Shinbashi.", "The", "proband's", "father,", "son,", "and", "daughter", "were", "found", "to", "be", "heterozygous", "for", "this", "mutation", "and", "their", "HDL-C", "and", "apoA-I", "levels", "were", "about", "half", "of", "normal", "levels,", "demonstrating", "a", "gene", "dosage", "effect.", "The", "father", "underwent", "coronary", "bypass", "surgery", "at", "age", "of", "70", "years.", "Lecithin-cholesterol", "acyltransferase", "(LCAT)", "activity", "was", "decreased", "by", "63%", "in", "the", "homozygote", "and", "31%", "in", "heterozygotes,", "respectively.", "This", "new", "case", "of", "apoA-I", "deficiency,", "apoA-I", "Shinbashi,", "is", "the", "first", "case", "involving", "a", "single", "gene", "defect", "of", "the", "apoA-I", "gene", "to", "develop", "all", "the", "characteristics", "for", "apoA-I", "deficiency,", "including", "premature", "coronary", "heart", "disease." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Familial HDL deficiency (FHD) is a rare autosomal dominant lipoprotein disorder. We describe a novel genetic variant of the apolipoprotein A-I (apoA-I) gene resulting in FHD. The proband is a 51-year-old woman who was hospitalized due to severe heart failure. Her plasma HDL-cholesterol (C) and apoA-I concentrations were 0.08mmol/l and 1mg/dl, respectively. She exhibited corneal opacities and planar xanthomas on eyelids and elbows. Coronary angiography demonstrated extensive obstructions in two major vessels. Genomic DNA sequencing of the patient's apoA-I gene revealed a homozygosity for a GC deletion between 5 GC repeats in exon 4, creating a frameshift and a stop codon at residue 178. We designated this mutation as apoA-I Shinbashi. The proband's father, son, and daughter were found to be heterozygous for this mutation and their HDL-C and apoA-I levels were about half of normal levels, demonstrating a gene dosage effect. The father underwent coronary bypass surgery at age of 70 years. Lecithin-cholesterol acyltransferase (LCAT) activity was decreased by 63% in the homozygote and 31% in heterozygotes, respectively. This new case of apoA-I deficiency, apoA-I Shinbashi, is the first case involving a single gene defect of the apoA-I gene to develop all the characteristics for apoA-I deficiency, including premature coronary heart disease.	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17671968	[ "Association", "study", "between", "Gilles", "de", "la", "Tourette", "Syndrome", "and", "two", "genes", "in", "the", "Robo-Slit", "pathway", "located", "in", "the", "chromosome", "11q24", "linked/associated", "region." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Association study between Gilles de la Tourette Syndrome and two genes in the Robo-Slit pathway located in the chromosome 11q24 linked/associated region.	[ 2, 3279, 2161, 2192, 18859, 1918, 2028, 5114, 24097, 6488, 4741, 1930, 2288, 2628, 1922, 1920, 4887, 1037, 17, 17354, 3374, 4810, 1922, 1920, 5597, 2513, 23470, 1006, 4624, 19, 2458, 3031, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
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15649253	[ "Primary", "malignant", "lymphoma", "of", "the", "brain:", "frequent", "abnormalities", "and", "inactivation", "of", "p14", "tumor", "suppressor", "gene." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene.	[ 2, 3065, 6558, 8636, 1927, 1920, 3068, 30, 6439, 6754, 1930, 8005, 1927, 21740, 2798, 9241, 2359, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
15377356	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
19365571	[ "PURPOSE:", "To", "identify", "mutations", "in", "the", "carbohydrate", "sulfotransferase", "gene", "(CHST6)", "for", "a", "Chinese", "family", "with", "macular", "corneal", "dystrophy", "(MCD)", "and", "to", "investigate", "the", "histopathological", "changes", "in", "the", "affected", "cornea.", "METHODS:", "A", "corneal", "button", "of", "the", "proband", "was", "obtained", "by", "penetrating", "keratoplasty.", "The", "half", "button", "and", "ultrathin", "sections", "from", "the", "other", "half", "button", "were", "examined", "with", "special", "stains", "under", "a", "light", "microscope", "(LM)", "and", "an", "electron", "microscope", "(EM)", "separately.", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "of", "11", "family", "members,", "and", "the", "coding", "region", "of", "CHST6", "was", "amplified", "by", "the", "polymerase", "chain", "reaction", "(PCR)", "method.", "The", "PCR", "products", "were", "analyzed", "by", "direct", "sequencing", "and", "restriction", "enzyme", "digestion.", "RESULTS:", "The", "positive", "reaction", "to", "colloidal", "iron", "stain", "(extracellular", "blue", "accumulations", "in", "the", "stroma)", "was", "detected", "under", "light", "microscopy.", "Transmission", "electron", "microscopy", "revealed", "the", "enlargement", "of", "smooth", "endoplasmic", "reticulum", "and", "the", "presence", "of", "intracytoplasmic", "vacuoles.", "The", "compound", "heterozygous", "mutations,", "c.892C>T", " ", "and", "c.1072T>C", ",", "were", "identified", "in", "exon", "3", "of", "CHST6", "in", "three", "patients.", "The", "two", "transversions", "resulted", "in", "the", "substitution", "of", "a", "stop", "codon", "for", "glutamine", "at", "codon", "298", "(", "p.Q298X", ")", "and", "a", "missense", "mutation", "at", "codon", "358,", "tyrosine", "to", "histidine", "(", "p.Y358H", ").", "The", "six", "unaffected", "family", "individuals", "carried", "alternative", "heterozygous", "mutations.", "These", "two", "mutations", "were", "not", "detected", "in", "any", "of", "the", "100", "control", "subjects.", "CONCLUSIONS:", "Those", "novel", "compound", "heterozygous", "mutations", "were", "thought", "to", "contribute", "to", "the", "loss", "of", "CHST6", "function,", "which", "induced", "the", "abnormal", "metabolism", "of", "keratan", "sulfate", "(KS)", "that", "deposited", "in", "the", "corneal", "stroma.", "It", "could", "be", "proved", "by", "the", "observation", "of", "a", "positive", "stain", "reaction", "and", "the", "enlarged", "collagen", "fibers", "as", "well", "as", "hyperplastic", "fibroblasts", "under", "microscopes." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea. METHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion. RESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C , were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 ( p.Q298X ) and a missense mutation at codon 358, tyrosine to histidine ( p.Y358H ). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects. CONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes.	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17962394	[ "AIMS:", "This", "study", "aimed", "to", "identify", "the", "underlying", "genetic", "defect", "of", "a", "large", "Turkish", "X", "linked", "nystagmus", "(NYS)", "family.", "METHODS:", "Both", "Xp11", "and", "Xq26", "loci", "were", "tested", "by", "linkage", "analysis.", "The", "12", "exons", "and", "intron-exon", "junctions", "of", "the", "FRMD7", "gene", "were", "screened", "by", "direct", "sequencing.", "X", "chromosome", "inactivation", "analysis", "was", "performed", "by", "enzymatic", "predigestion", "of", "DNA", "with", "a", "methylation-sensitive", "enzyme,", "followed", "by", "PCR", "of", "the", "polymorphic", "CAG", "repeat", "of", "the", "androgen", "receptor", "gene.", "RESULTS:", "The", "family", "contained", "162", "individuals,", "among", "whom", "28", "had", "NYS.", "Linkage", "analysis", "confirmed", "the", "Xq26", "locus.", "A", "novel", "missense", "c.686C>G", " ", "mutation,", "which", "causes", "the", "substitution", "of", "a", "conserved", "arginine", "at", "amino", "acid", "position", "229", "by", "glycine", "(", "p.R229G", ")", "in", "exon", "8", "of", "the", "FRMD7", "gene,", "was", "observed.", "This", "change", "was", "not", "documented", "in", "120", "control", "individuals.", "The", "clinical", "findings", "in", "a", "female", "who", "was", "homozygous", "for", "the", "mutation", "were", "not", "different", "from", "those", "of", "affected", "heterozygous", "females.", "Skewed", "X", "inactivation", "was", "remarkable", "in", "the", "affected", "females", "of", "the", "family.", "CONCLUSIONS:", "A", "novel", "p.R229G", " ", "mutation", "in", "the", "FRMD7", "gene", "causes", "the", "NYS", "phenotype,", "and", "skewed", "X", "inactivation", "influences", "the", "manifestation", "of", "the", "disease", "in", "X", "linked", "NYS", "females." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	AIMS: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. METHODS: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. RESULTS: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine ( p.R229G ) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. CONCLUSIONS: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.	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21126715	[ "Congenital", "generalized", "lipodystrophy", "(CGL)", "is", "a", "rare", "autosomal", "recessive", "disease", "that", "is", "characterized", "by", "a", "near-complete", "absence", "of", "adipose", "tissue", "from", "birth", "or", "early", "infancy.", "Mutations", "in", "the", "BSCL2", "gene", "are", "known", "to", "result", "in", "CGL2,", "a", "more", "severe", "phenotype", "than", "CGL1,", "with", "earlier", "onset,", "more", "extensive", "fat", "loss", "and", "biochemical", "changes,", "more", "severe", "intellectual", "impairment,", "and", "more", "severe", "cardiomyopathy.", "We", "report", "a", "3-month-old", "Taiwanese", "boy", "with", "initial", "presentation", "of", "a", "lack", "of", "subcutaneous", "fat,", "prominent", "musculature,", "generalized", "eruptive", "xanthomas,", "and", "extreme", "hypertriglyceridemia.", "Absence", "of", "mechanical", "adipose", "tissue", "in", "the", "orbits", "and", "scalp", "was", "revealed", "by", "head", "magnetic", "resonance", "imaging.", "Hepatomegaly", "was", "noticed,", "and", "histological", "examination", "of", "a", "liver", "biopsy", "specimen", "suggested", "severe", "hepatic", "steatosis", "and", "periportal", "necrosis.", "However,", "echocardiography", "indicated", "no", "sign", "of", "cardiomyopathy", "and", "he", "showed", "no", "distinct", "intellectual", "impairment", "that", "interfered", "with", "daily", "life.", "About", "1", "year", "later,", "abdominal", "computed", "tomography", "revealed", "enlargement", "of", "kidneys.", "He", "had", "a", "homozygous", "insertion", "of", "a", "nucleotide,", "783insG", " ", "(", "Ile262fs", " ", "mutation),", "in", "exon", "7", "of", "the", "BSCL2", "gene.", "We", "reviewed", "the", "genotype", "of", "CGL", "cases", "from", "Japan,", "India,", "China", "and", "Taiwan,", "and", "found", "that", "BSCL2", "is", "a", "major", "causative", "gene", "for", "CGL", "in", "Asian." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by a near-complete absence of adipose tissue from birth or early infancy. Mutations in the BSCL2 gene are known to result in CGL2, a more severe phenotype than CGL1, with earlier onset, more extensive fat loss and biochemical changes, more severe intellectual impairment, and more severe cardiomyopathy. We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia. Absence of mechanical adipose tissue in the orbits and scalp was revealed by head magnetic resonance imaging. Hepatomegaly was noticed, and histological examination of a liver biopsy specimen suggested severe hepatic steatosis and periportal necrosis. However, echocardiography indicated no sign of cardiomyopathy and he showed no distinct intellectual impairment that interfered with daily life. About 1 year later, abdominal computed tomography revealed enlargement of kidneys. He had a homozygous insertion of a nucleotide, 783insG ( Ile262fs mutation), in exon 7 of the BSCL2 gene. We reviewed the genotype of CGL cases from Japan, India, China and Taiwan, and found that BSCL2 is a major causative gene for CGL in Asian.	