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15154117
[ "A", "common", "haplotype", "of", "the", "nicotine", "acetylcholine", "receptor", "alpha", "4", "subunit", " ", "gene", "is", "associated", "with", "vulnerability", "to", "nicotine", "addiction", "in", "men.", "Nicotine", "is", "the", "major", "addictive", "substance", "in", "cigarettes,", "and", "genes", "involved", "in", "sensing", "nicotine", "are", "logical", "candidates", "for", "vulnerability", "to", "nicotine", "addiction.", "We", "studied", "six", "single-nucleotide", "polymorphisms", "(SNPs)", "in", "the", "CHRNA4", " ", "gene", "and", "four", "SNPs", "in", "the", "CHRNB2", " ", "gene", "with", "respect", "to", "nicotine", "dependence", "in", "a", "collection", "of", "901", "subjects", "(815", "siblings", "and", "86", "parents)", "from", "222", "nuclear", "families", "with", "multiple", "nicotine-addicted", "siblings.", "The", "subjects", "were", "assessed", "for", "addiction", "by", "both", "the", "Fagerstrom", "Test", "for", "Nicotine", "Dependence", "(FTND)", "and", "the", "Revised", "Tolerance", "Questionnaire", "(RTQ).", "Because", "only", "5.8%", "of", "female", "offspring", "were", "smokers,", "only", "male", "subjects", "were", "included", "in", "the", "final", "analyses", "(621", "men", "from", "206", "families).", "Univariate", "(single-marker)", "family-based", "association", "tests", "(FBATs)", "demonstrated", "that", "variant", "alleles", "at", "two", "SNPs,", "rs1044396", "and", "rs1044397,", "in", "exon", "5", "of", "the", "CHRNA4", " ", "gene", "were", "significantly", "associated", "with", "a", "protective", "effect", "against", "nicotine", "addiction", "as", "either", "a", "dichotomized", "trait", "or", "a", "quantitative", "phenotype", "(i.e.,", "age-adjusted", "FTND", "and", "RTQ", "scores),", "which", "was", "consistent", "with", "the", "results", "of", "the", "global", "haplotype", "FBAT.", "Furthermore,", "the", "haplotype-specific", "FBAT", "showed", "a", "common", "(22.5%)", "CHRNA4", " ", "haplotype,", "GCTATA,", "which", "was", "significantly", "associated", "with", "both", "a", "protective", "effect", "against", "nicotine", "addiction", "as", "a", "dichotomized", "trait", "(Z=-3.04,", "P<.005)", "and", "significant", "decreases", "of", "age-adjusted", "FTND", "(Z=-3.31,", "P<.005)", "or", "RTQ", "scores", "(Z=-2.73,", "P=.006).", "Our", "findings", "provide", "strong", "evidence", "suggesting", "a", "common", "CHRNA4", " ", "haplotype", "might", "be", "protective", "against", "vulnerability", "to", "nicotine", "addiction", "in", "men." ]
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A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men. Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction. We studied six single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and four SNPs in the CHRNB2 gene with respect to nicotine dependence in a collection of 901 subjects (815 siblings and 86 parents) from 222 nuclear families with multiple nicotine-addicted siblings. The subjects were assessed for addiction by both the Fagerstrom Test for Nicotine Dependence (FTND) and the Revised Tolerance Questionnaire (RTQ). Because only 5.8% of female offspring were smokers, only male subjects were included in the final analyses (621 men from 206 families). Univariate (single-marker) family-based association tests (FBATs) demonstrated that variant alleles at two SNPs, rs1044396 and rs1044397, in exon 5 of the CHRNA4 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype (i.e., age-adjusted FTND and RTQ scores), which was consistent with the results of the global haplotype FBAT. Furthermore, the haplotype-specific FBAT showed a common (22.5%) CHRNA4 haplotype, GCTATA, which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait (Z=-3.04, P<.005) and significant decreases of age-adjusted FTND (Z=-3.31, P<.005) or RTQ scores (Z=-2.73, P=.006). Our findings provide strong evidence suggesting a common CHRNA4 haplotype might be protective against vulnerability to nicotine addiction in men.
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15154114
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High prevalence of SLC6A8 deficiency in X-linked mental retardation. A novel X-linked mental retardation (XLMR) syndrome was recently identified, resulting from creatine deficiency in the brain caused by mutations in the creatine transporter gene, SLC6A8 . We have studied the prevalence of SLC6A8 mutations in a panel of 290 patients with nonsyndromic XLMR archived by the European XLMR Consortium. The full-length open reading frame and splice sites of the SLC6A8 gene were investigated by DNA sequence analysis. Six pathogenic mutations, of which five were novel, were identified in a total of 288 patients with XLMR, showing a prevalence of at least 2.1% (6/288). The novel pathogenic mutations are a nonsense mutation ( p.Y317X ) and four missense mutations. Three missense mutations ( p.G87R , p.P390L , and p.P554L ) were concluded to be pathogenic on the basis of conservation, segregation, chemical properties of the residues involved, as well as the absence of these and any other missense mutation in 276 controls. For the p.C337W mutation, additional material was available to biochemically prove (i.e., by increased urinary creatine : creatinine ratio) pathogenicity. In addition, we found nine novel polymorphisms ( IVS1+26G-->A , IVS7+37G-->A , IVS7+87A-->G , IVS7-35G-->A , IVS12-3C-->T , IVS2+88G-->C , IVS9-36G-->A , IVS12-82G-->C , and p.Y498 ) that were present in the XLMR panel and/or in the control panel. Two missense variants (p.V629I and p.M560V) that were not highly conserved and were not associated with increased creatine : creatinine ratio, one translational silent variant (p.L472), and 10 intervening sequence variants or untranslated region variants ( IVS6+9C-->T , IVS7-151_152delGA , IVS7-99C-->A , IVS8-35G-->A , IVS8+28C-->T , IVS10-18C-->T , IVS11+21G-->A , IVS12+15C-->T , *207G-->C , IVS12+32C-->A ) were found only in the XLMR panel but should be considered as unclassified variants or as a polymorphism ( p.M560V ). Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1 p.M560V p.V629I and p.M560V) that were not highly conserved and were not associated with increased creatine : creatinine ratio, one translational silent variant (p.L472), and 10 intervening sequence variants or untranslated region variants (IVS6+9C-->T, IVS7-151_152delGA, IVS7-99C-->A, IVS8-35G-->A, IVS8+28C-->T, IVS10-18C-->T, IVS11+21G-->A, IVS12+15C-->T, *207G-->C, IVS12+32C-->A) were found only in the XLMR panel but should be considered as unclassified variants or as a polymorphism (p.M560V). Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1, the gene responsible for fragile-X syndrome.
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8940265
[ "Mucopolysaccharidosis", "type", "II", "(Hunter", "syndrome):", "mutation", "\"hot", "spots\"", "in", "the", "iduronate-2-sulfatase", " ", "gene.", "Mucopolysaccharidosis", "type", "II", "(MPS", "II,", "Hunter", "syndrome)", "is", "an", "X-chromosomal", "storage", "disorder", "due", "to", "deficiency", "of", "the", "lysosomal", "enzyme", "iduronate-2-sulfatase", " ", "(", "IDS", ").", "We", "have", "identified", "IDS", " ", "mutations", "in", "a", "total", "of", "31", "families/patients", "with", "MPS", "II,", "of", "which", "20", "are", "novel", "and", "unique", "and", "a", "further", "1", "is", "novel", "but", "has", "been", "found", "in", "3", "unrelated", "patients.", "One", "of", "the", "mutations", "detected", "is", "of", "special", "interest", "as", "an", "AG-->G", "substitution", "in", "an", "intron,", "far", "apart", "from", "the", "coding", "region,", "is", "deleterious", "by", "creating", "a", "new", "5'-splice-donor", "site", "that", "results", "in", "the", "inclusion", "of", "a", "78-bp", "intronic", "sequence.", "While", "the", "distribution", "of", "gene", "rearrangements", "(deletions,", "insertions,", "and", "duplications)", "of", "<20", "bp", "seems", "to", "be", "random", "over", "the", "IDS", " ", "gene,", "the", "analysis", "of", "a", "total", "of", "101", "point", "mutations", "lying", "within", "the", "coding", "region", "shows", "that", "they", "tend", "to", "be", "more", "frequent", "in", "exons", "III,", "VIII,", "and", "IX.", "Forty-seven", "percent", "of", "the", "point", "mutations", "are", "at", "CpG", "dinucleotides,", "of", "which", "G:C-to-A:T", "transitions", "constitute", "nearly", "80%.", "Almost", "all", "recurrent", "point", "mutations", "involve", "CpG", "sites.", "Analysis", "of", "a", "collective", "of", "50", "families", "studied", "in", "our", "laboratory,", "to", "date,", "revealed", "that", "mutations", "occur", "more", "frequently", "in", "male", "meioses", "(estimated", "male-to-female", "ratio", "between", "3.76", "and", "6.3)." ]
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Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene. Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-chromosomal storage disorder due to deficiency of the lysosomal enzyme iduronate-2-sulfatase ( IDS ). We have identified IDS mutations in a total of 31 families/patients with MPS II, of which 20 are novel and unique and a further 1 is novel but has been found in 3 unrelated patients. One of the mutations detected is of special interest as an AG-->G substitution in an intron, far apart from the coding region, is deleterious by creating a new 5'-splice-donor site that results in the inclusion of a 78-bp intronic sequence. While the distribution of gene rearrangements (deletions, insertions, and duplications) of <20 bp seems to be random over the IDS gene, the analysis of a total of 101 point mutations lying within the coding region shows that they tend to be more frequent in exons III, VIII, and IX. Forty-seven percent of the point mutations are at CpG dinucleotides, of which G:C-to-A:T transitions constitute nearly 80%. Almost all recurrent point mutations involve CpG sites. Analysis of a collective of 50 families studied in our laboratory, to date, revealed that mutations occur more frequently in male meioses (estimated male-to-female ratio between 3.76 and 6.3).
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15726498
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Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene ( SOX9 ) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps approximately 900 kb upstream of SOX9 , which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter-->4p15.1::17q25.1-->17qter;7qter-->7p15.3::4p15.1-->4pter;8pter-->8q12.1::7p15.3-->7pter;17pter-->17q25.1::8q12.1-->8qter). Surprisingly, the 17q breakpoint maps approximately 1.3 Mb downstream of SOX9 , making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3' of SOX9 . By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.
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9718360
[ "\"Well-bear", "and", "well-rear\"", "in", "China?" ]
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"Well-bear and well-rear" in China?
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9829906
[ "Spectrum", "of", "mutations", "and", "sequence", "variants", "in", "the", "FALDH", " ", "gene", "in", "patients", "with", "Sjögren-Larsson", "syndrome.", "The", "gene", "encoding", "the", "human", "fatty", "aldehyde", "dehydrogenase", "(", "FALDH", "fatty", "aldehyde", "dehydrogenase", " ", "(FALDH)", "is", "located", "on", "17p11.2,", "causing", "Sjögren-Larsson", "syndrome", "(SLS)", "when", "mutated.", "SLS", "is", "an", "autosomal", "recessive", "disorder", "characterized", "by", "a", "combination", "of", "mental", "retardation,", "congenital", "ichthyosis,", "and", "spastic", "di-", "or", "tetraplegia.", "We", "report", "here", "on", "studies", "of", "16", "SLS", "families", "from", "Europe", "and", "the", "Middle", "East,", "which", "resulted", "in", "identification", "of", "11", "different", "mutations.", "The", "spectrum", "of", "mutations", "characterized", "in", "the", "present", "study", "are", "five", "nucleotide", "substitutions", "resulting", "in", "amino", "acid", "changes,", "five", "frameshift", "mutations", "introducing", "a", "stop", "codon,", "and", "one", "in-frame", "deletion", "with", "insertion", "at", "the", "same", "position.", "We", "also", "observed", "silent", "sequence", "variants", "in", "the", "FALDH", " ", "gene", "and", "a", "base", "pair", "substitution", "in", "exon", "5", "that", "alters", "aspartic", "acid", "to", "asparagine,", "all", "of", "which", "are", "considered", "polymorphisms." ]
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Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome. The gene encoding the human fatty aldehyde dehydrogenase ( FALDH fatty aldehyde dehydrogenase (FALDH) is located on 17p11.2, causing Sjögren-Larsson syndrome (SLS) when mutated. SLS is an autosomal recessive disorder characterized by a combination of mental retardation, congenital ichthyosis, and spastic di- or tetraplegia. We report here on studies of 16 SLS families from Europe and the Middle East, which resulted in identification of 11 different mutations. The spectrum of mutations characterized in the present study are five nucleotide substitutions resulting in amino acid changes, five frameshift mutations introducing a stop codon, and one in-frame deletion with insertion at the same position. We also observed silent sequence variants in the FALDH gene and a base pair substitution in exon 5 that alters aspartic acid to asparagine, all of which are considered polymorphisms.