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17962469	[ "PURPOSE:", "To", "report", "a", "large,", "consanguineous", "Algerian", "family", "affected", "with", "Leber", "congenital", "amaurosis", "(LCA)", "or", "early-onset", "retinal", "degeneration", "(EORD).", "METHODS:", "All", "accessible", "family", "members", "underwent", "a", "complete", "ophthalmic", "examination,", "and", "blood", "was", "obtained", "for", "DNA", "extraction.", "Homozygosity", "mapping", "was", "performed", "with", "markers", "flanking", "12", "loci", "associated", "with", "LCA.", "The", "15", "exons", "of", "TULP1", "were", "sequenced.", "RESULTS:", "Seven", "of", "30", "examined", "family", "members", "were", "affected,", "including", "five", "with", "EORD", "and", "two", "with", "LCA.", "All", "patients", "had", "nystagmus,", "hemeralopia,", "mild", "myopia,", "and", "low", "visual", "acuity", "without", "photophobia.", "Fundus", "features", "were", "variable", "among", "EORD", "patients:", "typical", "spicular", "retinitis", "pigmentosa", "or", "clumped", "pigmented", "retinopathy", "with", "age-dependent", "macular", "involvement.", "A", "salt-and-pepper", "retinopathy", "with", "midperipheral", "retinal", "pigment", "epithelium", "(RPE)", "atrophy", "was", "present", "in", "the", "older", "patients", "with", "LCA,", "whereas", "the", "retina", "appeared", "virtually", "normal", "in", "the", "younger", "ones.", "Both", "scotopic", "and", "photopic", "electroretinograms", "were", "nondetectable.", "Fundus", "imaging", "revealed", "a", "perifoveal", "ring", "of", "increased", "fundus", "autofluorescence", "(FAF)", "in", "the", "proband,", "and", "optical", "coherence", "tomography", "disclosed", "a", "thinned", "retina,", "mainly", "due", "to", "photoreceptor", "loss.", "Linkage", "analysis", "identified", "a", "region", "of", "homozygosity", "on", "chromosome", "6,", "region", "p21.3,", "and", "mutation", "screening", "revealed", "a", "novel", "6-base", "in-frame", "duplication,", "in", "the", "TULP1", "gene.", "CONCLUSIONS:", "Mutation", "in", "the", "TULP1", "gene", "is", "a", "rare", "cause", "of", "LCA/EORD,", "with", "only", "14", "mutations", "reported", "so", "far.", "The", "observed", "intrafamilial", "phenotypic", "variability", "could", "be", "attributed", "to", "disease", "progression", "or", "possibly", "modifier", "alleles.", "This", "study", "provides", "the", "first", "description", "of", "FAF", "and", "quantitative", "reflectivity", "profiles", "in", "TULP1-related", "retinopathy." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	PURPOSE: To report a large, consanguineous Algerian family affected with Leber congenital amaurosis (LCA) or early-onset retinal degeneration (EORD). METHODS: All accessible family members underwent a complete ophthalmic examination, and blood was obtained for DNA extraction. Homozygosity mapping was performed with markers flanking 12 loci associated with LCA. The 15 exons of TULP1 were sequenced. RESULTS: Seven of 30 examined family members were affected, including five with EORD and two with LCA. All patients had nystagmus, hemeralopia, mild myopia, and low visual acuity without photophobia. Fundus features were variable among EORD patients: typical spicular retinitis pigmentosa or clumped pigmented retinopathy with age-dependent macular involvement. A salt-and-pepper retinopathy with midperipheral retinal pigment epithelium (RPE) atrophy was present in the older patients with LCA, whereas the retina appeared virtually normal in the younger ones. Both scotopic and photopic electroretinograms were nondetectable. Fundus imaging revealed a perifoveal ring of increased fundus autofluorescence (FAF) in the proband, and optical coherence tomography disclosed a thinned retina, mainly due to photoreceptor loss. Linkage analysis identified a region of homozygosity on chromosome 6, region p21.3, and mutation screening revealed a novel 6-base in-frame duplication, in the TULP1 gene. CONCLUSIONS: Mutation in the TULP1 gene is a rare cause of LCA/EORD, with only 14 mutations reported so far. The observed intrafamilial phenotypic variability could be attributed to disease progression or possibly modifier alleles. This study provides the first description of FAF and quantitative reflectivity profiles in TULP1-related retinopathy.	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22180037	[ "Glutathione-S-transferase", "P1", "(GSTP1)", "is", "a", "critical", "enzyme", "of", "the", "phase", "II", "detoxification", "pathway.", "One", "of", "the", "common", "functional", "polymorphisms", "of", "GSTP1", "is", "A", ">", "G", "at", "nucleotide", "313", ",", "which", "results", "in", "an", "amino", "acid", "substitution", "(", "Ile105Val", ")", "at", "the", "substrate", "binding", "site", "of", "GSTP1", "and", "reduces", "catalytic", "activity", "of", "GSTP1.", "To", "investigate", "the", "GSTP1", "Ile105Val", " ", "genotype", "frequency", "in", "prostate", "cancer", "cases", "in", "the", "Kashmiri", "population,", "we", "designed", "a", "case-control", "study,", "in", "which", "50", "prostate", "cancer", "cases", "and", "45", "benign", "prostate", "hyperplasia", "cases", "were", "studied", "for", "GSTP1", "Ile105Val", " ", "polymorphism,", "compared", "to", "80", "controls", "taken", "from", "the", "general", "population,", "employing", "the", "PCR-RFLP", "technique.", "We", "found", "the", "frequency", "of", "the", "three", "different", "genotypes", "of", "GSTP1", "Ile105Val", " ", "in", "our", "ethnic", "Kashmir", "population,", "i.e.,", "Ile/Ile,", "Ile/Val", "and", "Val/Val,", "to", "be", "52.4,", "33.3", "and", "14.3%", "among", "prostate", "cancer", "cases,", "48.5,", "37.5", "and", "14%", "among", "benign", "prostate", "hyperplasia", "cases", "and", "73.8,", "21.3", "and", "5%", "in", "the", "control", "population,", "respectively.", "There", "was", "a", "significant", "association", "between", "the", "GSTP1", "Ile/Val", "genotype", "and", "the", "advanced", "age", "group", "among", "the", "cases.", "We", "conclude", "that", "GSTP1", "Ile/Val", "polymorphism", "is", "involved", "in", "the", "risk", "of", "prostate", "cancer", "development", "in", "our", "population." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Glutathione-S-transferase P1 (GSTP1) is a critical enzyme of the phase II detoxification pathway. One of the common functional polymorphisms of GSTP1 is A > G at nucleotide 313 , which results in an amino acid substitution ( Ile105Val ) at the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. To investigate the GSTP1 Ile105Val genotype frequency in prostate cancer cases in the Kashmiri population, we designed a case-control study, in which 50 prostate cancer cases and 45 benign prostate hyperplasia cases were studied for GSTP1 Ile105Val polymorphism, compared to 80 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of GSTP1 Ile105Val in our ethnic Kashmir population, i.e., Ile/Ile, Ile/Val and Val/Val, to be 52.4, 33.3 and 14.3% among prostate cancer cases, 48.5, 37.5 and 14% among benign prostate hyperplasia cases and 73.8, 21.3 and 5% in the control population, respectively. There was a significant association between the GSTP1 Ile/Val genotype and the advanced age group among the cases. We conclude that GSTP1 Ile/Val polymorphism is involved in the risk of prostate cancer development in our population.	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20523265	[]	[]		[ 2, 3 ]	[ 0, 0 ]	[ 1, 1 ]	[ -100, -100 ]
15041272	[ "A", "first", "Taiwanese", "Chinese", "family", "of", "type", "2B", "von", "Willebrand", "disease", "with", "R1306W", " ", "mutation." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0 ]	A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation.	[ 2, 43, 2561, 12760, 2124, 7185, 3416, 1927, 2601, 5751, 14147, 30067, 2573, 1956, 12041, 28319, 1018, 3979, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, -100 ]
16410744	[ "Current", "knowledge", "of", "genetic", "alterations", "in", "glioblastomas", "is", "based", "largely", "on", "genetic", "analyses", "of", "tumors", "from", "mainly", "caucasian", "patients", "in", "the", "United", "States", "and", "Europe.", "In", "the", "present", "study,", "screening", "for", "several", "key", "genetic", "alterations", "was", "performed", "on", "77", "primary", "(de", "novo)", "glioblastomas", "in", "Japanese", "patients.", "SSCP", "followed", "by", "DNA", "sequencing", "revealed", "TP53", "mutations", "in", "16", "of", "73", "(22%)", "glioblastomas", "and", "PTEN", "mutations", "in", "13", "of", "63", "(21%)", "cases", "analyzed.", "Polymerase", "chain", "reaction", "(PCR)", "showed", "EGFR", "amplification", "in", "25", "of", "77", "(32%)", "cases", "and", "p16", "homozygous", "deletion", "in", "32", "of", "77", "(42%)", "cases.", "Quantitative", "microsatellite", "analysis", "revealed", "LOH", "10q", "in", "41", "of", "59", "(69%)", "glioblastomas.", "The", "frequencies", "of", "these", "genetic", "alterations", "were", "similar", "to", "those", "reported", "for", "primary", "glioblastomas", "at", "the", "population", "level", "in", "Switzerland.", "As", "previously", "observed", "for", "glioblastomas", "in", "Europe,", "there", "was", "a", "positive", "association", "between", "EGFR", "amplification", "and", "p16", "deletion", "(p=0.009),", "whereas", "there", "was", "an", "inverse", "association", "between", "TP53", "mutations", "and", "p16", "deletion", "(p=0.049)", "in", "glioblastomas", "in", "Japan.", "Multivariate", "analyses", "showed", "that", "radiotherapy", "was", "significantly", "predictive", "for", "longer", "survival", "of", "glioblastoma", "patients", "(p=0.002).", "SSCP", "followed", "by", "DNA", "sequencing", "of", "the", "kinase", "domain", "(exons", "18-21)", "of", "the", "EGFR", "gene", "revealed", "mutations", "in", "2", "ou", "of", "69", "(3%)", "glioblastomas", "in", "Japan", "and", "in", "4", "of", "81", "(5%)", "glioblastomas", "in", "Switzerland.", "The", "allele", "frequencies", "of", "polymorphisms", "at", "codon", "787", "CAG/CAA", " ", "(Gln/Gln)", "in", "glioblastomas", "in", "Japan", "were", "G/G", "(82.4%),", "G/A", "(10.8%),", "A/A", "(6.8%),", "corresponding", "to", "G", "0.878", "versus", "A", "0.122,", "significantly", "different", "from", "those", "in", "glioblastomas", "in", "Switzerland:", "G/G", "(27.2%),", "G/A", "(28.4%),", "A/A", "(44.4%),", "corresponding", "to", "G", "0.414", "versus", "A", "0.586", "(p", "<", "0.0001).", "These", "results", "suggest", "that", "primary", "glioblastomas", "in", "Japan", "show", "genetic", "alterations", "similar", "to", "those", "in", "Switzerland,", "suggesting", "a", "similar", "molecular", "basis", "in", "caucasians", "and", "Asians,", "despite", "different", "genetic", "backgrounds,", "including", "different", "status", "of", "a", "polymorphism", "in", "the", "EGFR", "gene." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.	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17250663	[ "We", "ascertained", "a", "North", "American", "Caucasian", "family", "(LMG248)", "segregating", "autosomal", "dominant,", "non-syndromic,", "post-lingual,", "progressive", "sensorineural", "hearing", "loss.", "The", "hearing", "loss", "begins", "in", "the", "second", "decade", "of", "life", "and", "initially", "affects", "high", "frequencies.", "It", "progresses", "to", "profound", "deafness", "at", "all", "frequencies", "by", "the", "fourth", "or", "fifth", "decade.", "The", "phenotype", "co-segregates", "with", "short-tandem", "repeat", "markers", "flanking", "the", "TMC1", "gene", "at", "the", "DFNA36", "locus", "on", "chromosome", "9q31-q21.", "The", "affected", "individuals", "carry", "a", "novel", "missense", "substitution,", "p.D572H", " ", "(", "c.G1714C", "),", "of", "the", "TMC1", "gene.", "This", "mutation", "is", "at", "the", "same", "nucleotide", "and", "amino", "acid", "position", "as", "the", "only", "other", "reported", "DFNA36", "mutation,", "p.D572N", " ", "(", "c.G1714A", ").", "Our", "observations", "implicate", "a", "critical", "function", "for", "amino", "acid-572", "for", "wild-type", "TMC1", "function", "or", "the", "pathogenesis", "of", "DFNA36", "hearing", "loss.", "The", "slower", "progression", "of", "hearing", "loss", "associated", "with", "p.D572H", ",", "in", "comparison", "with", "that", "caused", "by", "p.D572N", ",", "may", "reflect", "a", "correlation", "of", "DFNA36", "phenotype", "with", "TMC1", "genotype." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H ( c.G1714C ), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N ( c.G1714A ). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H , in comparison with that caused by p.D572N , may reflect a correlation of DFNA36 phenotype with TMC1 genotype.	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14510914	[ "Congenital", "hypothyroidism", "due", "to", "a", "new", "deletion", "in", "the", "sodium/iodide", "symporter", "protein." ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein.	[ 2, 9901, 19316, 2810, 1942, 43, 2814, 5541, 1922, 1920, 5227, 19, 14220, 29148, 2718, 1915, 2213, 18, 3 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]

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Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein.

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15937959

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Loss of heterozygosity (LOH) analysis was performed in epithelial ovarian cancers (EOC) to further characterize a previously identified candidate tumor suppressor gene (TSG) region encompassing D17S801 at chromosomal region 17q25.1. LOH of at least one informative marker was observed for 100 (71%) of 140 malignant EOC samples in an analysis of 6 polymorphic markers (cen-D17S1839-D17S785-D17S1817-D17S801-D17S751-D17S722-tel). The combined LOH analysis revealed a 453 kilobase (Kb) minimal region of deletion (MRD) bounded by D17S1817 and D17S751. Human and mouse genome assemblies were used to resolve marker inconsistencies in the D17S1839-D17S722 interval and identify candidates. The region contains 32 known and strongly predicted genes, 9 of which overlap the MRD. The reference genomic sequences share nearly identical gene structures and the organization of the region is highly collinear. Although, the region does not show any large internal duplications, a 1.5 Kb inverted duplicated sequence of 87% nucleotide identity was observed in a 13 Kb region surrounding D17S801. Transcriptome analysis by Affymetrix GeneChip and reverse transcription (RT)-polymerase chain reaction (PCR) methods of 3 well characterized EOC cell lines and primary cultures of normal ovarian surface epithelial (NOSE) cells was performed with 32 candidates spanning D17S1839-D17S722 interval. RT-PCR analysis of 8 known or strongly predicted genes residing in the MRD in 10 EOC samples, that exhibited LOH of the MRD, identified FLJ22341 as a strong candidate TSG. The proximal repeat sequence of D17S801 occurs 8 Kb upstream of the putative promoter region of FLJ22341. RT-PCR analysis of the EOC samples and cell lines identified DKFZP434P0316 that maps proximal to the MRD, as a candidate. While Affymetrix technology was useful for initially eliminating less promising candidates, subsequent RT-PCR analysis of well-characterized EOC samples was essential to prioritize TSG candidates for further study.

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17311329

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[ -100, -100 ]

19370764

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Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense ( p.T286M ) and nonsense ( p.W111X ) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site ( c.610-2A>G ). Three microdeletions were also identified, two of which ( c.611delG and c.640_667del28 ) were located within the coding region whereas one ( c.609+28_610-16del ) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 ( p.G204_K247del ) or the retention of introns 8 and 9 ( p.G204VfsX28 ). RT-PCR analysis, performed on a patient homozygous for the intronic deletion ( c.609+28_610-16del ), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment.

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16575011

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PURPOSE: The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. PATIENTS AND METHODS: One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. RESULTS: Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/-6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. CONCLUSION: Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.

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18426832

[]

[ 2, 3 ]

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20352162

[ "4G/5G", "polymorphism", "and", "haplotypes", "of", "SERPINE1", "in", "atherosclerotic", "diseases", "of", "coronary", "arteries." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

4G/5G polymorphism and haplotypes of SERPINE1 in atherosclerotic diseases of coronary arteries.

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20529581

[ "BACKGROUND:", "Leukocyte", "adhesion", "deficiency", "type", "1", "(LAD-1)", "is", "a", "rare,", "autosomal", "recessive", "inherited", "immunodeficiency", "disease", "characterized", "by", "recurrent", "severe", "bacterial", "infection,", "impaired", "pus", "formation,", "poor", "wound", "healing,", "associated", "with", "the", "mutation", "in", "the", "CD18", "gene", "responsible", "for", "the", "ability", "of", "the", "leucocytes", "to", "migrate", "from", "the", "blood", "stream", "towards", "the", "site", "of", "inflammation.", "Correct", "and", "early", "diagnosis", "of", "LAD-1", "is", "vital", "to", "the", "success", "of", "treatment", "and", "prevention", "of", "aggressive", "infections.", "The", "purpose", "of", "this", "study", "was", "to", "collect", "the", "clinical", "findings", "of", "the", "disease", "and", "to", "identify", "the", "genetic", "entity.", "METHODS:", "CD18", "expression", "in", "the", "peripheral", "blood", "leukocytes", "from", "the", "patient,", "his", "parents", "and", "normal", "control", "was", "measured", "with", "flow", "cytometry.", "The", "entire", "coding", "regions", "of", "the", "CD18", "gene", "were", "screened", "with", "direct", "sequencing", "genomic", "DNA.", "RESULTS:", "CD18", "expression", "level", "on", "this", "patient's", "leukocyte", "surface", "was", "significantly", "decreased,", "with", "normal", "level", "in", "control", "group,", "his", "father", "and", "mother.", "Gene", "analysis", "revealed", "that", "this", "patient", "had", "a", "homozygous", "c.899A", ">", "T", " ", "missense", "mutation", "in", "exon", "8", "of", "CD18", "gene,", "causing", "the", "substitution", "of", "Asp", "to", "Val", "at", "the", "300", "amino", "acid.", "His", "parents", "were", "both", "heterozygous", "carriers", "while", "no", "such", "mutation", "was", "found", "in", "50", "normal", "controls.", "CONCLUSION:", "This", "study", "disclosed", "a", "novel", "point", "mutation", "Asp", "300", "Val", " ", "located", "in", "a", "highly", "conserved", "region", "(HCR)", "of", "CD18", "and", "confirmed", "the", "heterogeneity", "of", "the", "mutations", "causing", "LAD-1,", "indicating", "it", "was", "quite", "beneficial", "to", "establish", "correct", "and", "early", "diagnosis", "in", "children", "with", "severe", "LAD-1." ]

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BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation. Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections. The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity. METHODS: CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry. The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA. RESULTS: CD18 expression level on this patient's leukocyte surface was significantly decreased, with normal level in control group, his father and mother. Gene analysis revealed that this patient had a homozygous c.899A > T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid. His parents were both heterozygous carriers while no such mutation was found in 50 normal controls. CONCLUSION: This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region (HCR) of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1.

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21695597

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17175380

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We examined chromosome 3 in 32 childhood acute lymphoblastic leukemia (ALL) bone marrow samples. Using interphase multipoint FISH (mp-FISH), which was developed by our group, with 42 chromosome 3-specific probes, we detected clonal chromosome 3 aberrations in 4 T-cell ALL (T-ALL) cases. Four out of seven T-ALL cases carried 3q trisomies. One T-ALL case carried either trisomy 3 (in 15% of the cells) or a 23-megabase (Mb) 3p13 approximately p12 deletion in a different subpopulation of cells of 32%. Another T-ALL case had either 3q trisomy in 11% or a 12-Mb 3p12 approximately p13 deletion in 19% of the cells. The deletions were overlapping. In both cases, the majority of the bone marrow cells (47 and 70%, respectively) were normal chromosome 3 disomics. The interstitial deletions detected harbor a known homozygous deletion region between 72.6 and 78.8 Mb, which has been described in lung and breast tumors and contains the DUTT1/ROBO1 tumor suppressor gene. These deletions detected by mp-FISH would have remained unnoticed by conventional cytogenetics and multiplex FISH, as well as by current methods based on total tumor DNA analysis such as comparative genomic hybridization (CGH), array CGH, and loss of heterozygosity (LOH).