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22503634
[ "Genetic", "adaptation", "of", "fatty-acid", "metabolism:", "a", "human-specific", "haplotype", "increasing", "the", "biosynthesis", "of", "long-chain", "omega-3", "and", "omega-6", "fatty", "acids.", "Omega-3", "and", "omega-6", "long-chain", "polyunsaturated", "fatty", "acids", "(LC-PUFAs)", "are", "essential", "for", "the", "development", "and", "function", "of", "the", "human", "brain.", "They", "can", "be", "obtained", "directly", "from", "food,", "e.g.,", "fish,", "or", "synthesized", "from", "precursor", "molecules", "found", "in", "vegetable", "oils.", "To", "determine", "the", "importance", "of", "genetic", "variability", "to", "fatty-acid", "biosynthesis,", "we", "studied", "FADS1", " ", "and", "FADS2", ",", "which", "encode", "rate-limiting", "enzymes", "for", "fatty-acid", "conversion.", "We", "performed", "genome-wide", "genotyping", "(n", "=", "5,652", "individuals)", "and", "targeted", "resequencing", "(n", "=", "960", "individuals)", "of", "the", "FADS", "region", "in", "five", "European", "population", "cohorts.", "We", "also", "analyzed", "available", "genomic", "data", "from", "human", "populations,", "archaic", "hominins,", "and", "more", "distant", "primates.", "Our", "results", "show", "that", "present-day", "humans", "have", "two", "common", "FADS", "haplotypes-defined", "by", "28", "closely", "linked", "SNPs", "across", "38.9", "kb-that", "differ", "dramatically", "in", "their", "ability", "to", "generate", "LC-PUFAs.", "No", "independent", "effects", "on", "FADS", "activity", "were", "seen", "for", "rare", "SNPs", "detected", "by", "targeted", "resequencing.", "The", "more", "efficient,", "evolutionarily", "derived", "haplotype", "appeared", "after", "the", "lineage", "split", "leading", "to", "modern", "humans", "and", "Neanderthals", "and", "shows", "evidence", "of", "positive", "selection.", "This", "human-specific", "haplotype", "increases", "the", "efficiency", "of", "synthesizing", "essential", "long-chain", "fatty", "acids", "from", "precursors", "and", "thereby", "might", "have", "provided", "an", "advantage", "in", "environments", "with", "limited", "access", "to", "dietary", "LC-PUFAs.", "In", "the", "modern", "world,", "this", "haplotype", "has", "been", "associated", "with", "lifestyle-related", "diseases,", "such", "as", "coronary", "artery", "disease." ]
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Genetic adaptation of fatty-acid metabolism: a human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids. Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2 , which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.
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19896112
[ "CNTNAP2", " ", "and", "NRXN1", " ", "are", "mutated", "in", "autosomal-recessive", "Pitt-Hopkins-like", "mental", "retardation", "and", "determine", "the", "level", "of", "a", "common", "synaptic", "protein", "in", "Drosophila.", "Heterozygous", "copy-number", "variants", "and", "SNPs", "of", "CNTNAP2", " ", "and", "NRXN1", ",", "two", "distantly", "related", "members", "of", "the", "neurexin", "superfamily,", "have", "been", "repeatedly", "associated", "with", "a", "wide", "spectrum", "of", "neuropsychiatric", "disorders,", "such", "as", "developmental", "language", "disorders,", "autism", "spectrum", "disorders,", "epilepsy,", "and", "schizophrenia.", "We", "now", "identified", "homozygous", "and", "compound-heterozygous", "deletions", "and", "mutations", "via", "molecular", "karyotyping", "and", "mutational", "screening", "in", "CNTNAP2", " ", "and", "NRXN1", " ", "in", "four", "patients", "with", "severe", "mental", "retardation", "(MR)", "and", "variable", "features,", "such", "as", "autistic", "behavior,", "epilepsy,", "and", "breathing", "anomalies,", "phenotypically", "overlapping", "with", "Pitt-Hopkins", "syndrome.", "With", "a", "frequency", "of", "at", "least", "1%", "in", "our", "cohort", "of", "179", "patients,", "recessive", "defects", "in", "CNTNAP2", " ", "appear", "to", "significantly", "contribute", "to", "severe", "MR.", "Whereas", "the", "established", "synaptic", "role", "of", "NRXN1", " ", "suggests", "that", "synaptic", "defects", "contribute", "to", "the", "associated", "neuropsychiatric", "disorders", "and", "to", "severe", "MR", "as", "reported", "here,", "evidence", "for", "a", "synaptic", "role", "of", "the", "CNTNAP2-encoded", "protein", "CASPR2", " ", "has", "so", "far", "been", "lacking.", "Using", "Drosophila", "as", "a", "model,", "we", "now", "show", "that,", "as", "known", "for", "fly", "Nrx-I,", "the", "CASPR2", "Nrx-I", ",", "the", "CASPR2", "ortholog", "Nrx-IV", " ", "might", "also", "localize", "to", "synapses.", "Overexpression", "of", "either", "protein", "can", "reorganize", "synaptic", "morphology", "and", "induce", "increased", "density", "of", "active", "zones,", "the", "synaptic", "domains", "of", "neurotransmitter", "release.", "Moreover,", "both", "Nrx-I", " ", "and", "Nrx-IV", " ", "determine", "the", "level", "of", "the", "presynaptic", "active-zone", "protein", "bruchpilot,", "indicating", "a", "possible", "common", "molecular", "mechanism", "in", "Nrx-I", " ", "and", "Nrx-IV", " ", "mutant", "conditions.", "We", "therefore", "propose", "that", "an", "analogous", "shared", "synaptic", "mechanism", "contributes", "to", "the", "similar", "clinical", "phenotypes", "resulting", "from", "defects", "in", "human", "NRXN1", " ", "and", "CNTNAP2." ]
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CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1 , two distantly related members of the neurexin superfamily, have been repeatedly associated with a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, autism spectrum disorders, epilepsy, and schizophrenia. We now identified homozygous and compound-heterozygous deletions and mutations via molecular karyotyping and mutational screening in CNTNAP2 and NRXN1 in four patients with severe mental retardation (MR) and variable features, such as autistic behavior, epilepsy, and breathing anomalies, phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated neuropsychiatric disorders and to severe MR as reported here, evidence for a synaptic role of the CNTNAP2-encoded protein CASPR2 has so far been lacking. Using Drosophila as a model, we now show that, as known for fly Nrx-I, the CASPR2 Nrx-I , the CASPR2 ortholog Nrx-IV might also localize to synapses. Overexpression of either protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx-I and Nrx-IV mutant conditions. We therefore propose that an analogous shared synaptic mechanism contributes to the similar clinical phenotypes resulting from defects in human NRXN1 and CNTNAP2.
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Rare missense variants in ATP1A2 in families with clustering of common forms of migraine. Migraine is a recurrent neurovascular disease. Its two most common forms-migraine without aura (MO) and migraine with aura (MA)-both show familial clustering and a complex pattern of inheritance. Familial hemiplegic migraine (FHM) is a rare monogenic subform caused by mutations in the calcium channel gene CACNA1A or the Na(+)/K(+)-ATPase gene ATP1A2. An involvement of FHM genes in the pathogenesis of common forms of migraine is not proven. We therefore systematically screened ATP1A2 in families with several members affected by MA and/or MO. We identified two novel missense alterations [ c.520G>A ( p.E174 K ) and c.1544G>A ( p.C515Y c.1544G>A (p.C515Y)] in two out of 45 families, which were not found in 520 control chromosomes. Functional studies of these variants in Xenopus oocytes by two-electrode voltage clamp measurements and radiochemical determination of ATPase activity showed that C515Y leads to a complete loss of function comparable with the effect of FHM -mutations whereas for E174 K no functional alteration could be found in the in vitro assays. In conclusion we propose that rare variants in ATP1A2 are involved in the susceptibility to common forms of migraine, because of 1) the absence of alterations in controls, 2) the particular pattern of segregation in both families, 3) the high conservation of mutated residues in Na(+)/K(+)-ATPases, 4) the functional effect of C515Y , and 5) the involvement of ATP1A2 in a monogenic form of migraine.
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16138310
[ "Molecular", "diagnosis", "of", "inherited", "disorders:", "lessons", "from", "hemoglobinopathies.", "Hemoglobinopathies", "constitute", "a", "major", "health", "problem", "worldwide,", "with", "a", "high", "carrier", "frequency,", "particularly", "in", "certain", "regions", "where", "malaria", "has", "been", "endemic.", "These", "disorders", "are", "characterized", "by", "a", "vast", "clinical", "and", "hematological", "phenotypic", "heterogeneity.", "Over", "1,200", "different", "genetic", "alterations", "that", "affect", "the", "DNA", "sequence", "of", "the", "human", "alpha-like", "(", "HBZ", ",", "HBA2", ",", "HBA1", ",", "and", "HBQ1", ")", "and", "beta-like", "(", "HBE1", ",", "HBG2", ",", "HBG1", ",", "HBD", ",", "and", "HBB", ")", "globin", " ", "genes", "are", "mainly", "responsible", "for", "the", "observed", "clinical", "heterogeneity.", "These", "mutations,", "together", "with", "detailed", "information", "about", "the", "resulting", "phenotype,", "are", "documented", "in", "the", "globin", "locus-specific", "HbVar", "database.", "Family", "studies", "and", "comprehensive", "hematological", "analyses", "provide", "useful", "insights", "for", "accurately", "diagnosing", "thalassemia", "at", "the", "DNA", "level.", "For", "this", "purpose,", "numerous", "techniques", "can", "provide", "accurate,", "rapid,", "and", "cost-effective", "identification", "of", "the", "underlying", "genetic", "defect", "in", "affected", "individuals.", "The", "aim", "of", "this", "article", "is", "to", "review", "the", "diverse", "methodological", "and", "technical", "platforms", "available", "for", "the", "molecular", "diagnosis", "of", "inherited", "disorders,", "using", "thalassemia", "and", "hemoglobinopathies", "as", "a", "model.", "This", "article", "also", "attempts", "to", "shed", "light", "on", "issues", "closely", "related", "to", "thalassemia", "diagnostics,", "such", "as", "prenatal", "and", "preimplantation", "genetic", "diagnoses", "and", "genetic", "counseling,", "for", "better-quality", "disease", "management." ]
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Molecular diagnosis of inherited disorders: lessons from hemoglobinopathies. Hemoglobinopathies constitute a major health problem worldwide, with a high carrier frequency, particularly in certain regions where malaria has been endemic. These disorders are characterized by a vast clinical and hematological phenotypic heterogeneity. Over 1,200 different genetic alterations that affect the DNA sequence of the human alpha-like ( HBZ , HBA2 , HBA1 , and HBQ1 ) and beta-like ( HBE1 , HBG2 , HBG1 , HBD , and HBB ) globin genes are mainly responsible for the observed clinical heterogeneity. These mutations, together with detailed information about the resulting phenotype, are documented in the globin locus-specific HbVar database. Family studies and comprehensive hematological analyses provide useful insights for accurately diagnosing thalassemia at the DNA level. For this purpose, numerous techniques can provide accurate, rapid, and cost-effective identification of the underlying genetic defect in affected individuals. The aim of this article is to review the diverse methodological and technical platforms available for the molecular diagnosis of inherited disorders, using thalassemia and hemoglobinopathies as a model. This article also attempts to shed light on issues closely related to thalassemia diagnostics, such as prenatal and preimplantation genetic diagnoses and genetic counseling, for better-quality disease management.
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19327736
[ "TMEM126A", ",", "encoding", "a", "mitochondrial", "protein,", "is", "mutated", "in", "autosomal-recessive", "nonsyndromic", "optic", "atrophy.", "Nonsyndromic", "autosomal-recessive", "optic", "neuropathies", "are", "rare", "conditions", "of", "unknown", "genetic", "and", "molecular", "origin.", "Using", "an", "approach", "of", "whole-genome", "homozygosity", "mapping", "and", "positional", "cloning,", "we", "have", "identified", "the", "first", "gene,", "to", "our", "knowledge,", "responsible", "for", "this", "condition,", "TMEM126A", ",", "in", "a", "large", "multiplex", "inbred", "Algerian", "family", "and", "subsequently", "in", "three", "other", "families", "originating", "from", "the", "Maghreb.", "TMEM126A", " ", "is", "conserved", "in", "higher", "eukaryotes", "and", "encodes", "a", "transmembrane", "mitochondrial", "protein", "of", "unknown", "function,", "supporting", "the", "view", "that", "mitochondrial", "dysfunction", "may", "be", "a", "hallmark", "of", "inherited", "optic", "neuropathies", "including", "isolated", "autosomal-recessive", "forms." ]
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TMEM126A , encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy. Nonsyndromic autosomal-recessive optic neuropathies are rare conditions of unknown genetic and molecular origin. Using an approach of whole-genome homozygosity mapping and positional cloning, we have identified the first gene, to our knowledge, responsible for this condition, TMEM126A , in a large multiplex inbred Algerian family and subsequently in three other families originating from the Maghreb. TMEM126A is conserved in higher eukaryotes and encodes a transmembrane mitochondrial protein of unknown function, supporting the view that mitochondrial dysfunction may be a hallmark of inherited optic neuropathies including isolated autosomal-recessive forms.