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15282322

[ "Deletion", "of", "mouse", "rad9", "causes", "abnormal", "cellular", "responses", "to", "DNA", "damage,", "genomic", "instability,", "and", "embryonic", "lethality." ]

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Deletion of mouse rad9 causes abnormal cellular responses to DNA damage, genomic instability, and embryonic lethality.

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18813858

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[ 2, 3 ]

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22295085

[ "Genetic", "and", "epigenetic", "alterations", "of", "the", "NF2", "gene", "in", "sporadic", "vestibular", "schwannomas." ]

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Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas.

[ 2, 3299, 1930, 8542, 5996, 1927, 1920, 4651, 1028, 2359, 1922, 13088, 15752, 16511, 4956, 18, 3 ]

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16796766

[ "Genomic", "characterization", "of", "five", "deletions", "in", "the", "LDL", "receptor", "gene", "in", "Danish", "Familial", "Hypercholesterolemic", "subjects." ]

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Genomic characterization of five deletions in the LDL receptor gene in Danish Familial Hypercholesterolemic subjects.

[ 2, 4935, 7285, 1927, 3628, 10550, 1922, 1920, 8017, 3148, 2359, 1922, 18247, 11444, 19284, 4197, 3297, 18, 3 ]

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19101703

[]

[ 2, 3 ]

[ 0, 0 ]

[ 1, 1 ]

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17392687

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PURPOSE: betaB2-crystallin is one of the most abundant proteins of the adult ocular lens of mammals although it is expressed at lower levels in several extralenticular locations. While mutations in betaB2-crystallin are known to result in lens opacities, alterations in tissues besides the lens have not been previously investigated in these mutants. Since we found mice harboring the Crybb2Phil mutation bred poorly, here we assess the contribution of betaB2-crystallin to mouse fertility and determine the expression pattern of betaB2-crystallin in the testis. METHODS: The expression pattern of betaB2-crystallin in the testis was analyzed by rt-PCR, western blotting, and immunohistochemistry. The fecundity of wildtype and Crybb2Phil mice was analyzed by quantitative fertility testing. The morphology of testes and ovaries was assessed by hematoxylin and eosin staining. RESULTS: In the mouse testis, betaB2-crystallin mRNA is found at low levels at birth, but its expression upregulates in this tissue as the testis is primed to initiate spermatogenesis. Western blotting detected betaB2-crystallin protein in sperm obtained from mice, cattle, and humans while immunolocalization detected this protein in developing sperm from the spermatocyte stage onward. Male and female mice homozygous for a 12 nucleotide inframe deletion mutation in betaB2-crystallin are subfertile when analyzed on a Swiss Webster derived background due to defects in egg and sperm production. However, mice harboring the same mutation on the C57Bl/6 genetic background did not exhibit any defects in reproductive function. CONCLUSIONS: betaB2-crystallin is expressed in developing and mature sperm and mice of both sexes harboring the Philly mutation in the betaB2-crystallin gene are subfertile when analyzed on a Swiss Webster genetic background. While these data are suggestive of a role for betaB2-crystallin in fertility, definitive determination of this will await the creation of a betaB2-crystallin null mouse.

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21059483

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Classic galactosemia is an autosomal recessive disorder of galactose metabolism manifesting in the first weeks of life following exposure to a milk-based diet. Despite the benefit of avoidance of lactose, many patients suffer from long-term complications including neurological deficits and ovarian failure. To date, over 230 mutations have been described in the GALT gene resulting in galactosemia. Recently, an unusual mutation was characterized causing a 5.5 kb deletion, with a relatively high carrier rate in subjects of Ashkenazi Jewish (AJ) descent. The aim of this study was to estimate the carrier frequency of this mutation in the AJ population in Israel. For this purpose we developed a high-throughput methodology to genotype both normal and deleted alleles using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer and Multiplex PCR. DNA samples of 760 anonymous AJ subjects were submitted for analysis, subsequently detecting six individuals heterozygous for the GALT deletion mutation, giving a carrier frequency of 1 in 127 (0.79%). Based on these results, we suggest that the method described here provides a basis for genetic screening and prenatal counseling and can potentially reduce the morbidity and mortality associated with delayed diagnosis of galactosemia in this patient population.

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16628674

[ "A", "novel", "multidrug-resistance", "protein", "2", "gene", "mutation", "identifies", "a", "subgroup", "of", "patients", "with", "primary", "biliary", "cirrhosis", "and", "pruritus." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus.

[ 2, 43, 4008, 16398, 17, 3554, 2213, 22, 2359, 3979, 14133, 43, 6200, 1927, 2132, 1956, 3065, 13210, 11260, 1930, 27496, 18, 3 ]

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15353880

[]

[ 2, 3 ]

[ 0, 0 ]

[ 1, 1 ]

[ -100, -100 ]

12820697

[]

[ 2, 3 ]

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[ 1, 1 ]

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19542096

[ "Arthrogryposis", "multiplex", "congenita", "(AMC)", "is", "a", "group", "of", "disorders", "characterized", "by", "congenital", "joint", "contractures", "caused", "by", "reduced", "fetal", "movements.", "AMC", "has", "an", "incidence", "of", "1", "in", "3000", "newborns", "and", "is", "genetically", "heterogeneous.", "We", "describe", "an", "autosomal", "recessive", "form", "of", "myogenic", "AMC", "in", "a", "large", "consanguineous", "family.", "The", "disease", "is", "characterized", "by", "bilateral", "clubfoot,", "decreased", "fetal", "movements,", "delay", "in", "motor", "milestones,", "then", "progressive", "motor", "decline", "after", "the", "first", "decade.", "Genome-wide", "linkage", "analysis", "revealed", "a", "single", "locus", "on", "chromosome", "6q25", "with", "Z(max)", "=", "3.55", "at", "theta", "=", "0.0", "and", "homozygosity", "of", "the", "polymorphic", "markers", "at", "this", "locus", "in", "patients.", "Homozygous", "A", "to", "G", "nucleotide", "substitution", "of", "the", "conserved", "AG", "splice", "acceptor", "site", "at", "the", "junction", "of", "intron", "136", "and", "exon", "137", "of", "the", "SYNE-1", "gene", "was", "found", "in", "patients.", "This", "mutation", "results", "in", "an", "aberrant", "retention", "of", "intron", "136", "of", "SYNE-1", "RNA", "leading", "to", "premature", "stop", "codons", "and", "the", "lack", "of", "the", "C-terminal", "transmembrane", "domain", "KASH", "of", "nesprin-1,", "the", "SYNE-1", "gene", "product.", "Mice", "lacking", "the", "KASH", "domain", "of", "nesprin-1", "display", "a", "myopathic", "phenotype", "similar", "to", "that", "observed", "in", "patients.", "Altogether,", "these", "data", "strongly", "suggest", "that", "the", "splice", "site", "mutation", "of", "SYNE-1", "gene", "found", "in", "the", "family", "is", "responsible", "for", "AMC.", "Recent", "reports", "have", "shown", "that", "mutations", "of", "the", "SYNE-1", "gene", "might", "be", "responsible", "for", "autosomal", "recessive", "adult", "onset", "cerebellar", "ataxia.", "These", "data", "indicate", "that", "mutations", "of", "nesprin-1", "which", "interacts", "with", "lamin", "A/C", "may", "lead", "to", "at", "least", "two", "distinct", "human", "disease", "phenotypes,", "myopathic", "or", "neurological,", "a", "feature", "similar", "to", "that", "found", "in", "laminopathies." ]

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Arthrogryposis multiplex congenita (AMC) is a group of disorders characterized by congenital joint contractures caused by reduced fetal movements. AMC has an incidence of 1 in 3000 newborns and is genetically heterogeneous. We describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterized by bilateral clubfoot, decreased fetal movements, delay in motor milestones, then progressive motor decline after the first decade. Genome-wide linkage analysis revealed a single locus on chromosome 6q25 with Z(max) = 3.55 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Homozygous A to G nucleotide substitution of the conserved AG splice acceptor site at the junction of intron 136 and exon 137 of the SYNE-1 gene was found in patients. This mutation results in an aberrant retention of intron 136 of SYNE-1 RNA leading to premature stop codons and the lack of the C-terminal transmembrane domain KASH of nesprin-1, the SYNE-1 gene product. Mice lacking the KASH domain of nesprin-1 display a myopathic phenotype similar to that observed in patients. Altogether, these data strongly suggest that the splice site mutation of SYNE-1 gene found in the family is responsible for AMC. Recent reports have shown that mutations of the SYNE-1 gene might be responsible for autosomal recessive adult onset cerebellar ataxia. These data indicate that mutations of nesprin-1 which interacts with lamin A/C may lead to at least two distinct human disease phenotypes, myopathic or neurological, a feature similar to that found in laminopathies.

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20126413

[ "U87MG", "decoded:", "the", "genomic", "sequence", "of", "a", "cytogenetically", "aberrant", "human", "cancer", "cell", "line." ]

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U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line.

[ 2, 18617, 9759, 2344, 21564, 30, 1920, 4935, 3244, 1927, 43, 18486, 2169, 9801, 2616, 2539, 2024, 2823, 18, 3 ]

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[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]

19435819

[ "High-resolution", "genomic", "copy", "number", "profiling", "of", "glioblastoma", "multiforme", "by", "single", "nucleotide", "polymorphism", "DNA", "microarray." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray.

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19521089

[ "Parkinson's", "disease", "(PD)", "is", "a", "neurodegenerative", "disorder", "causing", "muscular", "rigidity,", "resting", "tremor", "and", "bradykinesia.", "We", "conducted", "an", "association", "study", "assessing", "how", "PD", "risk", "in", "Italy", "was", "influenced", "by", "the", "serotonin", "transporter", "gene", "(SLC6A4)", "polymorphic", "region", "5-HTTLPR,", "consisting", "of", "an", "insertion/deletion", "(long", "allele-L/short", "allele-S)", "of", "43", "bp", "in", "the", "SLC6A4", "promoter", "region.", "The", "SLC6A4", "promoter", "single", "nucleotide", "polymorphism", "rs25531", "(", "A-->G", ")", "was", "evaluated", "too.", "We", "collected", "837", "independent", "subjects", "(393", "PD,", "444", "controls).", "An", "association", "between", "the", "5-HTTLPR", "polymorphism", "and", "risk", "of", "PD", "(S/S", "genotype", "OR", "[95%", "CI]:", "1.7[1.2-2.5],", "p", "=", "0.002)", "was", "found.", "The", "rs25531", " ", "and", "the", "haplotype", "5-HTTLPR/", "rs25531", " ", "did", "not", "associate", "with", "risk", "of", "PD.", "Our", "data", "indicate", "that", "the", "5-HTTLPR", "polymorphic", "element", "within", "the", "SLC6A4", "promoter", "may", "govern", "the", "genetic", "risk", "of", "PD", "in", "Italians." ]

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Parkinson's disease (PD) is a neurodegenerative disorder causing muscular rigidity, resting tremor and bradykinesia. We conducted an association study assessing how PD risk in Italy was influenced by the serotonin transporter gene (SLC6A4) polymorphic region 5-HTTLPR, consisting of an insertion/deletion (long allele-L/short allele-S) of 43 bp in the SLC6A4 promoter region. The SLC6A4 promoter single nucleotide polymorphism rs25531 ( A-->G ) was evaluated too. We collected 837 independent subjects (393 PD, 444 controls). An association between the 5-HTTLPR polymorphism and risk of PD (S/S genotype OR [95% CI]: 1.7[1.2-2.5], p = 0.002) was found. The rs25531 and the haplotype 5-HTTLPR/ rs25531 did not associate with risk of PD. Our data indicate that the 5-HTTLPR polymorphic element within the SLC6A4 promoter may govern the genetic risk of PD in Italians.

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19218574

[]

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[ 0, 0 ]

[ 1, 1 ]

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15316799

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Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein, structurally unrelated to apoE, that transports small hydrophobic ligands including cholesterol and sterols. Levels are increased in the hippocampus and CSF of Alzheimer's disease (AD) patients. We tested whether variation in the APOD gene affects AD risk. Four single nucleotide polymorphisms (SNPs) were investigated (in map order): exon 2, 15T-->C encodes an amino acid substitution Phe-->Ser at codon 15 ; intron 2, -352G-->A ; intron 3, +45C-->T ; intron 4, +718C-->T , determined by SNaPshot assay. SNP frequencies for 394 eastern Finnish AD patients were compared with those found for 470 control subjects, dividing subjects also into early-onset AD (EOAD; < or = 65 years) and late-onset AD (LOAD; >65 years) groups. The -352G allele was associated with a significant 3-fold increase in the risk of EOAD (OR: 2.7; 95% CI: 1.1-6.5). The -352G containing haplotypes were more common for EOAD cases (TGCC: 0.48 vs 0.41; TGCT: 0.08 vs 0.01 (p = 0.002). In the Grade-of-membership analysis, APOD genotype frequencies at each SNP site and disease status were used to construct two latent groups: the affected group carried -352 as GG or GA and +45 CC, was often women and enriched in APOE epsilon4. Each method suggested that the -352G allele frequency is higher for EOAD in the eastern Finnish population.

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20693575

[ "BACKGROUND:", "HCN", "channels", "activate", "the", "pacemaker", "current", "I(f),", "which", "is", "thought", "to", "contribute", "significantly", "to", "generation", "and", "regulation", "of", "heart", "rhythm.", "HCN4", "represents", "the", "dominant", "isotype", "in", "the", "sinoatrial", "node", "and", "binding", "of", "cAMP", "was", "suggested", "to", "be", "necessary", "for", "autonomic", "heart", "rate", "regulation.", "METHODS", "AND", "RESULTS:", "In", "a", "candidate", "gene", "approach,", "a", "heterozygous", "insertion", "of", "13", "nucleotides", "in", "exon", "6", "of", "the", "HCN4", "gene", "leading", "to", "a", "truncated", "cyclic", "nucleotide-binding", "domain", "was", "identified", "in", "a", "45-year-old", "woman", "with", "sinus", "bradycardia.", "Biophysical", "properties", "determined", "by", "whole-cell", "patch-clamp", "recording", "of", "HEK293", "cells", "demonstrated", "that", "mutant", "subunits", "(HCN4-695X)", "were", "insensitive", "to", "cAMP.", "Heteromeric", "channels", "composed", "of", "wild-type", "and", "mutant", "subunits", "failed", "to", "respond", "to", "cAMP-like", "homomeric", "mutant", "channels,", "indicating", "a", "dominant-negative", "suppression", "of", "cAMP-induced", "channel", "activation", "by", "mutant", "subunits.", "Pedigree", "analysis", "identified", "7", "additional", "living", "carriers", "showing", "similar", "clinical", "phenotypes,", "that", "is,", "sinus", "node", "dysfunction", "with", "mean", "resting", "heart", "rate", "of", "45.9", " ", "4.6", "bpm", "(n=8)", "compared", "with", "66.5", " ", "9.1", "bpm", "of", "unaffected", "relatives", "(n=6;", "P<0.01).", "Clinical", "evaluation", "revealed", "no", "ischemic", "or", "structural", "heart", "disease", "in", "any", "family", "member.", "Importantly,", "mutant", "carriers", "exhibited", "normal", "heart", "rate", "variance", "and", "full", "ability", "to", "accelerate", "heart", "rate", "under", "physical", "activity", "or", "pharmacological", "stimulation.", "Moreover,", "mutant", "carriers", "displayed", "distinctive", "sinus", "arrhythmias", "and", "premature", "beats", "linked", "to", "adrenergic", "stress.", "CONCLUSIONS:", "In", "humans,", "cAMP", "responsiveness", "of", "I(f)", "determines", "basal", "heart", "rate", "but", "is", "not", "critical", "for", "maximum", "heart", "rate,", "heart", "rate", "variability,", "or", "chronotropic", "competence.", "Furthermore,", "cAMP-activated", "I(f)", "may", "stabilize", "heart", "rhythm", "during", "chronotropic", "response." ]

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BACKGROUND: HCN channels activate the pacemaker current I(f), which is thought to contribute significantly to generation and regulation of heart rhythm. HCN4 represents the dominant isotype in the sinoatrial node and binding of cAMP was suggested to be necessary for autonomic heart rate regulation. METHODS AND RESULTS: In a candidate gene approach, a heterozygous insertion of 13 nucleotides in exon 6 of the HCN4 gene leading to a truncated cyclic nucleotide-binding domain was identified in a 45-year-old woman with sinus bradycardia. Biophysical properties determined by whole-cell patch-clamp recording of HEK293 cells demonstrated that mutant subunits (HCN4-695X) were insensitive to cAMP. Heteromeric channels composed of wild-type and mutant subunits failed to respond to cAMP-like homomeric mutant channels, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. Pedigree analysis identified 7 additional living carriers showing similar clinical phenotypes, that is, sinus node dysfunction with mean resting heart rate of 45.9 4.6 bpm (n=8) compared with 66.5 9.1 bpm of unaffected relatives (n=6; P<0.01). Clinical evaluation revealed no ischemic or structural heart disease in any family member. Importantly, mutant carriers exhibited normal heart rate variance and full ability to accelerate heart rate under physical activity or pharmacological stimulation. Moreover, mutant carriers displayed distinctive sinus arrhythmias and premature beats linked to adrenergic stress. CONCLUSIONS: In humans, cAMP responsiveness of I(f) determines basal heart rate but is not critical for maximum heart rate, heart rate variability, or chronotropic competence. Furthermore, cAMP-activated I(f) may stabilize heart rhythm during chronotropic response.

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18046082

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14633686

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17175380

[ "Multipoint", "interphase", "FISH", "in", "childhood", "T-acute", "lymphoblastic", "leukemia", "detects", "subpopulations", "that", "carry", "different", "chromosome", "3", "aberrations." ]

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Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations.

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21790735

[ "C1", "inhibitor", "(C1-INH)", "deficiency", "[hereditary", "or", "acquired", "angio-oedema", "(HAE", "or", "AAE)]", "is", "characterized", "by", "recurring", "episodes", "of", "subcutaneous", "or", "submucosal", "oedema.", "Many", "different", "mutations", "in", "the", "C1-INH", "gene", "have", "been", "identified", "as", "a", "cause", "of", "HAE.", "We", "investigated", "the", "molecular", "basis", "of", "the", "disease", "in", "a", "Japanese", "woman", "with", "sporadic", "HAE.", "Direct", "sequencing", "of", "genomic", "DNA", "revealed", "no", "point", "mutation", "in", "the", "C1-INH", "gene.", "Quantitative", "real-time", "PCR", "showed", "that", "the", "copy", "number", "of", "the", "C1-INH", "gene", "in", "the", "patient", "was", "half", "that", "of", "a", "healthy", "control.", "Furthermore,", "we", "identified", "a", "650-kbp", "deletion", "on", "the", "chromosome,", "which", "included", "the", "C1-INH", "gene.", "We", "evaluated", "the", "correlation", "between", "the", "patient's", "attacks", "and", "her", "coagulation", "activity.", "The", "levels", "of", "D-dimer", "were", "high", "during", "the", "angio-oedema", "attacks,", "and", "often", "exceeded", "the", "normal", "range", "even", "during", "remission,", "thus", "the", "level", "of", "D-dimer", "reflected", "the", "activity", "of", "HAE", "in", "this", "patient." ]

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C1 inhibitor (C1-INH) deficiency [hereditary or acquired angio-oedema (HAE or AAE)] is characterized by recurring episodes of subcutaneous or submucosal oedema. Many different mutations in the C1-INH gene have been identified as a cause of HAE. We investigated the molecular basis of the disease in a Japanese woman with sporadic HAE. Direct sequencing of genomic DNA revealed no point mutation in the C1-INH gene. Quantitative real-time PCR showed that the copy number of the C1-INH gene in the patient was half that of a healthy control. Furthermore, we identified a 650-kbp deletion on the chromosome, which included the C1-INH gene. We evaluated the correlation between the patient's attacks and her coagulation activity. The levels of D-dimer were high during the angio-oedema attacks, and often exceeded the normal range even during remission, thus the level of D-dimer reflected the activity of HAE in this patient.