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19944400
[ "Deletions", "and", "point", "mutations", "of", "LRRC50", " ", "cause", "primary", "ciliary", "dyskinesia", "due", "to", "dynein", "arm", "defects.", "Genetic", "defects", "affecting", "motility", "of", "cilia", "and", "flagella", "cause", "chronic", "destructive", "airway", "disease,", "randomization", "of", "left-right", "body", "asymmetry,", "and,", "frequently,", "male", "infertility", "in", "primary", "ciliary", "dyskinesia", "(PCD).", "The", "most", "frequent", "defects", "involve", "outer", "and", "inner", "dynein", "arms", "(ODAs", "and", "IDAs)", "that", "are", "large", "multiprotein", "complexes", "responsible", "for", "cilia-beat", "generation", "and", "regulation,", "respectively.", "Here,", "we", "demonstrate", "that", "large", "genomic", "deletions,", "as", "well", "as", "point", "mutations", "involving", "LRRC50", ",", "are", "responsible", "for", "a", "distinct", "PCD", "variant", "that", "is", "characterized", "by", "a", "combined", "defect", "involving", "assembly", "of", "the", "ODAs", "and", "IDAs.", "Functional", "analyses", "showed", "that", "LRRC50", " ", "deficiency", "disrupts", "assembly", "of", "distally", "and", "proximally", "DNAH5", "-", "and", "DNAI2", "-containing", "ODA", "complexes,", "as", "well", "as", "DNALI1", "-containing", "IDA", "complexes,", "resulting", "in", "immotile", "cilia.", "On", "the", "basis", "of", "these", "findings,", "we", "assume", "that", "LRRC50", " ", "plays", "a", "role", "in", "assembly", "of", "distinct", "dynein-arm", "complexes." ]
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Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility in primary ciliary dyskinesia (PCD). The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Here, we demonstrate that large genomic deletions, as well as point mutations involving LRRC50 , are responsible for a distinct PCD variant that is characterized by a combined defect involving assembly of the ODAs and IDAs. Functional analyses showed that LRRC50 deficiency disrupts assembly of distally and proximally DNAH5 - and DNAI2 -containing ODA complexes, as well as DNALI1 -containing IDA complexes, resulting in immotile cilia. On the basis of these findings, we assume that LRRC50 plays a role in assembly of distinct dynein-arm complexes.
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21394829
[ "WAVe:", "web", "analysis", "of", "the", "variome.", "DNA", "sequence", "variation", "is", "the", "underlying", "basis", "of", "common", "human", "traits", "and", "rarer", "single-gene", "disorders.", "Understanding", "the", "variome,", "the", "variants", "in", "an", "individual's", "genome,", "is", "essential", "to", "enable", "the", "ultimate", "goals", "of", "personalized", "medicine.", "This", "critical", "research", "field", "has", "grown", "dramatically", "in", "recent", "years,", "mostly", "due", "to", "the", "spread", "and", "development", "of", "genotyping", "technologies.", "Despite", "these", "activities", "being", "promoted", "by", "the", "Human", "Genome", "Variation", "Society", "and", "projects", "such", "as", "the", "Human", "Variome", "Project", "or", "the", "European", "GEN2PHEN", "Project,", "variome", "data-integration", "systems", "are", "far", "from", "being", "widely", "used", "in", "the", "research", "community", "workflow.", "Most", "of", "ongoing", "research", "is", "focused", "on", "improving", "locus-specific", "databases.", "Although", "the", "quality", "and", "manual", "curation", "of", "LSDBs", "adds", "true", "value", "to", "this", "domain,", "they", "are", "often", "narrow,", "heterogeneous,", "and", "independent", "systems.", "This", "hampers", "data", "harmonization", "and", "interoperability", "between", "systems,", "stifling", "the", "aggregation", "of", "data", "from", "LSDBs", "and", "related", "data", "sources.", "A", "new", "platform", "entitled", "Web", "Analysis", "of", "the", "Variome,", "WAVe,", "is", "introduced.", "It", "offers", "direct", "and", "programmatic", "access", "to", "multiple", "locus-specific", "databases,", "with", "the", "integration", "of", "genetic", "variation", "datasets", "and", "enrichment", "with", "relevant", "information.", "WAVe's", "agile", "and", "innovative", "Web", "interface", "is", "accessible", "at", "http://bioinformatics.ua.pt/WAVe." ]
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WAVe: web analysis of the variome. DNA sequence variation is the underlying basis of common human traits and rarer single-gene disorders. Understanding the variome, the variants in an individual's genome, is essential to enable the ultimate goals of personalized medicine. This critical research field has grown dramatically in recent years, mostly due to the spread and development of genotyping technologies. Despite these activities being promoted by the Human Genome Variation Society and projects such as the Human Variome Project or the European GEN2PHEN Project, variome data-integration systems are far from being widely used in the research community workflow. Most of ongoing research is focused on improving locus-specific databases. Although the quality and manual curation of LSDBs adds true value to this domain, they are often narrow, heterogeneous, and independent systems. This hampers data harmonization and interoperability between systems, stifling the aggregation of data from LSDBs and related data sources. A new platform entitled Web Analysis of the Variome, WAVe, is introduced. It offers direct and programmatic access to multiple locus-specific databases, with the integration of genetic variation datasets and enrichment with relevant information. WAVe's agile and innovative Web interface is accessible at http://bioinformatics.ua.pt/WAVe.
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7726158
[ "Seven", "novel", "mutations", "in", "the", "methylenetetrahydrofolate", "reductase", " ", "gene", "and", "genotype/phenotype", "correlations", "in", "severe", "methylenetetrahydrofolate", "reductase", " ", "deficiency.", "5-Methyltetrahydrofolate,", "the", "major", "form", "of", "folate", "in", "plasma,", "is", "a", "carbon", "donor", "for", "the", "remethylation", "of", "homocysteine", "to", "methionine.", "This", "form", "of", "folate", "is", "generated", "from", "5,10-methylenetetrahydrofolate", "through", "the", "action", "of", "5,10-methylenetetrahydrofolate", "reductase", "(", "MTHFR", "5,10-methylenetetrahydrofolate", "reductase", " ", "(MTHFR),", "a", "cytosolic", "flavoprotein.", "Patients", "with", "an", "autosomal", "recessive", "severe", "deficiency", "of", "MTHFR", " ", "have", "homocystinuria", "and", "a", "wide", "range", "of", "neurological", "and", "vascular", "disturbances.", "We", "have", "recently", "described", "the", "isolation", "of", "a", "cDNA", "for", "MTHFR", " ", "and", "the", "identification", "of", "two", "mutations", "in", "patients", "with", "severe", "MTHFR", " ", "deficiency.", "We", "report", "here", "the", "characterization", "of", "seven", "novel", "mutations", "in", "this", "gene:", "six", "missense", "mutations", "and", "a", "5'", "splice-site", "defect", "that", "activates", "a", "cryptic", "splice", "site", "in", "the", "coding", "sequence.", "We", "also", "present", "a", "preliminary", "analysis", "of", "the", "relationship", "between", "genotype", "and", "phenotype", "for", "all", "nine", "mutations", "identified", "thus", "far", "in", "this", "gene.", "A", "nonsense", "mutation", "and", "two", "missense", "mutations", "(proline", "to", "leucine", "and", "threonine", "to", "methionine)", "in", "the", "homozygous", "state", "are", "associated", "with", "extremely", "low", "activity", "(0%-3%)", "and", "onset", "of", "symptoms", "within", "the", "1st", "year", "of", "age.", "Other", "missense", "mutations", "(arginine", "to", "cysteine", "and", "arginine", "to", "glutamine)", "are", "associated", "with", "higher", "enzyme", "activity", "and", "later", "onset", "of", "symptoms." ]
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Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. 5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase ( MTHFR 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5' splice-site defect that activates a cryptic splice site in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms.
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17357082
[ "Identification", "of", "a", "novel", "risk", "locus", "for", "progressive", "supranuclear", "palsy", "by", "a", "pooled", "genomewide", "scan", "of", "500,288", "single-nucleotide", "polymorphisms.", "To", "date,", "only", "the", "H1", "MAPT", " ", "haplotype", "has", "been", "consistently", "associated", "with", "risk", "of", "developing", "the", "neurodegenerative", "disease", "progressive", "supranuclear", "palsy", "(PSP).", "We", "hypothesized", "that", "additional", "genetic", "loci", "may", "be", "involved", "in", "conferring", "risk", "of", "PSP", "that", "could", "be", "identified", "through", "a", "pooling-based", "genomewide", "association", "study", "of", ">500,000", "SNPs.", "Candidate", "SNPs", "with", "large", "differences", "in", "allelic", "frequency", "were", "identified", "by", "ranking", "all", "SNPs", "by", "their", "probe-intensity", "difference", "between", "cohorts.", "The", "MAPT", " ", "H1", "haplotype", "was", "strongly", "detected", "by", "this", "methodology,", "as", "was", "a", "second", "major", "locus", "on", "chromosome", "11p12-p11", "that", "showed", "evidence", "of", "association", "at", "allelic", "(P<.001),", "genotypic", "(P<.001),", "and", "haplotypic", "(P<.001)", "levels", "and", "was", "narrowed", "to", "a", "single", "haplotype", "block", "containing", "the", "DNA", "damage-binding", "protein", "2", " ", "(", "DDB2", ")", "and", "lysosomal", "acid", "phosphatase", "2", " ", "(", "ACP2", ")", "genes.", "Since", "DNA", "damage", "and", "lysosomal", "dysfunction", "have", "been", "implicated", "in", "aging", "and", "neurodegenerative", "processes,", "both", "genes", "are", "viable", "candidates", "for", "conferring", "risk", "of", "disease." ]
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Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms. To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 ( DDB2 ) and lysosomal acid phosphatase 2 ( ACP2 ) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease.
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9452022
[ "Low", "basal", "transcripts", "of", "the", "COL2A1", " ", "collagen", "gene", "from", "lymphoblasts", "show", "alternative", "splicing", "of", "exon", "12", "in", "the", "Kniest", "form", "of", "spondyloepiphyseal", "dysplasia." ]
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Low basal transcripts of the COL2A1 collagen gene from lymphoblasts show alternative splicing of exon 12 in the Kniest form of spondyloepiphyseal dysplasia.
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21353196
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Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor ( PEDF ), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.
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8352283
[ "Better", "data", "analysis", "through", "data", "exploration." ]
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Better data analysis through data exploration.
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8434594
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Educating the medical community through a teratology newsletter. To educate a geographically and professionally diverse group of health care providers about teratology in an economic and efficient manner, we developed a locally written and distributed teratology newsletter. Response to the newsletter, from readers as well as from our staff and funding agencies, suggests that such a newsletter can be a valuable tool in educating medical communities about teratology.
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[ "Germline", "TP53", " ", "mutations", "and", "Li-Fraumeni", "syndrome.", "There", "are", "now", "reports", "of", "nearly", "250", "independent", "germline", "TP53", " ", "(", "p53", ")", "mutations", "in", "over", "100", "publications.", "Such", "mutations", "are", "typically", "associated", "with", "Li-Fraumeni", "or", "Li-Fraumeni-like", "syndrome,", "although", "many", "have", "been", "identified", "in", "cohorts", "of", "patients", "with", "tumors", "considered", "to", "be", "typical", "of", "LFS.", "In", "general,", "the", "spectrum", "of", "mutations", "that", "has", "been", "detected", "in", "the", "germline", "reflects", "that", "found", "in", "tumors,", "although", "there", "are", "some", "notable", "exceptions", "in", "certain", "tumor", "types.", "Detailed", "knowledge", "of", "the", "pedigrees", "allows", "a", "comprehensive", "analysis", "of", "genotype-phenotype", "correlations", "and", "an", "understanding", "of", "the", "tumors", "that", "are", "associated", "with", "germline", "TP53", " ", "mutations.", "This", "review", "will", "discuss", "the", "spectrum", "of", "mutations", "and", "the", "methods", "for", "mutation", "detection,", "the", "tumors", "associated", "with", "inheritance", "of", "a", "germline", "mutation,", "and", "some", "of", "the", "ethical", "and", "clinical", "problems", "in", "patients", "with", "a", "germline", "TP53", " ", "mutation." ]
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Germline TP53 mutations and Li-Fraumeni syndrome. There are now reports of nearly 250 independent germline TP53 ( p53 ) mutations in over 100 publications. Such mutations are typically associated with Li-Fraumeni or Li-Fraumeni-like syndrome, although many have been identified in cohorts of patients with tumors considered to be typical of LFS. In general, the spectrum of mutations that has been detected in the germline reflects that found in tumors, although there are some notable exceptions in certain tumor types. Detailed knowledge of the pedigrees allows a comprehensive analysis of genotype-phenotype correlations and an understanding of the tumors that are associated with germline TP53 mutations. This review will discuss the spectrum of mutations and the methods for mutation detection, the tumors associated with inheritance of a germline mutation, and some of the ethical and clinical problems in patients with a germline TP53 mutation.
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A novel mutation impairing the tertiary structure and stability of γC-crystallin ( CRYGC γC-crystallin (CRYGC) leads to cataract formation in humans and zebrafish lens. Congenital cataract is one of the leading causes of human blindness. In this study, we identified a novel, heterozygous c.385G<T mutation in CRYGC that resulted in the substitution of a highly conserved glycine by cysteine at codon 129 ( p.Gly129Cys ) in a three-generation Chinese family with autosomal dominant congenital nuclear cataract by sequencing candidate genes. Using zebrafish as a model, we demonstrated that γC-crystallin p.Gly129Cys mutant caused the vacuole and the incomplete denucleation of lens, recapitulating the cataract phenotype in human beings. Molecular modeling and spectroscopic studies indicated that the mutation impaired the tertiary structure of the protein by modifying the H-bonding network in the C-terminal domain. The mutation led to a dramatic decrease in the thermal stability of γC-crystallin, and a significant increase in the propensity of aggregation when subject to storage at high concentrations, heat, and UV- irradiation stresses. Taken together, these results indicate that a novel γC-crystallin p.Gly129Cys γC-crystallin γC-crystallin p.Gly129Cys mutant caused the vacuole and the incomplete denucleation of lens, recapitulating the cataract phenotype in human beings. Molecular modeling and spectroscopic studies indicated that the mutation impaired the tertiary structure of the protein by modifying the H-bonding network in the C-terminal domain. The mutation led to a dramatic decrease in the thermal stability of γC-crystallin , and a significant increase in the propensity of aggregation when subject to storage at high concentrations, heat, and UV- irradiation stresses. Taken together, these results indicate that a novel γC-crystallin p.Gly129Cys mutation impaired the tertiary structure of the protein and caused cataract formation, which provides a new insight into how the mutation may affect the γC-crystallin structure, stability, and function. Our study also highlighted zebrafish as a valuable model tool for studying congenital inherited cataract.
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A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterized by autoimmune hypoparathyroidism, autoimmune adrenocortical failure, and mucocutaneous candidiasis. Recently, an autoimmune regulator gene (AIRE-1), which is located on chromosome 21q22.3, has been identified, and mutations in European kindreds with APS1 have been described. We used SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp coding region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (964del13) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 964del13 ) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations ( R15L , L28P , and Y90C ), and a nonsense mutation ( R257* ). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.
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Rapid preparation of genomic DNA from dried blood and saliva spots for polymerase chain reaction.
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17311297
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Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. We describe 94 pathogenic NF1 gene alterations in a cohort of 97 Austrian neurofibromatosis type 1 patients meeting the NIH criteria. All mutations were fully characterized at the genomic and mRNA levels. Over half of the patients carried novel mutations, and only a quarter carried recurrent minor-lesion mutations at 16 mutational warm spots. The remaining patients carried NF1 microdeletions (7%) and rare recurring mutations. Thirty-six of the mutations (38%) altered pre-mRNA splicing, and fall into five groups: exon skipping resulting from mutations at authentic splice sites (type I), cryptic exon inclusion caused by deep intronic mutations (type II), creation of de novo splice sites causing loss of exonic sequences (type III), activation of cryptic splice sites upon authentic splice-site disruption (type IV), and exonic sequence alterations causing exon skipping (type V). Extensive in silico analyses of 37 NF1 exons and surrounding intronic sequences suggested that the availability of a cryptic splice site combined with a strong natural upstream 3' splice site (3'ss)is the main determinant of cryptic splice-site activation upon 5' splice-site disruption. Furthermore, the exonic sequences downstream of exonic cryptic 5' splice sites (5'ss) resemble intronic more than exonic sequences with respect to exonic splicing enhancer and silencer density, helping to distinguish between exonic cryptic and pseudo 5'ss. This study provides valuable predictors for the splicing pathway used upon 5'ss mutation, and underscores the importance of using RNA-based techniques, together with methods to identify microdeletions and intragenic copy-number changes, for effective and reliable NF1 mutation detection.
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17571465
[ "Arthur", "G.", "Steinberg,", "1912-2006." ]
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Arthur G. Steinberg, 1912-2006.
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8644710
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The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population. Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an autosomal recessive progressive encephalopathy of childhood enriched in the western part of Finland, with a local incidence of 1 in 1500. We recently assigned the locus for vLINCL, CLN5 , to 13q21.1-q32. In the present study, the haplotype analysis of Finnish CLN5 chromosomes provides evidence that one single mutation causes vLINCL in the Finnish population. Eight microsatellite markers closely linked to the CLN5 gene on chromosome 13q were analyzed, to study identity by descent by shared haplotype analysis. One single haplotype formed by flanking markers D13S160 and D13S162 in strong linkage disequilibrium (P < .0001) was present in 81% of disease-bearing chromosomes. Allele 4 at the marker locus D13S162 was detected in 94% of disease-bearing chromosomes. To evaluate the age of the CLN5 mutation by virtue of its restricted geographical distribution, church records were used to identify the common ancestors for 18 vLINCL families diagnosed in Finland. The pedigrees of the vLINCL ancestors merged on many occasions, which also supports a single founder mutation that obviously happened 20 to 30 generations ago (i.e., approximately 500 years ago) in this isolated population. Linkage disequilibrium was detected with seven markers covering an extended genetic distance of 11 cM, which further supports the young age of the CLN5 mutation. When the results of genealogical and linkage disequilibrium studies were combined, the CLN5 CLN5 mutation. When the results of genealogical and linkage disequilibrium studies were combined, the CLN5 gene was predicted to lie approximately 200 - 400 kb (total range 30 - 1360 kb) from the closest marker D13S162.
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8430703
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The postulated X-inactivation center at Xq27 is most reasonably explained by ascertainment bias: heterozygous expression of recessive mutations is a powerful means of detecting unbalanced X inactivation.
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10738001
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A novel polymorphism ( 219G>A ) in the transferrin receptor gene.
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19847796
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Evaluation of SNPs in miR-146a, miR196a2 and miR-499 as low-penetrance alleles in German and Italian familial breast cancer cases. Recently, the SNPs rs11614913 in hsa-mir-196a2 and rs3746444 in hsa-mir-499 were reported to be associated with increased breast cancer risk, and the SNP rs2910164 hsa-mir-196a2 and rs3746444 in hsa-mir-499 were reported to be associated with increased breast cancer risk, and the SNP rs2910164 in hsa-mir-146a was shown to have an effect on age of breast cancer diagnosis. In order to further investigate the effect of these SNPs, we genotyped a total of 1894 breast cancer cases negative for disease-causing mutations or unclassified variants in BRCA1 and BRCA2 , and 2760 controls from Germany and Italy. We compared the genotype and allele frequencies of rs2910164 , rs11614913 and rs3746444 in cases versus controls of the German and Italian series, and of the two series combined; we also investigated the effect of the three SNPs on age at breast cancer diagnosis. None of the performed analyses showed statistically significant results. In conclusion, our data suggested lack of association between SNPs rs2910164 , rs11614913 and rs3746444 and breast cancer risk, or age at breast cancer onset.
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7981721
[ "A", "tandem", "CC-->TT", "transition", "in", "the", "p53", " ", "gene", "of", "a", "breast", "cancer." ]
[ 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0 ]
A tandem CC-->TT transition in the p53 gene of a breast cancer.
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20602914
[ "Whole", "exome", "sequencing", "and", "homozygosity", "mapping", "identify", "mutation", "in", "the", "cell", "polarity", "protein", "GPSM2", " ", "as", "the", "cause", "of", "nonsyndromic", "hearing", "loss", "DFNB82.", "Massively", "parallel", "sequencing", "of", "targeted", "regions,", "exomes,", "and", "complete", "genomes", "has", "begun", "to", "dramatically", "increase", "the", "pace", "of", "discovery", "of", "genes", "responsible", "for", "human", "disorders.", "Here", "we", "describe", "how", "exome", "sequencing", "in", "conjunction", "with", "homozygosity", "mapping", "led", "to", "rapid", "identification", "of", "the", "causative", "allele", "for", "nonsyndromic", "hearing", "loss", "DFNB82", "in", "a", "consanguineous", "Palestinian", "family.", "After", "filtering", "out", "worldwide", "and", "population-specific", "polymorphisms", "from", "the", "whole", "exome", "sequence,", "only", "a", "single", "deleterious", "mutation", "remained", "in", "the", "homozygous", "region", "linked", "to", "DFNB82.", "The", "nonsense", "mutation", "leads", "to", "an", "early", "truncation", "of", "the", "G", "protein", "signaling", "modulator", " ", "GPSM2", ",", "a", "protein", "that", "is", "essential", "for", "maintenance", "of", "cell", "polarity", "and", "spindle", "orientation.", "In", "the", "mouse", "inner", "ear,", "GPSM2", " ", "is", "localized", "to", "apical", "surfaces", "of", "hair", "cells", "and", "supporting", "cells", "and", "is", "most", "highly", "expressed", "during", "embryonic", "development.", "Identification", "of", "GPSM2", " ", "as", "essential", "to", "the", "development", "of", "normal", "hearing", "suggests", "dysregulation", "of", "cell", "polarity", "as", "a", "mechanism", "underlying", "hearing", "loss." ]
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Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82. The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2 , a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss.
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9497255
[ "Autosomal", "genomic", "scan", "for", "loci", "linked", "to", "obesity", "and", "energy", "metabolism", "in", "Pima", "Indians.", "An", "autosomal", "genomic", "scan", "to", "search", "for", "linkage", "to", "obesity", "and", "energy", "metabolism", "was", "completed", "in", "Pima", "Indians,", "a", "population", "prone", "to", "obesity.", "Obesity", "was", "assessed", "by", "percent", "body", "fat", "(by", "hydrodensitometry)", "and", "fat", "distribution", "(the", "ratio", "of", "waist", "circumference", "to", "thigh", "circumference).", "Energy", "metabolism", "was", "measured", "in", "a", "respiratory", "chamber", "as", "24-h", "metabolic", "rate,", "sleeping", "metabolic", "rate,", "and", "24-h", "respiratory", "quotient", "(24RQ),", "an", "indicator", "of", "the", "ratio", "of", "carbohydrate", "oxidation", "to", "fat", "oxidation.", "Five", "hundred", "sixteen", "microsatellite", "markers", "with", "a", "median", "spacing", "of", "6.4", "cM", "were", "analyzed,", "in", "362", "siblings", "who", "had", "measurements", "of", "body", "composition", "and", "in", "220", "siblings", "who", "had", "measurements", "of", "energy", "metabolism.", "These", "comprised", "451", "sib", "pairs", "in", "127", "nuclear", "families,", "for", "linkage", "analysis", "to", "obesity,", "and", "236", "sib", "pairs", "in", "82", "nuclear", "families,", "for", "linkage", "analysis", "to", "energy", "metabolism.", "Pointwise", "and", "multipoint", "methods", "for", "regression", "of", "sib-pair", "differences", "in", "identity", "by", "descent,", "as", "well", "as", "a", "sibling-based", "variance-components", "method,", "were", "used", "to", "detect", "linkage.", "LOD", "scores", ">=2", "were", "found", "at", "11q21-q22,", "for", "percent", "body", "fat", "(LOD=2.1;", "P=.001),", "at", "11q23-q24,", "for", "24-h", "energy", "expenditure", "(LOD=2.0;", "P=.001),", "and", "at", "1p31-p21", "(LOD=2.0)", "and", "20q11.2", "(LOD=3.0;", "P=.0001),", "for", "24RQ,", "by", "pointwise", "and", "multipoint", "analyses.", "With", "the", "variance-components", "method,", "the", "highest", "LOD", "score", "(LOD=2.3", "P=.0006)", "was", "found", "at", "18q21,", "for", "percent", "body", "fat,", "and", "at", "1p31-p21", "(LOD=2.8;", "P=.0003),", "for", "24RQ.", "Possible", "candidate", "genes", "include", "LEPR", " ", "(leptin", "receptor),", " ", "at", "1p31,", "and", "ASIP", " ", "(agouti-signaling", "protein),", " ", "at", "20q11.2." ]
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Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. An autosomal genomic scan to search for linkage to obesity and energy metabolism was completed in Pima Indians, a population prone to obesity. Obesity was assessed by percent body fat (by hydrodensitometry) and fat distribution (the ratio of waist circumference to thigh circumference). Energy metabolism was measured in a respiratory chamber as 24-h metabolic rate, sleeping metabolic rate, and 24-h respiratory quotient (24RQ), an indicator of the ratio of carbohydrate oxidation to fat oxidation. Five hundred sixteen microsatellite markers with a median spacing of 6.4 cM were analyzed, in 362 siblings who had measurements of body composition and in 220 siblings who had measurements of energy metabolism. These comprised 451 sib pairs in 127 nuclear families, for linkage analysis to obesity, and 236 sib pairs in 82 nuclear families, for linkage analysis to energy metabolism. Pointwise and multipoint methods for regression of sib-pair differences in identity by descent, as well as a sibling-based variance-components method, were used to detect linkage. LOD scores >=2 were found at 11q21-q22, for percent body fat (LOD=2.1; P=.001), at 11q23-q24, for 24-h energy expenditure (LOD=2.0; P=.001), and at 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0; P=.0001), for 24RQ, by pointwise and multipoint analyses. With the variance-components method, the highest LOD score (LOD=2.3 P=.0006) was found at 18q21, for percent body fat, and at 1p31-p21 (LOD=2.8; P=.0003), for 24RQ. Possible candidate genes include LEPR (leptin receptor), at 1p31, and ASIP (agouti-signaling protein), at 20q11.2.