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17868390

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22125978

[ "OBJECTIVE:", "To", "identify", "the", "disease", "causing", "gene", "in", "a", "four", "generation", "consanguineous", "family", "in", "which", "eleven", "family", "members", "were", "suffering", "from", "Woolly", "hair/hypotrichosis", "phenotype.", "METHODS:", "Linkage", "analysis", "was", "carried", "out", "to", "identify", "the", "disease-causing", "gene", "in", "this", "family.", "Genomic", "DNA", "of", "all", "the", "available", "family", "members", "was", "genotyped", "for", "the", "microsatellite", "markers", "for", "all", "the", "known", "woolly", "hair/hypotrichosis", "loci.Automated", "DNA", "sequencing", "of", "the", "candidate", "gene", "was", "performed", "to", "identify", "the", "disease-causing", "mutation.", "RESULTS:", "By", "using", "homozygosity", "linkage", "analysis", "we", "have", "mapped", "the", "family", "on", "chromosome", "3q27.3", "with", "a", "two", "point", "LOD", "score", "of", "4.04,", "Mutation", "screening", "of", "the", "LIPH", "gene", "revealed", "a", "homozygous", "c.659_660delTA", " ", "deletion", "mutation", "segregating", "with", "the", "disease", "phenotype.", "CONCLUSION:", "The", "results", "indicate", "that", "the", "c.659_660delTA", " ", "mutation", "in", "the", "LIPH", "gene", "cause", "autosomal", "recessive", "WH/hypotrichosis", "phenotype", "in", "this", "family.", "This", "mutation", "has", "been", "reported", "in", "several", "Pakistani", "and", "Guyanese", "families", "suggesting", "a", "founder", "mutation", "in", "the", "LIPH", "gene", "in", "Indo-Pak", "sub-continent." ]

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OBJECTIVE: To identify the disease causing gene in a four generation consanguineous family in which eleven family members were suffering from Woolly hair/hypotrichosis phenotype. METHODS: Linkage analysis was carried out to identify the disease-causing gene in this family. Genomic DNA of all the available family members was genotyped for the microsatellite markers for all the known woolly hair/hypotrichosis loci.Automated DNA sequencing of the candidate gene was performed to identify the disease-causing mutation. RESULTS: By using homozygosity linkage analysis we have mapped the family on chromosome 3q27.3 with a two point LOD score of 4.04, Mutation screening of the LIPH gene revealed a homozygous c.659_660delTA deletion mutation segregating with the disease phenotype. CONCLUSION: The results indicate that the c.659_660delTA mutation in the LIPH gene cause autosomal recessive WH/hypotrichosis phenotype in this family. This mutation has been reported in several Pakistani and Guyanese families suggesting a founder mutation in the LIPH gene in Indo-Pak sub-continent.

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14722925

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16989765

[ "A", "novel", "His158Arg", " ", "mutation", "in", "TIMP3", "causes", "a", "late-onset", "form", "of", "Sorsby", "fundus", "dystrophy." ]

[ 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy.

[ 2, 43, 4008, 4167, 22633, 2419, 3979, 1922, 18300, 1010, 5092, 43, 5058, 17, 4727, 2386, 1927, 6548, 1036, 4864, 18862, 19321, 18, 3 ]

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[ -100, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]

18391980

[]

[ 2, 3 ]

[ 0, 0 ]

[ 1, 1 ]

[ -100, -100 ]

18164595

[ "Mutations", "in", "the", "hairless", "gene", "underlie", "APL", "in", "three", "families", "of", "Pakistani", "origin." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

Mutations in the hairless gene underlie APL in three families of Pakistani origin.

[ 2, 3527, 1922, 1920, 7018, 5427, 2359, 14150, 18373, 1922, 2559, 5767, 1927, 21493, 1033, 4853, 18, 3 ]

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[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]

21182502

[ "A", "novel", "homozygous", "splice", "site", "mutation", "in", "COL7A1", "in", "a", "Chinese", "patient", "with", "severe", "recessive", "dystrophic", "epidermolysis", "bullosa", "and", "squamous", "cell", "carcinoma." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

A novel homozygous splice site mutation in COL7A1 in a Chinese patient with severe recessive dystrophic epidermolysis bullosa and squamous cell carcinoma.

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[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]

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19664890

[]

[ 2, 3 ]

[ 0, 0 ]

[ 1, 1 ]

[ -100, -100 ]

20143913

[]

[ 2, 3 ]

[ 0, 0 ]

[ 1, 1 ]

[ -100, -100 ]

16614502

[ "Insertion/deletion", "polymorphism", "of", "angiotensin", "converting", "enzyme", "gene", "in", "Kawasaki", "disease." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

Insertion/deletion polymorphism of angiotensin converting enzyme gene in Kawasaki disease.

[ 2, 7413, 19, 5541, 8218, 1927, 10814, 15025, 4113, 2359, 1922, 22131, 29299, 2573, 18, 3 ]

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16311014

[ "This", "study", "demonstrates", "an", "array-based", "platform", "to", "genotype", "simultaneously", "single", "nucleotide", "polymorphisms", "(SNPs)", "and", "some", "short", "insertions/deletions", "(indels)", "by", "the", "integration", "of", "the", "universal", "tag/anti-tag", "(TAT)", "system,", "liquid-phase", "primer", "extension", "(LIPEX),", "and", "a", "novel", "two-color", "detection", "strategy", "on", "an", "array", "format", "(TATLIPEXA).", "The", "TAT", "system", "permits", "a", "universal", "chip", "to", "be", "used", "for", "many", "applications,", "and", "the", "LIPEX", "simplifies", "the", "sample", "preparation", "but", "improves", "the", "sensitivity", "significantly.", "More", "importantly,", "all", "SNPs", "and", "some", "short", "indels", "can", "be", "interrogated", "in", "a", "single", "reaction", "with", "only", "two", "fluorescent", "ddNTPs.", "The", "concept", "of", "TATLIPEXA", "is", "demonstrated", "for", "nine", "SNPs", "(eight", "point", "mutations", "and", "one", "single-base", "insertion),", "and", "genotypes", "obtained", "show", "a", "remarkable", "concordance", "rate", "of", "100%", "with", "both", "DNA", "sequencing", "and", "restriction", "fragment", "length", "polymorphism.", "Moreover,", "TATLIPEXA", "is", "able", "to", "provide", "quantitative", "information", "on", "allele", "frequency", "in", "pooled", "DNA", "samples,", "which", "could", "serve", "as", "a", "rapid", "screening", "tool", "for", "SNPs", "associated", "with", "diseases." ]

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This study demonstrates an array-based platform to genotype simultaneously single nucleotide polymorphisms (SNPs) and some short insertions/deletions (indels) by the integration of the universal tag/anti-tag (TAT) system, liquid-phase primer extension (LIPEX), and a novel two-color detection strategy on an array format (TATLIPEXA). The TAT system permits a universal chip to be used for many applications, and the LIPEX simplifies the sample preparation but improves the sensitivity significantly. More importantly, all SNPs and some short indels can be interrogated in a single reaction with only two fluorescent ddNTPs. The concept of TATLIPEXA is demonstrated for nine SNPs (eight point mutations and one single-base insertion), and genotypes obtained show a remarkable concordance rate of 100% with both DNA sequencing and restriction fragment length polymorphism. Moreover, TATLIPEXA is able to provide quantitative information on allele frequency in pooled DNA samples, which could serve as a rapid screening tool for SNPs associated with diseases.

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15623763

[ "TGFBI", "gene", "mutations", "causing", "lattice", "and", "granular", "corneal", "dystrophies", "in", "Indian", "patients." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients.

[ 2, 5525, 3821, 2359, 3527, 7538, 13018, 1930, 16284, 9990, 10612, 2789, 2062, 1922, 10733, 2132, 18, 3 ]

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18827003

[ "A", "novel", "point", "mutation", "in", "the", "amino", "terminal", "domain", "of", "the", "human", "glucocorticoid", "receptor", "(hGR)", "gene", "enhancing", "hGR-mediated", "gene", "expression." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression.

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20086182

[ "Caspase", "8", "(CASP8)", "is", "an", "apoptosis-related", "cysteine", "peptidase", "involved", "in", "the", "death", "receptor", "pathway", "and", "likely", "in", "the", "mitochondrial", "pathway.", "A", "CASP8", "promoter", "region", "six-nucleotide", "deletion/insertion", "(", "-652", "6N", "ins/del", ")", "variant", "and", "a", "coding", "region", "D302H", " ", "polymorphism", "are", "reportedly", "important", "in", "cancer", "development,", "but", "no", "reported", "study", "has", "assessed", "the", "associations", "of", "these", "genetic", "variations", "with", "risk", "of", "head", "and", "neck", "cancer.", "In", "a", "hospital-based", "study", "of", "non-Hispanic", "whites,", "we", "genotyped", "CASP8", "-652", "6N", "del", " ", "and", "302H", "variants", "in", "1,023", "patients", "with", "squamous", "cell", "carcinoma", "of", "the", "head", "and", "neck", "(SCCHN)", "and", "1,052", "cancer-free", "controls.", "Crude", "and", "adjusted", "odds", "ratios", "(OR)", "and", "95%", "confidence", "intervals", "(CI)", "were", "estimated", "using", "unconditional", "logistic", "regression", "models.", "The", "CASP8", "-652", "6N", "del", " ", "variant", "genotypes", "or", "haplotypes", "were", "inversely", "associated", "with", "SCCHN", "risk", "(adjusted", "OR,", "0.70;", "95%", "CI,", "0.57-0.85", "for", "the", "ins/del", "+", "del/del", "genotypes", "compared", "with", "the", "ins/ins", "genotype;", "adjusted", "OR,", "0.73;", "95%", "CI,", "0.55-0.97", "for", "the", "del-D", "haplotype", "compared", "with", "the", "ins-D", "haplotype).", "Furthermore,", "the", "number", "of", "the", "CASP8", "-652", "6N", "del", " ", "(but", "not", "302H)", "variant", "allele", "tended", "to", "correlate", "with", "increased", "levels", "of", "camptothecin-induced", "p53-mediated", "apoptosis", "in", "T", "lymphocytes", "from", "170", "cancer-free", "controls.", "We", "concluded", "that", "the", "CASP8", "-652", "6N", "del", " ", "variant", "allele", "may", "contribute", "to", "the", "risk", "of", "developing", "SCCHN", "in", "non-Hispanic", "white", "populations.", "Further", "validation", "by", "population-based", "case-control", "studies", "and", "rigorous", "mechanistic", "studies", "is", "warranted." ]

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Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion ( -652 6N ins/del ) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted.