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8554048
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Fine mapping of the EDA gene: a translocation breakpoint is associated with a CpG island that is transcribed. In order to identify the gene for human X-linked anhidrotic ectodermal dysplasia (EDA), a translocation breakpoint in a female with t(X;1)(q13.1;p36.3) and EDA (patient AK) was finely mapped. The EDA EDA (patient AK) was finely mapped. The EDA region contains five groups of rare-cutter restriction sites that define CpG islands. The two more centromeric of these islands are associated with transcripts of 3.5 kb and 1.8 kb. The third CpG island maps within <1 kb of the translocation breakpoint in patient AK, as indicated by a genomic rearrangement, and approximately 100 kb centromeric from another previously mapped translocation breakpoint (patient AnLy). Northern analysis with a probe from this CpG island detected an approximately 6-kb mRNA in several fetal tissues tested. An extended YAC contig of 1,200 kb with an average of fivefold coverage was constructed. The two most telomeric CpG islands map 350 kb telomeric of the two translocations. Taken together, the results suggest that the CpG island just proximal of the AK translocation breakpoint lies at the 5' end of a candidate gene for EDA .
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1357966
[ "Linkage", "disequilibrium", "among", "RFLPs", "at", "the", "insulin-receptor", "locus", "despite", "intervening", "Alu", "repeat", "sequences.", "Multiple", "mutations", "of", "the", "insulin", "receptor", "(", "INSR", "insulin", "receptor", " ", "(INSR)", "gene", "have", "been", "identified", "in", "individuals", "with", "extreme", "insulin", "resistance.", "These", "mutations", "have", "included", "recombination", "events", "between", "Alu", "repeat", "units", "in", "the", "tyrosine", "kinase-encoding", "beta-chain", "region", "of", "the", "gene.", "To", "evaluate", "the", "influence", "of", "Alu", "and", "dinucleotide", "repetitive", "sequences", "on", "recombination", "events", "within", "the", "insulin", "receptor", "gene,", "I", "examined", "the", "degree", "of", "linkage", "disequilibrium", "between", "RFLP", "pairs", "spanning", "the", "gene.", "I", "established", "228", "independent", "haplotypes", "for", "seven", "RFLPs", "(two", "each", "for", "PstI,", " ", "RsaI,", " ", "and", "SstI", " ", "and", "one", "for", "MspI", " ", "and", "172", "independent", "haplotypes", "which", "included", "an", "additional", "RFLP", "with", "BglII", ")", "from", "19", "pedigrees.", "These", "RFLPs", "span", ">", "130", "kb", "of", "this", "gene,", "and", "my", "colleagues", "and", "I", "previously", "demonstrated", "that", "multiple", "Alu", "sequences", "separate", "RFLP", "pairs.", "Observed", "haplotype", "frequencies", "deviated", "significantly", "from", "those", "predicted.", "Pairwise", "analysis", "of", "RFLP", "showed", "high", "levels", "of", "linkage", "disequilibrium", "among", "RFLP", "in", "the", "beta-chain", "region", "of", "the", "insulin", "receptor,", "but", "not", "between", "alpha-chain", "RFLPs", "and", "those", "of", "the", "beta-chain.", "Disequilibrium", "was", "present", "among", "beta-chain", "RFLPs,", "despite", "separation", "by", "one", "or", "more", "Alu", "repeat", "sequences.", "The", "very", "strong", "linkage", "disequilibrium", "which", "was", "present", "in", "sizable", "regions", "of", "the", "INSR", " ", "gene", "despite", "the", "presence", "of", "both", "Alu", "and", "microsatellite", "repeats", "suggested", "that", "these", "regions", "do", "not", "have", "a", "major", "impact", "on", "recombinations", "at", "this", "locus." ]
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Linkage disequilibrium among RFLPs at the insulin-receptor locus despite intervening Alu repeat sequences. Multiple mutations of the insulin receptor ( INSR insulin receptor (INSR) gene have been identified in individuals with extreme insulin resistance. These mutations have included recombination events between Alu repeat units in the tyrosine kinase-encoding beta-chain region of the gene. To evaluate the influence of Alu and dinucleotide repetitive sequences on recombination events within the insulin receptor gene, I examined the degree of linkage disequilibrium between RFLP pairs spanning the gene. I established 228 independent haplotypes for seven RFLPs (two each for PstI, RsaI, and SstI and one for MspI and 172 independent haplotypes which included an additional RFLP with BglII ) from 19 pedigrees. These RFLPs span > 130 kb of this gene, and my colleagues and I previously demonstrated that multiple Alu sequences separate RFLP pairs. Observed haplotype frequencies deviated significantly from those predicted. Pairwise analysis of RFLP showed high levels of linkage disequilibrium among RFLP in the beta-chain region of the insulin receptor, but not between alpha-chain RFLPs and those of the beta-chain. Disequilibrium was present among beta-chain RFLPs, despite separation by one or more Alu repeat sequences. The very strong linkage disequilibrium which was present in sizable regions of the INSR gene despite the presence of both Alu and microsatellite repeats suggested that these regions do not have a major impact on recombinations at this locus.
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10408782
[ "Molecular", "characterization", "of", "phenylalanine", "hydroxylase", "deficiency", "in", "Chile.", "Mutations", "in", "brief", "no.", "243.", "Online.", "Both", "the", "haplotype", "distribution", "and", "the", "mutational", "spectrum", "of", "the", "phenylalanine", "hydroxylase", "(PAH)", "gene", "has", "been", "defined", "for", "the", "Chilean", "phenylketonuria", "(PKU)", "population.", "Mutation", "analysis", "was", "performed", "using", "a", "combined", "approach", "of", "screening", "for", "common", "European", "and", "Oriental", "mutations", "and", "application", "of", "the", "DGGE", "scanning", "method", "in", "the", "remaining", "uncharacterized", "alleles.", "A", "total", "of", "16", "different", "mutations", "have", "been", "identified,", "including", "two", "novel", "ones,", "Q232X", " ", "and", "IVS11nt5", ".", "The", "most", "frequent", "mutations", "were", "IVS10nt-11", "and", "V388M", "IVS10nt-11", "phenylalanine", "hydroxylase", " ", "(", "PAH", ")", "gene", "has", "been", "defined", "for", "the", "Chilean", "phenylketonuria", "(PKU)", "population.", "Mutation", "analysis", "was", "performed", "using", "a", "combined", "approach", "of", "screening", "for", "common", "European", "and", "Oriental", "mutations", "and", "application", "of", "the", "DGGE", "scanning", "method", "in", "the", "remaining", "uncharacterized", "alleles.", "A", "total", "of", "16", "different", "mutations", "have", "been", "identified,", "including", "two", "novel", "ones,", "Q232X", "and", "IVS11nt5.", "The", "most", "frequent", "mutations", "were", "IVS10nt-11", "and", "V388M", "present", "both", "in", "the", "13%", "of", "the", "mutant", "chromosomes.", "The", "rest", "of", "the", "mutations", "are", "rare.", "The", "haplotype", "association", "including", "VNTR", "and", "STR", "alleles,", "was", "examined", "to", "investigated", "the", "origin", "and", "distribution", "of", "PAH", "alleles", "in", "Chile.", "Our", "results", "are", "consistent", "with", "Southern", "Europeans", "as", "the", "major", "source", "of", "PAH", "mutations", "in", "Latin", "America.", "However,", "we", "have", "also", "detected", "mutations", "from", "East", "and", "Central", "Europe,", "such", "IVS12nt1", ",", "R408W", " ", "and", "R252W", ".", "It", "is", "clear", "that", "the", "PKU", "mutation", "present", "in", "each", "Latin", "American", "country", "varies", "with", "the", "demographic", "profile", "and", "specific", "mutation", "scanning", "is", "necessary", "in", "each", "population", "both", "for", "diagnostic", "and", "prognostic", "purposes.", "The", "correlation", "between", "the", "genotypes", "and", "the", "phenotypes", "is", "consistent", "with", "the", "emerging", "pattern", "of", "mutation", "severity", "deduced", "from", "previous", "studies", "in", "related", "populations." ]
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Molecular characterization of phenylalanine hydroxylase deficiency in Chile. Mutations in brief no. 243. Online. Both the haplotype distribution and the mutational spectrum of the phenylalanine hydroxylase (PAH) gene has been defined for the Chilean phenylketonuria (PKU) population. Mutation analysis was performed using a combined approach of screening for common European and Oriental mutations and application of the DGGE scanning method in the remaining uncharacterized alleles. A total of 16 different mutations have been identified, including two novel ones, Q232X and IVS11nt5 . The most frequent mutations were IVS10nt-11 and V388M IVS10nt-11 phenylalanine hydroxylase ( PAH ) gene has been defined for the Chilean phenylketonuria (PKU) population. Mutation analysis was performed using a combined approach of screening for common European and Oriental mutations and application of the DGGE scanning method in the remaining uncharacterized alleles. A total of 16 different mutations have been identified, including two novel ones, Q232X and IVS11nt5. The most frequent mutations were IVS10nt-11 and V388M present both in the 13% of the mutant chromosomes. The rest of the mutations are rare. The haplotype association including VNTR and STR alleles, was examined to investigated the origin and distribution of PAH alleles in Chile. Our results are consistent with Southern Europeans as the major source of PAH mutations in Latin America. However, we have also detected mutations from East and Central Europe, such IVS12nt1 , R408W and R252W . It is clear that the PKU mutation present in each Latin American country varies with the demographic profile and specific mutation scanning is necessary in each population both for diagnostic and prognostic purposes. The correlation between the genotypes and the phenotypes is consistent with the emerging pattern of mutation severity deduced from previous studies in related populations.
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17847000
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Cowden syndrome-affected patients with PTEN promoter mutations demonstrate abnormal protein translation. Germline mutations of PTEN (phosphatase and tensin homolog deleted on chromosome 10) are associated with the multihamartomatous disorder Cowden syndrome (CS). Moreover, patients with CS with germline PTEN promoter mutations have aberrant PTEN protein expression and an increased frequency of breast cancer. Here, we examined the downstream effect of five PTEN promoter variants ( -861G/T , -853C/G , -834C/T , -798G/C , and -764G/A ) that are not within any known cis-acting regulatory elements. Clinically, all five of these patients have been given diagnoses of breast, thyroid, and/or endometrial cancer. We demonstrated that protein binding to the PTEN promoter (-893 to -755) was not altered in the five variants when compared with the wild-type (WT) promoter. However, reporter assays indicated that three of the variants ( -861G/T , -853C/G , and -764G/A ) demonstrated an ~50% decrease in luciferase activity compared with the WT construct. PTEN messenger RNA (mRNA) levels were not altered in these variants, whereas secondary structure predictions indicated that different PTEN 5' untranslated region transcript-folding patterns exist in three variants, suggesting an inhibition of protein translation. This was confirmed by PTEN protein analysis. These data indicate that variants causing large mRNA secondary structure alterations result in an inhibition of protein translation and a decrease in PTEN protein expression. These data emphasize the importance of PTEN promoter nucleotide variations and their ability to lead to CS progression by a novel regulatory mechanism. Importantly, these patients have a high prevalence of breast, thyroid, and endometrial malignancies; thus, understanding of the mechanism of PTEN dysfunction in these patients will lead to more-sensitive molecular diagnostic and predictive testing and, ultimately, to rational targeted therapies to treat or prevent malignancy.
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Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus. We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders--including social phobia, agoraphobia, and simple phobia--in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P<.05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.
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8364588
[ "Paternal", "mosaicism", "for", "a", "COL1A1", " ", "dominant", "mutation", "(", "alpha", "1", "Ser-415", ")", "causes", "recurrent", "osteogenesis", "imperfecta.", "We", "describe", "a", "dominant", "point", "mutation", "in", "the", "COL1A1", " ", "gene", "causing", "extremely", "severe", "osteogenesis", "imperfecta", "(OI", "type", "II/III)", "which", "was", "detected", "in", "the", "dermal", "fibroblasts", "of", "a", "proband,", "diagnosed", "by", "ultrasonography", "at", "24", "weeks", "of", "gestation.", "Type", "I", "collagen", " ", "secretion", "was", "reduced", "and", "pro", "alpha", "1(I)", "chains", "were", "overmodified.", "The", "mutation", "was", "localised", "in", "one", "COL1A1", " ", "allele", "by", "chemical", "cleavage", "of", "mismatched", "bases", "in", "normal", "cDNA/proband's", "mRNA", "heteroduplexes,", "and", "identified", "by", "cloning", "and", "sequencing.", "A", "G-to-A", "transition", "which", "causes", "the", "substitution", "of", "Gly-415", "with", "serine", " ", "in", "the", "alpha", "1(I)", "triple", "helical", "domain", "was", "found.", "The", "same", "mutation", "was", "detected", "in", "the", "father's", "spermatozoa", "and", "lymphocytes.", "Mosaicism", "in", "the", "father's", "germline", "explains", "the", "occurrence", "in", "the", "family", "of", "two", "additional", "OI", "pregnancies,", "which", "were", "documented", "by", "X-ray", "and", "ultrasound", "investigations." ]
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Paternal mosaicism for a COL1A1 dominant mutation ( alpha 1 Ser-415 ) causes recurrent osteogenesis imperfecta. We describe a dominant point mutation in the COL1A1 gene causing extremely severe osteogenesis imperfecta (OI type II/III) which was detected in the dermal fibroblasts of a proband, diagnosed by ultrasonography at 24 weeks of gestation. Type I collagen secretion was reduced and pro alpha 1(I) chains were overmodified. The mutation was localised in one COL1A1 allele by chemical cleavage of mismatched bases in normal cDNA/proband's mRNA heteroduplexes, and identified by cloning and sequencing. A G-to-A transition which causes the substitution of Gly-415 with serine in the alpha 1(I) triple helical domain was found. The same mutation was detected in the father's spermatozoa and lymphocytes. Mosaicism in the father's germline explains the occurrence in the family of two additional OI pregnancies, which were documented by X-ray and ultrasound investigations.
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11462173
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p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand-split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation ( K193E ), a nonsense mutation ( Q634X ), and a mutation in the 3' splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 R280H ) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.
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11309687
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A confidence-set approach for finding tightly linked genomic regions. As more studies adopt the approach of whole-genome screening, geneticists are faced with the challenge of having to interpret results from traditional approaches that were not designed for genome-scan data. Frequently, two-point analysis by the LOD method is performed to search for signals of linkage throughout the genome, for each of hundreds or even thousands of markers. This practice has raised the question of how to adjust the significance level for the fact that multiple tests are being performed. Various recommendations have been made, but no consensus has emerged. In this article, we propose a new method, the confidence-set approach, that circumvents the need to correct for the level of significance according to the number of markers tested. In the search for the gene location of a monogenic disorder, multiplicity adjustment is not needed in order to maintain the desired level of confidence. For complex diseases involving multiple genes, one needs only to adjust the level of significance according to the number of disease genes--a much smaller number than the number of markers in a genome screen-to ensure a predetermined genomewide confidence level. Furthermore, our formulation of the tests enables us to localize disease genes to small genomic regions, an extremely desirable feature that the traditional LOD method lacks. Our simulation study shows that, for sib-pair data, even when the coverage probability of the confidence set is chosen to be as high as 99%, our approach is able to implicate only the markers that are closely linked to the disease genes.
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1346075
[ "Mechanisms", "of", "ring", "chromosome", "formation", "in", "11", "cases", "of", "human", "ring", "chromosome", "21.", "We", "studied", "the", "mechanism", "of", "ring", "chromosome", "21", "(r(21))", "formation", "in", "13", "patients", "(11", "unique", "r(21)s),", "consisting", "of", "7", "from", "five", "families", "with", "familial", "r(21)", "and", "6", "with", "de", "novo", "r(21).", "The", "copy", "number", "of", "chromosome", "21", "sequences", "in", "the", "rings", "of", "these", "patients", "was", "determined", "by", "quantitative", "dosage", "analyses", "for", "13", "loci", "on", "21q.", "Nine", "of", "11", "r(21)s,", "including", "the", "5", "familial", "r(21)s,", "showed", "no", "evidence", "for", "duplication", "of", "21q", "sequences", "but", "did", "show", "molecular", "evidence", "of", "partial", "deletion", "of", "21q.", "These", "data", "were", "consistent", "with", "the", "breakage", "and", "reunion", "of", "short-", "and", "long-arm", "regions", "to", "form", "the", "r(21),", "resulting", "in", "deletion", "of", "varying", "amounts", "of", "21q22.1", "to", "21qter.", "The", "data", "from", "one", "individual", "who", "had", "a", "Down", "syndrome", "phenotype", "were", "consistent", "with", "asymmetric", "breakage", "and", "reunion", "of", "21q", "sequences", "from", "an", "intermediate", "isochromosome", "or", "Robertsonian", "translocation", "chromosome", "as", "reported", "by", "Wong", "et", "al.", "Another", "patient,", "who", "also", "exhibited", "Down", "syndrome,", "showed", "evidence", "of", "a", "third", "mechanism", "of", "ring", "formation.", "The", "likely", "initial", "event", "was", "breakage", "and", "reunion", "of", "the", "short", "and", "long", "arms,", "resulting", "in", "a", "small", "r(21),", "followed", "by", "a", "sister-chromatid", "exchange", "resulting", "in", "a", "double-sized", "and", "symmetrically", "dicentric", "r(21).", "The", "phenotype", "of", "patients", "correlated", "well", "with", "the", "extent", "of", "deletion", "or", "duplication", "of", "chromosome", "21", "sequences.", "These", "data", "demonstrate", "three", "mechanisms", "of", "r(21)", "formation", "and", "show", "that", "the", "phenotype", "of", "r(21)", "patients", "varies", "with", "the", "extent", "of", "chromosome", "21", "monosomy", "or", "trisomy." ]
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Mechanisms of ring chromosome formation in 11 cases of human ring chromosome 21. We studied the mechanism of ring chromosome 21 (r(21)) formation in 13 patients (11 unique r(21)s), consisting of 7 from five families with familial r(21) and 6 with de novo r(21). The copy number of chromosome 21 sequences in the rings of these patients was determined by quantitative dosage analyses for 13 loci on 21q. Nine of 11 r(21)s, including the 5 familial r(21)s, showed no evidence for duplication of 21q sequences but did show molecular evidence of partial deletion of 21q. These data were consistent with the breakage and reunion of short- and long-arm regions to form the r(21), resulting in deletion of varying amounts of 21q22.1 to 21qter. The data from one individual who had a Down syndrome phenotype were consistent with asymmetric breakage and reunion of 21q sequences from an intermediate isochromosome or Robertsonian translocation chromosome as reported by Wong et al. Another patient, who also exhibited Down syndrome, showed evidence of a third mechanism of ring formation. The likely initial event was breakage and reunion of the short and long arms, resulting in a small r(21), followed by a sister-chromatid exchange resulting in a double-sized and symmetrically dicentric r(21). The phenotype of patients correlated well with the extent of deletion or duplication of chromosome 21 sequences. These data demonstrate three mechanisms of r(21) formation and show that the phenotype of r(21) patients varies with the extent of chromosome 21 monosomy or trisomy.
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SSCP and segregation analysis of the human type X collagen gene ( COL10A1 ) in heritable forms of chondrodysplasia. Type X collagen is a homotrimeric, short chain, nonfibrillar collagen that is expressed exclusively by hypertrophic chondrocytes at the sites of endochondral ossification. The distribution and pattern of expression of the type X collagen gene ( COL10A1 type X collagen human type X collagen gene (COL10A1) in heritable forms of chondrodysplasia. Type X collagen is a homotrimeric, short chain, nonfibrillar collagen that is expressed exclusively by hypertrophic chondrocytes at the sites of endochondral ossification. The distribution and pattern of expression of the type X collagen gene (COL10A1) suggests that mutations altering the structure and synthesis of the protein may be responsible for causing heritable forms of chondrodysplasia. We investigated whether mutations within the human COL10A1 gene were responsible for causing the disorders achondroplasia, hypochondroplasia, pseudoachondroplasia, and thanatophoric dysplasia, by analyzing the coding regions of the gene by using PCR and the single-stranded conformational polymorphism technique. By this approach, seven sequence changes were identified within and flanking the coding regions of the gene of the affected persons. We demonstrated that six of these sequence changes were not responsible for causing these forms of chondrodysplasia but were polymorphic in nature. The sequence changes were used to demonstrate discordant segregation between the COL10A1 locus and achondroplasia and pseudoachondroplasia, in nuclear families. This lack of segregation suggests that mutations within or near the COL10A1 locus are not responsible for these disorders. The seventh sequence change resulted in a valine-to-methionine substitution in the carboxyl-terminal domain of the molecule and was identified in only two hypochondroplasic individuals from a single family. Segregation analysis in this family was inconclusive, and the significance of this substitution remains uncertain.
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16532395
[ "Spread", "of", "an", "inactive", "form", "of", "caspase-12", "in", "humans", "is", "due", "to", "recent", "positive", "selection.", "The", "human", "caspase-12", "caspase-12", " ", "in", "humans", "is", "due", "to", "recent", "positive", "selection.", "The", "human", "caspase-12", "gene", "is", "polymorphic", "for", "the", "presence", "or", "absence", "of", "a", "stop", "codon,", "which", "results", "in", "the", "occurrence", "of", "both", "active", "(ancestral)", "and", "inactive", "(derived)", "forms", "of", "the", "gene", "in", "the", "population.", "It", "has", "been", "shown", "elsewhere", "that", "carriers", "of", "the", "inactive", "gene", "are", "more", "resistant", "to", "severe", "sepsis.", "We", "have", "now", "investigated", "whether", "the", "inactive", "form", "has", "spread", "because", "of", "neutral", "drift", "or", "positive", "selection.", "We", "determined", "its", "distribution", "in", "a", "worldwide", "sample", "of", "52", "populations", "and", "resequenced", "the", "gene", "in", "77", "individuals", "from", "the", "HapMap", "Yoruba,", "Han", "Chinese,", "and", "European", "populations.", "There", "is", "strong", "evidence", "of", "positive", "selection", "from", "low", "diversity,", "skewed", "allele-frequency", "spectra,", "and", "the", "predominance", "of", "a", "single", "haplotype.", "We", "suggest", "that", "the", "inactive", "form", "of", "the", "gene", "arose", "in", "Africa", "approximately", "100-500", "thousand", "years", "ago", "(KYA)", "and", "was", "initially", "neutral", "or", "almost", "neutral", "but", "that", "positive", "selection", "beginning", "approximately", "60-100", "KYA", "drove", "it", "to", "near", "fixation.", "We", "further", "propose", "that", "its", "selective", "advantage", "was", "sepsis", "resistance", "in", "populations", "that", "experienced", "more", "infectious", "diseases", "as", "population", "sizes", "and", "densities", "increased." ]
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Spread of an inactive form of caspase-12 in humans is due to recent positive selection. The human caspase-12 caspase-12 in humans is due to recent positive selection. The human caspase-12 gene is polymorphic for the presence or absence of a stop codon, which results in the occurrence of both active (ancestral) and inactive (derived) forms of the gene in the population. It has been shown elsewhere that carriers of the inactive gene are more resistant to severe sepsis. We have now investigated whether the inactive form has spread because of neutral drift or positive selection. We determined its distribution in a worldwide sample of 52 populations and resequenced the gene in 77 individuals from the HapMap Yoruba, Han Chinese, and European populations. There is strong evidence of positive selection from low diversity, skewed allele-frequency spectra, and the predominance of a single haplotype. We suggest that the inactive form of the gene arose in Africa approximately 100-500 thousand years ago (KYA) and was initially neutral or almost neutral but that positive selection beginning approximately 60-100 KYA drove it to near fixation. We further propose that its selective advantage was sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased.
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16906510
[ "Visualization", "of", "MAPT", " ", "inversion", "on", "stretched", "chromosomes", "of", "tau-negative", "frontotemporal", "dementia", "patients." ]
[ 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Visualization of MAPT inversion on stretched chromosomes of tau-negative frontotemporal dementia patients.