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22125978

[]

[ 2, 3 ]

[ 0, 0 ]

[ 1, 1 ]

[ -100, -100 ]

20949073

[]

[ 2, 3 ]

[ 0, 0 ]

[ 1, 1 ]

[ -100, -100 ]

15607529

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Inactivating mutations in the LH receptor are the predominant cause for male pseudohermaphroditism in subjects with Leydig cell hypoplasia (LCH). The severity of the mutations, correlates with residual receptor activities. Here, we detail the clinical presentation of one subject with complete male pseudohermaphroditism and LCH. We identify within the proband and her similarly afflicted sibling a homozygous T to G transversion at nucleotide 1836 in exon 11 of the LH/CGR gene. This causes conversion of a tyrosine codon into a stop codon at codon 612 in the seventh transmembrane domain, resulting in a truncated receptor that lacks a cytoplasmic tail. In vitro, in contrast to cells expressing a normal LHR, cells transfected with the mutant cDNA exhibit neither surface binding of radiolabeled hCG nor cAMP generation. In vitro expression under the control of the LHR signal peptide of either a wild type or mutant LHR-GFP fusion protein shows no differences in receptor cellular localization. In conclusion, the in vitro studies suggest that residues in the seventh transmembrane domain and cytoplasmic tail are important for receptor binding and activation without playing a major role in receptor cellular trafficking.

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12809638

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14709355

[ "Familial", "HDL", "deficiency", "(FHD)", "is", "a", "rare", "autosomal", "dominant", "lipoprotein", "disorder.", "We", "describe", "a", "novel", "genetic", "variant", "of", "the", "apolipoprotein", "A-I", "(apoA-I)", "gene", "resulting", "in", "FHD.", "The", "proband", "is", "a", "51-year-old", "woman", "who", "was", "hospitalized", "due", "to", "severe", "heart", "failure.", "Her", "plasma", "HDL-cholesterol", "(C)", "and", "apoA-I", "concentrations", "were", "0.08mmol/l", "and", "1mg/dl,", "respectively.", "She", "exhibited", "corneal", "opacities", "and", "planar", "xanthomas", "on", "eyelids", "and", "elbows.", "Coronary", "angiography", "demonstrated", "extensive", "obstructions", "in", "two", "major", "vessels.", "Genomic", "DNA", "sequencing", "of", "the", "patient's", "apoA-I", "gene", "revealed", "a", "homozygosity", "for", "a", "GC", "deletion", "between", "5", "GC", "repeats", "in", "exon", "4,", "creating", "a", "frameshift", "and", "a", "stop", "codon", "at", "residue", "178.", "We", "designated", "this", "mutation", "as", "apoA-I", "Shinbashi.", "The", "proband's", "father,", "son,", "and", "daughter", "were", "found", "to", "be", "heterozygous", "for", "this", "mutation", "and", "their", "HDL-C", "and", "apoA-I", "levels", "were", "about", "half", "of", "normal", "levels,", "demonstrating", "a", "gene", "dosage", "effect.", "The", "father", "underwent", "coronary", "bypass", "surgery", "at", "age", "of", "70", "years.", "Lecithin-cholesterol", "acyltransferase", "(LCAT)", "activity", "was", "decreased", "by", "63%", "in", "the", "homozygote", "and", "31%", "in", "heterozygotes,", "respectively.", "This", "new", "case", "of", "apoA-I", "deficiency,", "apoA-I", "Shinbashi,", "is", "the", "first", "case", "involving", "a", "single", "gene", "defect", "of", "the", "apoA-I", "gene", "to", "develop", "all", "the", "characteristics", "for", "apoA-I", "deficiency,", "including", "premature", "coronary", "heart", "disease." ]

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Familial HDL deficiency (FHD) is a rare autosomal dominant lipoprotein disorder. We describe a novel genetic variant of the apolipoprotein A-I (apoA-I) gene resulting in FHD. The proband is a 51-year-old woman who was hospitalized due to severe heart failure. Her plasma HDL-cholesterol (C) and apoA-I concentrations were 0.08mmol/l and 1mg/dl, respectively. She exhibited corneal opacities and planar xanthomas on eyelids and elbows. Coronary angiography demonstrated extensive obstructions in two major vessels. Genomic DNA sequencing of the patient's apoA-I gene revealed a homozygosity for a GC deletion between 5 GC repeats in exon 4, creating a frameshift and a stop codon at residue 178. We designated this mutation as apoA-I Shinbashi. The proband's father, son, and daughter were found to be heterozygous for this mutation and their HDL-C and apoA-I levels were about half of normal levels, demonstrating a gene dosage effect. The father underwent coronary bypass surgery at age of 70 years. Lecithin-cholesterol acyltransferase (LCAT) activity was decreased by 63% in the homozygote and 31% in heterozygotes, respectively. This new case of apoA-I deficiency, apoA-I Shinbashi, is the first case involving a single gene defect of the apoA-I gene to develop all the characteristics for apoA-I deficiency, including premature coronary heart disease.

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17671968

[ "Association", "study", "between", "Gilles", "de", "la", "Tourette", "Syndrome", "and", "two", "genes", "in", "the", "Robo-Slit", "pathway", "located", "in", "the", "chromosome", "11q24", "linked/associated", "region." ]

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Association study between Gilles de la Tourette Syndrome and two genes in the Robo-Slit pathway located in the chromosome 11q24 linked/associated region.

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17951029

[]

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17327131

[]

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15649253

[ "Primary", "malignant", "lymphoma", "of", "the", "brain:", "frequent", "abnormalities", "and", "inactivation", "of", "p14", "tumor", "suppressor", "gene." ]

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Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene.

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15377356

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19365571

[ "PURPOSE:", "To", "identify", "mutations", "in", "the", "carbohydrate", "sulfotransferase", "gene", "(CHST6)", "for", "a", "Chinese", "family", "with", "macular", "corneal", "dystrophy", "(MCD)", "and", "to", "investigate", "the", "histopathological", "changes", "in", "the", "affected", "cornea.", "METHODS:", "A", "corneal", "button", "of", "the", "proband", "was", "obtained", "by", "penetrating", "keratoplasty.", "The", "half", "button", "and", "ultrathin", "sections", "from", "the", "other", "half", "button", "were", "examined", "with", "special", "stains", "under", "a", "light", "microscope", "(LM)", "and", "an", "electron", "microscope", "(EM)", "separately.", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "of", "11", "family", "members,", "and", "the", "coding", "region", "of", "CHST6", "was", "amplified", "by", "the", "polymerase", "chain", "reaction", "(PCR)", "method.", "The", "PCR", "products", "were", "analyzed", "by", "direct", "sequencing", "and", "restriction", "enzyme", "digestion.", "RESULTS:", "The", "positive", "reaction", "to", "colloidal", "iron", "stain", "(extracellular", "blue", "accumulations", "in", "the", "stroma)", "was", "detected", "under", "light", "microscopy.", "Transmission", "electron", "microscopy", "revealed", "the", "enlargement", "of", "smooth", "endoplasmic", "reticulum", "and", "the", "presence", "of", "intracytoplasmic", "vacuoles.", "The", "compound", "heterozygous", "mutations,", "c.892C>T", " ", "and", "c.1072T>C", ",", "were", "identified", "in", "exon", "3", "of", "CHST6", "in", "three", "patients.", "The", "two", "transversions", "resulted", "in", "the", "substitution", "of", "a", "stop", "codon", "for", "glutamine", "at", "codon", "298", "(", "p.Q298X", ")", "and", "a", "missense", "mutation", "at", "codon", "358,", "tyrosine", "to", "histidine", "(", "p.Y358H", ").", "The", "six", "unaffected", "family", "individuals", "carried", "alternative", "heterozygous", "mutations.", "These", "two", "mutations", "were", "not", "detected", "in", "any", "of", "the", "100", "control", "subjects.", "CONCLUSIONS:", "Those", "novel", "compound", "heterozygous", "mutations", "were", "thought", "to", "contribute", "to", "the", "loss", "of", "CHST6", "function,", "which", "induced", "the", "abnormal", "metabolism", "of", "keratan", "sulfate", "(KS)", "that", "deposited", "in", "the", "corneal", "stroma.", "It", "could", "be", "proved", "by", "the", "observation", "of", "a", "positive", "stain", "reaction", "and", "the", "enlarged", "collagen", "fibers", "as", "well", "as", "hyperplastic", "fibroblasts", "under", "microscopes." ]

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PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea. METHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion. RESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C , were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 ( p.Q298X ) and a missense mutation at codon 358, tyrosine to histidine ( p.Y358H ). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects. CONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes.

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17962394

[ "AIMS:", "This", "study", "aimed", "to", "identify", "the", "underlying", "genetic", "defect", "of", "a", "large", "Turkish", "X", "linked", "nystagmus", "(NYS)", "family.", "METHODS:", "Both", "Xp11", "and", "Xq26", "loci", "were", "tested", "by", "linkage", "analysis.", "The", "12", "exons", "and", "intron-exon", "junctions", "of", "the", "FRMD7", "gene", "were", "screened", "by", "direct", "sequencing.", "X", "chromosome", "inactivation", "analysis", "was", "performed", "by", "enzymatic", "predigestion", "of", "DNA", "with", "a", "methylation-sensitive", "enzyme,", "followed", "by", "PCR", "of", "the", "polymorphic", "CAG", "repeat", "of", "the", "androgen", "receptor", "gene.", "RESULTS:", "The", "family", "contained", "162", "individuals,", "among", "whom", "28", "had", "NYS.", "Linkage", "analysis", "confirmed", "the", "Xq26", "locus.", "A", "novel", "missense", "c.686C>G", " ", "mutation,", "which", "causes", "the", "substitution", "of", "a", "conserved", "arginine", "at", "amino", "acid", "position", "229", "by", "glycine", "(", "p.R229G", ")", "in", "exon", "8", "of", "the", "FRMD7", "gene,", "was", "observed.", "This", "change", "was", "not", "documented", "in", "120", "control", "individuals.", "The", "clinical", "findings", "in", "a", "female", "who", "was", "homozygous", "for", "the", "mutation", "were", "not", "different", "from", "those", "of", "affected", "heterozygous", "females.", "Skewed", "X", "inactivation", "was", "remarkable", "in", "the", "affected", "females", "of", "the", "family.", "CONCLUSIONS:", "A", "novel", "p.R229G", " ", "mutation", "in", "the", "FRMD7", "gene", "causes", "the", "NYS", "phenotype,", "and", "skewed", "X", "inactivation", "influences", "the", "manifestation", "of", "the", "disease", "in", "X", "linked", "NYS", "females." ]

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AIMS: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. METHODS: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. RESULTS: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine ( p.R229G ) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. CONCLUSIONS: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.