[ 2, 9966, 1927, 4446, 1031, 14825, 1990, 25239, 8597, 1927, 7462, 17, 3136, 27047, 2057, 6588, 6277, 7811, 2132, 18, 3 ]
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14974085
[ "Noonan", "syndrome-associated", "SHP2", "/", "PTPN11", " ", "mutants", "cause", "EGF-dependent", "prolonged", "GAB1", "EGF", "-dependent", "prolonged", "GAB1", "binding", "and", "sustained", "ERK2", "/", "MAPK1", " ", "activation.", "Noonan", "syndrome", "is", "a", "developmental", "disorder", "with", "dysmorphic", "facies,", "short", "stature,", "cardiac", "defects,", "and", "skeletal", "anomalies,", "which", "can", "be", "caused", "by", "missense", "PTPN11", " ", "mutations.", "PTPN11", " ", "encodes", "Src", "homology", "2", "domain-containing", "tyrosine", "phosphatase", "2", " ", "(", "SHP2", " ", "or", "SHP-2", "),", "a", "protein", "tyrosine", "phosphatase", "that", "acts", "in", "signal", "transduction", "downstream", "to", "growth", "factor,", "hormone,", "and", "cytokine", "receptors.", "We", "compared", "the", "functional", "effects", "of", "three", "Noonan", "syndrome-causative", "PTPN11", " ", "mutations", "on", "SHP2's", " ", "phosphatase", "activity,", "interaction", "with", "a", "binding", "partner,", "and", "signal", "transduction.", "All", "SHP2", " ", "mutants", "had", "significantly", "increased", "basal", "phosphatase", "activity", "compared", "to", "wild", "type,", "but", "that", "activity", "varied", "significantly", "between", "mutants", "and", "was", "further", "increased", "after", "epidermal", "growth", "factor", "stimulation.", "Cells", "expressing", "SHP2", " ", "mutants", "had", "prolonged", "extracellular", "signal-regulated", "kinase", "2", " ", "activation,", "which", "was", "ligand-dependent.", "Binding", "of", "SHP2", " ", "mutants", "to", "Grb2-associated", "binder-1", "was", "increased", "and", "sustained,", "and", "tyrosine", "phosphorylation", "of", "both", "proteins", "was", "prolonged.", "Coexpression", "of", "Grb2-associated", "binder-1-FF,", "which", "lacks", "SHP2", "binding", "motifs,", "blocked", "the", "epidermal", "growth", "factor-mediated", "increase", "in", "SHP2's", "phosphatase", "activity", "and", "resulted", "in", "a", "dramatic", "reduction", "of", "extracellular", "signal-regulated", "kinase", "2", "activation.", "Taken", "together,", "these", "results", "document", "that", "Noonan", "syndrome-associated", "PTPN11", "mutations", "increase", "SHP2's", "basal", "phosphatase", "activity,", "with", "greater", "activation", "when", "residues", "directly", "involved", "in", "binding", "at", "the", "interface", "between", "the", "N-terminal", "Src", "homology", "2", "and", "protein", "tyrosine", "phosphatase", "domains", "are", "altered.", "The", "SHP2", "mutants", "prolonged", "signal", "flux", "through", "the", "RAS/mitogen-activated", "protein", "kinase", "(ERK2/MAPK1)", "pathway", "in", "a", "ligand-dependent", "manner", "that", "required", "docking", "through", "Grb2-associated", "binder-1", "(", "GAB1", "Grb2-associated", "binder-1", "MAPK1", "ERK2", "RAS", "/", "mitogen-activated", "protein", "kinase", "SHP2", " ", "binding", "motifs,", "blocked", "the", "epidermal", "growth", "factor-mediated", "increase", "in", "SHP2", "'s", "phosphatase", "activity", "and", "resulted", "in", "a", "dramatic", "reduction", "of", "extracellular", "signal-regulated", "kinase", "2", "activation.", "Taken", "together,", "these", "results", "document", "that", "Noonan", "syndrome-associated", "PTPN11", "mutations", "increase", "SHP2", "PTPN11", " ", "mutations", "increase", "SHP2's", "basal", "phosphatase", "activity,", "with", "greater", "activation", "when", "residues", "directly", "involved", "in", "binding", "at", "the", "interface", "between", "the", "N-terminal", "Src", "homology", "2", "and", "protein", "tyrosine", "phosphatase", "domains", "are", "altered.", "The", "SHP2", "mutants", "prolonged", "signal", "flux", "through", "the", "RAS/mitogen-activated", "protein", "kinase", "(ERK2/MAPK1)", "pathway", "in", "a", "ligand-dependent", "manner", "that", "required", "docking", "through", "Grb2-associated", "binder-1", "(GAB1),", "leading", "to", "increased", "cell", "proliferation." ]
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Noonan syndrome-associated SHP2 / PTPN11 mutants cause EGF-dependent prolonged GAB1 EGF -dependent prolonged GAB1 binding and sustained ERK2 / MAPK1 activation. Noonan syndrome is a developmental disorder with dysmorphic facies, short stature, cardiac defects, and skeletal anomalies, which can be caused by missense PTPN11 mutations. PTPN11 encodes Src homology 2 domain-containing tyrosine phosphatase 2 ( SHP2 or SHP-2 ), a protein tyrosine phosphatase that acts in signal transduction downstream to growth factor, hormone, and cytokine receptors. We compared the functional effects of three Noonan syndrome-causative PTPN11 mutations on SHP2's phosphatase activity, interaction with a binding partner, and signal transduction. All SHP2 mutants had significantly increased basal phosphatase activity compared to wild type, but that activity varied significantly between mutants and was further increased after epidermal growth factor stimulation. Cells expressing SHP2 mutants had prolonged extracellular signal-regulated kinase 2 activation, which was ligand-dependent. Binding of SHP2 mutants to Grb2-associated binder-1 was increased and sustained, and tyrosine phosphorylation of both proteins was prolonged. Coexpression of Grb2-associated binder-1-FF, which lacks SHP2 binding motifs, blocked the epidermal growth factor-mediated increase in SHP2's phosphatase activity and resulted in a dramatic reduction of extracellular signal-regulated kinase 2 activation. Taken together, these results document that Noonan syndrome-associated PTPN11 mutations increase SHP2's basal phosphatase activity, with greater activation when residues directly involved in binding at the interface between the N-terminal Src homology 2 and protein tyrosine phosphatase domains are altered. The SHP2 mutants prolonged signal flux through the RAS/mitogen-activated protein kinase (ERK2/MAPK1) pathway in a ligand-dependent manner that required docking through Grb2-associated binder-1 ( GAB1 Grb2-associated binder-1 MAPK1 ERK2 RAS / mitogen-activated protein kinase SHP2 binding motifs, blocked the epidermal growth factor-mediated increase in SHP2 's phosphatase activity and resulted in a dramatic reduction of extracellular signal-regulated kinase 2 activation. Taken together, these results document that Noonan syndrome-associated PTPN11 mutations increase SHP2 PTPN11 mutations increase SHP2's basal phosphatase activity, with greater activation when residues directly involved in binding at the interface between the N-terminal Src homology 2 and protein tyrosine phosphatase domains are altered. The SHP2 mutants prolonged signal flux through the RAS/mitogen-activated protein kinase (ERK2/MAPK1) pathway in a ligand-dependent manner that required docking through Grb2-associated binder-1 (GAB1), leading to increased cell proliferation.
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10094553
[ "Identification", "of", "twenty-one", "new", "mutations", "in", "the", "factor", "IX", " ", "gene", "by", "SSCP", "analysis.", "In", "this", "study", "we", "have", "analyzed", "the", "factor", "IX", " ", "gene", "from", "84", "hemophilia", "B", "patients", "of", "Spanish", "origin.", "It", "included", "single-strand", "conformation", "polymorphism", "(SSCP)", "analysis", "of", "all", "functional", "regions", "of", "the", "gene", "and", "further", "sequencing", "of", "all", "fragments", "showing", "abnormal", "migration.", "In", "76", "patients", "(90.4%),", "it", "was", "possible", "to", "identify", "molecular", "alterations", "leading", "to", "the", "appearance", "of", "the", "disease.", "Twenty-one", "new", "mutations", "were", "identified,", "including", "13", "missense", "mutations,", "two", "nonsense", "mutations,", "three", "splice-site", "mutations,", "one", "frameshift", "deletion,", "one", "frameshift", "insertion,", "and", "one", "non-frameshift", "deletion.", "The", "approach", "appears", "to", "be", "very", "suitable", "for", "molecular", "diagnosis", "of", "hemophilia", "B." ]
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Identification of twenty-one new mutations in the factor IX gene by SSCP analysis. In this study we have analyzed the factor IX gene from 84 hemophilia B patients of Spanish origin. It included single-strand conformation polymorphism (SSCP) analysis of all functional regions of the gene and further sequencing of all fragments showing abnormal migration. In 76 patients (90.4%), it was possible to identify molecular alterations leading to the appearance of the disease. Twenty-one new mutations were identified, including 13 missense mutations, two nonsense mutations, three splice-site mutations, one frameshift deletion, one frameshift insertion, and one non-frameshift deletion. The approach appears to be very suitable for molecular diagnosis of hemophilia B.
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9143927
[ "Deletions", "spanning", "the", "neurofibromatosis", "type", "1", " ", "gene:", "implications", "for", "genotype-phenotype", "correlations", "in", "neurofibromatosis", "type", "1?", "Neurofibromatosis", "type", "1", "(NF1)", "is", "an", "autosomal", "dominant", "disorder", "characterized", "by", "abnormalities", "of", "tissues", "predominantly", "derived", "from", "the", "neural", "crest.", "Symptoms", "are", "highly", "variable", "and", "severity", "cannot", "be", "predicted,", "even", "within", "families.", "DNA", "of", "84", "unrelated", "patients", "with", "NF1,", "unselected", "for", "clinical", "features", "or", "severity,", "were", "screened", "with", "intragenic", "polymorphic", "repeat", "markers", "and", "by", "Southern", "analysis", "with", "cDNA", "probes.", "Deletions", "of", "the", "entire", "gene", "were", "detected", "in", "five", "patients", "from", "four", "unrelated", "families.", "Their", "phenotype", "resembled", "that", "of", "five", "previously", "reported", "patients", "with", "deletions,", "including", "intellectual", "impairment", "and", "dysmorphic", "features,", "but", "without", "an", "excessive", "number", "of", "dermal", "neurofibromas.", "This", "report", "supports", "the", "hypothesis", "that", "large", "deletions", "spanning", "the", "entire", "NF1", " ", "gene", "may", "lead", "to", "a", "specific", "phenotype." ]
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Deletions spanning the neurofibromatosis type 1 gene: implications for genotype-phenotype correlations in neurofibromatosis type 1? Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by abnormalities of tissues predominantly derived from the neural crest. Symptoms are highly variable and severity cannot be predicted, even within families. DNA of 84 unrelated patients with NF1, unselected for clinical features or severity, were screened with intragenic polymorphic repeat markers and by Southern analysis with cDNA probes. Deletions of the entire gene were detected in five patients from four unrelated families. Their phenotype resembled that of five previously reported patients with deletions, including intellectual impairment and dysmorphic features, but without an excessive number of dermal neurofibromas. This report supports the hypothesis that large deletions spanning the entire NF1 gene may lead to a specific phenotype.
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19931040
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Simultaneous genotype calling and haplotype phasing improves genotype accuracy and reduces false-positive associations for genome-wide association studies. We present a novel method for simultaneous genotype calling and haplotype-phase inference. Our method employs the computationally efficient BEAGLE haplotype-frequency model, which can be applied to large-scale studies with millions of markers and thousands of samples. We compare genotype calls made with our method to genotype calls made with the BIRDSEED, CHIAMO, GenCall, and ILLUMINUS genotype-calling methods, using genotype data from the Illumina 550K and Affymetrix 500K arrays. We show that our method has higher genotype-call accuracy and yields fewer uncalled genotypes than competing methods. We perform single-marker analysis of data from the Wellcome Trust Case Control Consortium bipolar disorder and type 2 diabetes studies. For bipolar disorder, the genotype calls in the original study yield 25 markers with apparent false-positive association with bipolar disorder at a p < 10(-7) significance level, whereas genotype calls made with our method yield no associated markers at this significance threshold. Conversely, for markers with replicated association with type 2 diabetes, there is good concordance between genotype calls used in the original study and calls made by our method. Results from single-marker and haplotypic analysis of our method's genotype calls for the bipolar disorder study indicate that our method is highly effective at eliminating genotyping artifacts that cause false-positive associations in genome-wide association studies. Our new genotype-calling methods are implemented in the BEAGLE and BEAGLECALL software packages.