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21126715

[ "Congenital", "generalized", "lipodystrophy", "(CGL)", "is", "a", "rare", "autosomal", "recessive", "disease", "that", "is", "characterized", "by", "a", "near-complete", "absence", "of", "adipose", "tissue", "from", "birth", "or", "early", "infancy.", "Mutations", "in", "the", "BSCL2", "gene", "are", "known", "to", "result", "in", "CGL2,", "a", "more", "severe", "phenotype", "than", "CGL1,", "with", "earlier", "onset,", "more", "extensive", "fat", "loss", "and", "biochemical", "changes,", "more", "severe", "intellectual", "impairment,", "and", "more", "severe", "cardiomyopathy.", "We", "report", "a", "3-month-old", "Taiwanese", "boy", "with", "initial", "presentation", "of", "a", "lack", "of", "subcutaneous", "fat,", "prominent", "musculature,", "generalized", "eruptive", "xanthomas,", "and", "extreme", "hypertriglyceridemia.", "Absence", "of", "mechanical", "adipose", "tissue", "in", "the", "orbits", "and", "scalp", "was", "revealed", "by", "head", "magnetic", "resonance", "imaging.", "Hepatomegaly", "was", "noticed,", "and", "histological", "examination", "of", "a", "liver", "biopsy", "specimen", "suggested", "severe", "hepatic", "steatosis", "and", "periportal", "necrosis.", "However,", "echocardiography", "indicated", "no", "sign", "of", "cardiomyopathy", "and", "he", "showed", "no", "distinct", "intellectual", "impairment", "that", "interfered", "with", "daily", "life.", "About", "1", "year", "later,", "abdominal", "computed", "tomography", "revealed", "enlargement", "of", "kidneys.", "He", "had", "a", "homozygous", "insertion", "of", "a", "nucleotide,", "783insG", " ", "(", "Ile262fs", " ", "mutation),", "in", "exon", "7", "of", "the", "BSCL2", "gene.", "We", "reviewed", "the", "genotype", "of", "CGL", "cases", "from", "Japan,", "India,", "China", "and", "Taiwan,", "and", "found", "that", "BSCL2", "is", "a", "major", "causative", "gene", "for", "CGL", "in", "Asian." ]

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Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by a near-complete absence of adipose tissue from birth or early infancy. Mutations in the BSCL2 gene are known to result in CGL2, a more severe phenotype than CGL1, with earlier onset, more extensive fat loss and biochemical changes, more severe intellectual impairment, and more severe cardiomyopathy. We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia. Absence of mechanical adipose tissue in the orbits and scalp was revealed by head magnetic resonance imaging. Hepatomegaly was noticed, and histological examination of a liver biopsy specimen suggested severe hepatic steatosis and periportal necrosis. However, echocardiography indicated no sign of cardiomyopathy and he showed no distinct intellectual impairment that interfered with daily life. About 1 year later, abdominal computed tomography revealed enlargement of kidneys. He had a homozygous insertion of a nucleotide, 783insG ( Ile262fs mutation), in exon 7 of the BSCL2 gene. We reviewed the genotype of CGL cases from Japan, India, China and Taiwan, and found that BSCL2 is a major causative gene for CGL in Asian.

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17962469

[ "PURPOSE:", "To", "report", "a", "large,", "consanguineous", "Algerian", "family", "affected", "with", "Leber", "congenital", "amaurosis", "(LCA)", "or", "early-onset", "retinal", "degeneration", "(EORD).", "METHODS:", "All", "accessible", "family", "members", "underwent", "a", "complete", "ophthalmic", "examination,", "and", "blood", "was", "obtained", "for", "DNA", "extraction.", "Homozygosity", "mapping", "was", "performed", "with", "markers", "flanking", "12", "loci", "associated", "with", "LCA.", "The", "15", "exons", "of", "TULP1", "were", "sequenced.", "RESULTS:", "Seven", "of", "30", "examined", "family", "members", "were", "affected,", "including", "five", "with", "EORD", "and", "two", "with", "LCA.", "All", "patients", "had", "nystagmus,", "hemeralopia,", "mild", "myopia,", "and", "low", "visual", "acuity", "without", "photophobia.", "Fundus", "features", "were", "variable", "among", "EORD", "patients:", "typical", "spicular", "retinitis", "pigmentosa", "or", "clumped", "pigmented", "retinopathy", "with", "age-dependent", "macular", "involvement.", "A", "salt-and-pepper", "retinopathy", "with", "midperipheral", "retinal", "pigment", "epithelium", "(RPE)", "atrophy", "was", "present", "in", "the", "older", "patients", "with", "LCA,", "whereas", "the", "retina", "appeared", "virtually", "normal", "in", "the", "younger", "ones.", "Both", "scotopic", "and", "photopic", "electroretinograms", "were", "nondetectable.", "Fundus", "imaging", "revealed", "a", "perifoveal", "ring", "of", "increased", "fundus", "autofluorescence", "(FAF)", "in", "the", "proband,", "and", "optical", "coherence", "tomography", "disclosed", "a", "thinned", "retina,", "mainly", "due", "to", "photoreceptor", "loss.", "Linkage", "analysis", "identified", "a", "region", "of", "homozygosity", "on", "chromosome", "6,", "region", "p21.3,", "and", "mutation", "screening", "revealed", "a", "novel", "6-base", "in-frame", "duplication,", "in", "the", "TULP1", "gene.", "CONCLUSIONS:", "Mutation", "in", "the", "TULP1", "gene", "is", "a", "rare", "cause", "of", "LCA/EORD,", "with", "only", "14", "mutations", "reported", "so", "far.", "The", "observed", "intrafamilial", "phenotypic", "variability", "could", "be", "attributed", "to", "disease", "progression", "or", "possibly", "modifier", "alleles.", "This", "study", "provides", "the", "first", "description", "of", "FAF", "and", "quantitative", "reflectivity", "profiles", "in", "TULP1-related", "retinopathy." ]

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PURPOSE: To report a large, consanguineous Algerian family affected with Leber congenital amaurosis (LCA) or early-onset retinal degeneration (EORD). METHODS: All accessible family members underwent a complete ophthalmic examination, and blood was obtained for DNA extraction. Homozygosity mapping was performed with markers flanking 12 loci associated with LCA. The 15 exons of TULP1 were sequenced. RESULTS: Seven of 30 examined family members were affected, including five with EORD and two with LCA. All patients had nystagmus, hemeralopia, mild myopia, and low visual acuity without photophobia. Fundus features were variable among EORD patients: typical spicular retinitis pigmentosa or clumped pigmented retinopathy with age-dependent macular involvement. A salt-and-pepper retinopathy with midperipheral retinal pigment epithelium (RPE) atrophy was present in the older patients with LCA, whereas the retina appeared virtually normal in the younger ones. Both scotopic and photopic electroretinograms were nondetectable. Fundus imaging revealed a perifoveal ring of increased fundus autofluorescence (FAF) in the proband, and optical coherence tomography disclosed a thinned retina, mainly due to photoreceptor loss. Linkage analysis identified a region of homozygosity on chromosome 6, region p21.3, and mutation screening revealed a novel 6-base in-frame duplication, in the TULP1 gene. CONCLUSIONS: Mutation in the TULP1 gene is a rare cause of LCA/EORD, with only 14 mutations reported so far. The observed intrafamilial phenotypic variability could be attributed to disease progression or possibly modifier alleles. This study provides the first description of FAF and quantitative reflectivity profiles in TULP1-related retinopathy.

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22180037

[ "Glutathione-S-transferase", "P1", "(GSTP1)", "is", "a", "critical", "enzyme", "of", "the", "phase", "II", "detoxification", "pathway.", "One", "of", "the", "common", "functional", "polymorphisms", "of", "GSTP1", "is", "A", ">", "G", "at", "nucleotide", "313", ",", "which", "results", "in", "an", "amino", "acid", "substitution", "(", "Ile105Val", ")", "at", "the", "substrate", "binding", "site", "of", "GSTP1", "and", "reduces", "catalytic", "activity", "of", "GSTP1.", "To", "investigate", "the", "GSTP1", "Ile105Val", " ", "genotype", "frequency", "in", "prostate", "cancer", "cases", "in", "the", "Kashmiri", "population,", "we", "designed", "a", "case-control", "study,", "in", "which", "50", "prostate", "cancer", "cases", "and", "45", "benign", "prostate", "hyperplasia", "cases", "were", "studied", "for", "GSTP1", "Ile105Val", " ", "polymorphism,", "compared", "to", "80", "controls", "taken", "from", "the", "general", "population,", "employing", "the", "PCR-RFLP", "technique.", "We", "found", "the", "frequency", "of", "the", "three", "different", "genotypes", "of", "GSTP1", "Ile105Val", " ", "in", "our", "ethnic", "Kashmir", "population,", "i.e.,", "Ile/Ile,", "Ile/Val", "and", "Val/Val,", "to", "be", "52.4,", "33.3", "and", "14.3%", "among", "prostate", "cancer", "cases,", "48.5,", "37.5", "and", "14%", "among", "benign", "prostate", "hyperplasia", "cases", "and", "73.8,", "21.3", "and", "5%", "in", "the", "control", "population,", "respectively.", "There", "was", "a", "significant", "association", "between", "the", "GSTP1", "Ile/Val", "genotype", "and", "the", "advanced", "age", "group", "among", "the", "cases.", "We", "conclude", "that", "GSTP1", "Ile/Val", "polymorphism", "is", "involved", "in", "the", "risk", "of", "prostate", "cancer", "development", "in", "our", "population." ]

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Glutathione-S-transferase P1 (GSTP1) is a critical enzyme of the phase II detoxification pathway. One of the common functional polymorphisms of GSTP1 is A > G at nucleotide 313 , which results in an amino acid substitution ( Ile105Val ) at the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. To investigate the GSTP1 Ile105Val genotype frequency in prostate cancer cases in the Kashmiri population, we designed a case-control study, in which 50 prostate cancer cases and 45 benign prostate hyperplasia cases were studied for GSTP1 Ile105Val polymorphism, compared to 80 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of GSTP1 Ile105Val in our ethnic Kashmir population, i.e., Ile/Ile, Ile/Val and Val/Val, to be 52.4, 33.3 and 14.3% among prostate cancer cases, 48.5, 37.5 and 14% among benign prostate hyperplasia cases and 73.8, 21.3 and 5% in the control population, respectively. There was a significant association between the GSTP1 Ile/Val genotype and the advanced age group among the cases. We conclude that GSTP1 Ile/Val polymorphism is involved in the risk of prostate cancer development in our population.

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20523265

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15041272

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A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation.

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16410744

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Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.

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17250663

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We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H ( c.G1714C ), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N ( c.G1714A ). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H , in comparison with that caused by p.D572N , may reflect a correlation of DFNA36 phenotype with TMC1 genotype.

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14510914

[ "Congenital", "hypothyroidism", "due", "to", "a", "new", "deletion", "in", "the", "sodium/iodide", "symporter", "protein." ]

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Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein.

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Datasets:

Brizape
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multiCorp_tokenized_split_LabelNorm_0404_dev

Dataset Card for "multiCorp_tokenized_split_LabelNorm_0404_dev"