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19836009
[ "Homozygous", "mutations", "in", "ADAMTS10", " ", "and", "ADAMTS17", " ", "cause", "lenticular", "myopia,", "ectopia", "lentis,", "glaucoma,", "spherophakia,", "and", "short", "stature.", "Weill-Marchesani", "syndrome", "(WMS)", "is", "a", "well-characterized", "disorder", "in", "which", "patients", "develop", "eye", "and", "skeletal", "abnormalities.", "Autosomal-recessive", "and", "autosomal-dominant", "forms", "of", "WMS", "are", "caused", "by", "mutations", "in", "ADAMTS10", " ", "and", "FBN1", " ", "genes,", "respectively.", "Here", "we", "report", "on", "13", "patients", "from", "seven", "unrelated", "families", "from", "the", "Arabian", "Peninsula.", "These", "patients", "have", "a", "constellation", "of", "features", "that", "fall", "within", "the", "WMS", "spectrum", "and", "follow", "an", "autosomal-recessive", "mode", "of", "inheritance.", "Individuals", "who", "came", "from", "two", "families", "and", "met", "the", "diagnostic", "criteria", "for", "WMS", "were", "each", "found", "to", "have", "a", "different", "homozygous", "missense", "mutation", "in", "ADAMTS10", ".", "Linkage", "analysis", "and", "direct", "sequencing", "of", "candidate", "genes", "in", "another", "two", "families", "and", "a", "sporadic", "case", "with", "phenotypes", "best", "described", "as", "WMS-like", "led", "to", "the", "identification", "of", "three", "homozygous", "mutations", "in", "the", "closely", "related", "ADAMTS17", " ", "gene.", "Our", "clinical", "and", "genetic", "findings", "suggest", "that", "ADAMTS17", " ", "plays", "a", "role", "in", "crystalline", "lens", "zonules", "and", "connective", "tissue", "formation", "and", "that", "mutations", "in", "ADAMTS17", " ", "are", "sufficient", "to", "produce", "some", "of", "the", "main", "features", "typically", "described", "in", "WMS." ]
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Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10 . Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.
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15526234
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Sex-specific genetic architecture of whole blood serotonin levels. Recently, a quantitative-trait locus (QTL) for whole blood serotonin level was identified in a genomewide linkage and association study in a founder population. Because serotonin level is a sexually dimorphic trait, in the present study, we evaluated the sex-specific genetic architecture of whole blood serotonin level in the same population. Here, we use an extended homozygosity-by-descent linkage method that is suitable for large complex pedigrees. Although both males and females have high broad heritability (H2=0.99), females have a higher additive component (h2=0.63 in females; h2=0.27 in males). Furthermore, the serotonin QTL on 17q that was identified previously in this population, integrin beta 3 (ITGB3), and a novel locus on 2q influence serotonin levels only in males, whereas linkage to a region on chromosome 6q is specific to females. Both sexes contribute to linkage signals on 12q and 16p. There were, overall, more associations meeting criteria for suggestive significance in males than in females, including those of ITGB3 ITGB3 integrin beta 3 (ITGB3), and a novel locus on 2q influence serotonin levels only in males, whereas linkage to a region on chromosome 6q is specific to females. Both sexes contribute to linkage signals on 12q and 16p. There were, overall, more associations meeting criteria for suggestive significance in males than in females, including those of ITGB3 and the serotonin transporter gene ( 5HTT ). This analysis is consistent with heritable sexual dimorphism in whole blood serotonin levels resulting from the effects of a combination of sex-specific and sex-independent loci.
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9150164
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A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24. We performed linkage analysis in a Belgian family with autosomal dominant midfrequency hearing loss, which has a prelingual onset and a nonprogressive course in most patients. We found LOD scores >6 with markers on chromosome 11q. Analysis of key recombinants maps this deafness gene (DFNA12) to a 36-cM interval on chromosome 11q22-24, between markers D11S4120 and D11S912. The critical regions for the recessive deafness locus DFNB2 and the dominant locus DFNA11, which were previously localized to the long arm of chromosome 11, do not overlap with the candidate interval of DFNA12.
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23084292
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Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans. We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci ( HLA-DRB1 (∗)03:01, HLA-DRB1 (∗)08:01, and HLA-DQA1 (∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4 ) and rs2246618 ( MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).
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20607857
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UMD-CFTR: a database dedicated to CF and CFTR-related disorders. With the increasing knowledge of cystic fibrosis (CF) and CFTR-related diseases (CFTR-RD), the number of sequence variations in the CFTR gene is constantly raising. CF and particularly CFTR-RD provide a particular challenge because of many unclassified variants and identical genotypes associated with different phenotypes. Using the Universal Mutation Database (UMD) software we have constructed UMD-CFTR (freely available at the URL: http://www.umd.be/CFTR/), the first comprehensive relational CFTR database that allows an in-depth analysis and annotation of all variations identified in individuals whose CFTR genes have been analyzed extensively. The system has been tested on the molecular data from 757 patients (540 CF and 217 CBAVD) including disease-causing, unclassified, and nonpathogenic alterations (301 different sequence variations) representing 3,973 entries. Tools are provided to assess the pathogenicity of mutations. UMD-CFTR also offers a number of query tools and graphical views providing instant access to the list of mutations, their frequencies, positions and predicted consequences, or correlations between genotypes, haplotypes, and phenotypes. UMD-CFTR offers a way to compile not only disease-causing genotypes but also haplotypes. It will help the CFTR scientific and medical communities to improve sequence variation interpretation, evaluate the putative influence of haplotypes on mutations, and correlate molecular data with phenotypes.
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16960810
[ "Familial", "chilblain", "lupus,", "a", "monogenic", "form", "of", "cutaneous", "lupus", "erythematosus,", "maps", "to", "chromosome", "3p.", "Systemic", "lupus", "erythematosus", "is", "a", "prototypic", "autoimmune", "disease.", "Apart", "from", "rare", "monogenic", "deficiencies", "of", "complement", "factors,", "where", "lupuslike", "disease", "may", "occur", "in", "association", "with", "other", "autoimmune", "diseases", "or", "high", "susceptibility", "to", "bacterial", "infections,", "its", "etiology", "is", "multifactorial", "in", "nature.", "Cutaneous", "findings", "are", "a", "hallmark", "of", "the", "disease", "and", "manifest", "either", "alone", "or", "in", "association", "with", "internal-organ", "disease.", "We", "describe", "a", "novel", "genodermatosis", "characterized", "by", "painful", "bluish-red", "inflammatory", "papular", "or", "nodular", "lesions", "in", "acral", "locations", "such", "as", "fingers,", "toes,", "nose,", "cheeks,", "and", "ears.", "The", "lesions", "sometimes", "appear", "plaquelike", "and", "tend", "to", "ulcerate.", "Manifestation", "usually", "begins", "in", "early", "childhood", "and", "is", "precipitated", "by", "cold", "and", "wet", "exposure.", "Apart", "from", "arthralgias,", "there", "is", "no", "evidence", "for", "internal-organ", "disease", "or", "an", "increased", "susceptibility", "to", "infection.", "Histological", "findings", "include", "a", "deep", "inflammatory", "infiltrate", "with", "perivascular", "distribution", "and", "granular", "deposits", "of", "immunoglobulins", "and", "complement", "along", "the", "basement", "membrane.", "Some", "affected", "individuals", "show", "antinuclear", "antibodies", "or", "immune", "complex", "formation,", "whereas", "cryoglobulins", "or", "cold", "agglutinins", "are", "absent.", "Thus,", "the", "findings", "are", "consistent", "with", "chilblain", "lupus,", "a", "rare", "form", "of", "cutaneous", "lupus", "erythematosus.", "Investigation", "of", "a", "large", "German", "kindred", "with", "18", "affected", "members", "suggests", "a", "highly", "penetrant", "trait", "with", "autosomal", "dominant", "inheritance.", "By", "single-nucleotide-polymorphism-based", "genomewide", "linkage", "analysis,", "the", "locus", "was", "mapped", "to", "chromosome", "3p.", "Haplotype", "analysis", "defined", "the", "locus", "to", "a", "13.8-cM", "interval", "with", "a", "LOD", "score", "of", "5.04.", "This", "is", "the", "first", "description", "of", "a", "monogenic", "form", "of", "cutaneous", "lupus", "erythematosus.", "Identification", "of", "the", "gene", "responsible", "for", "familial", "chilblain", "lupus", "may", "shed", "light", "on", "the", "pathogenesis", "of", "common", "forms", "of", "connective-tissue", "disease", "such", "as", "systemic", "lupus", "erythematosus." ]
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Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Systemic lupus erythematosus is a prototypic autoimmune disease. Apart from rare monogenic deficiencies of complement factors, where lupuslike disease may occur in association with other autoimmune diseases or high susceptibility to bacterial infections, its etiology is multifactorial in nature. Cutaneous findings are a hallmark of the disease and manifest either alone or in association with internal-organ disease. We describe a novel genodermatosis characterized by painful bluish-red inflammatory papular or nodular lesions in acral locations such as fingers, toes, nose, cheeks, and ears. The lesions sometimes appear plaquelike and tend to ulcerate. Manifestation usually begins in early childhood and is precipitated by cold and wet exposure. Apart from arthralgias, there is no evidence for internal-organ disease or an increased susceptibility to infection. Histological findings include a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals show antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins are absent. Thus, the findings are consistent with chilblain lupus, a rare form of cutaneous lupus erythematosus. Investigation of a large German kindred with 18 affected members suggests a highly penetrant trait with autosomal dominant inheritance. By single-nucleotide-polymorphism-based genomewide linkage analysis, the locus was mapped to chromosome 3p. Haplotype analysis defined the locus to a 13.8-cM interval with a LOD score of 5.04. This is the first description of a monogenic form of cutaneous lupus erythematosus. Identification of the gene responsible for familial chilblain lupus may shed light on the pathogenesis of common forms of connective-tissue disease such as systemic lupus erythematosus.
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8651277
[ "Maternally", "inherited", "cardiomyopathy", "and", "hearing", "loss", "associated", "with", "a", "novel", "mutation", "in", "the", "mitochondrial", "tRNA(Lys)", "gene", "(", "G8363A", "mitochondrial", "tRNA(Lys)", "gene", " ", "(G8363A).", "A", "novel", "G8363A", " ", "mutation", "in", "the", "mtDNA", "tRNA(Lys)", " ", "gene", "was", "associated,", "in", "two", "unrelated", "families,", "with", "a", "syndrome", "consisting", "of", "encephalomyopathy,", "sensorineural", "hearing", "loss,", "and", "hypertrophic", "cardiomyopathy.", "Muscle", "biopsies", "from", "the", "probands", "showed", "mitochondrial", "proliferation", "and", "partial", "defects", "of", "complexes", "I,", "III,", "and", "IV", "of", "the", "electron-transport", "chain.", "The", "G8363A", " ", "mutation", "was", "very", "abundant", "(>95%)", "in", "muscle", "samples", "from", "the", "probands", "and", "was", "less", "copious", "in", "blood", "from", "18", "maternal", "relatives", "(mean", "81.3%", "+/-", "8.5%).", "Single-muscle-fiber", "analysis", "showed", "significantly", "higher", "levels", "of", "mutant", "genomes", "in", "cytochrome", "(c)", "oxidase-negative", "fibers", "than", "in", "cytochrome", "(c)", "oxidase-positive", "fibers.", "The", "mutation", "was", "not", "found", "in", ">200", "individuals,", "including", "normal", "controls", "and", "patients", "with", "other", "mitochondrial", "encephalomyopathies,", "thus", "fulfilling", "accepted", "criteria", "for", "pathogenicity." ]
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Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene ( G8363A mitochondrial tRNA(Lys) gene (G8363A). A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome (c) oxidase-negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity.
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10521296
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The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events. Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two South African subpopulations, one of mixed ancestry and one of northern-European descent. Previously, we had detected three novel mutations- Ala797Thr in the beta-myosin heavy-chain gene ( betaMHC ), Arg92Trp in the cardiac troponin T gene ( cTnT ), and Arg645His in the myosin-binding protein C gene ( MyBPC )-and two documented betaMHC mutations ( Arg403Trp and Arg249Gln ). Here we report three additional novel mutations- Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and beta-myosin heavy-chain gene (betaMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC)-and two documented betaMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations-Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and the documented betaMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the betaMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.
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11359216
[ "Mitochondria", "and", "the", "quality", "of", "human", "gametes." ]
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Mitochondria and the quality of human gametes.
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8723698
[ "Simple", "detection", "of", "a", "(Finnish)", "hereditary", "tyrosinemia", "type", "1", " ", "mutation." ]
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Simple detection of a (Finnish) hereditary tyrosinemia type 1 mutation.
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16917930
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Structural assessment of single amino acid mutations: application to TP53 function. Single amino acid substitution is the type of protein alteration most related to human diseases. Current studies seek primarily to distinguish neutral mutations from harmful ones. Very few methods offer an explanation of the final prediction result in terms of the probable structural or functional effect on the protein. In this study, we describe the use of three novel parameters to identify experimentally-verified critical residues of the TP53 protein ( p53 ). The first two parameters make use of a surface clustering method to calculate the protein surface area of highly conserved regions or regions with high nonlocal atomic interaction energy (ANOLEA) score. These parameters help identify important functional regions on the surface of a protein. The last parameter involves the use of a new method for pseudobinding free-energy estimation to specifically probe the importance of residue side-chains to the stability of protein fold. A decision tree was designed to optimally combine these three parameters. The result was compared to the functional data stored in the International Agency for Research on Cancer (IARC) TP53 mutation database. The final prediction achieved a prediction accuracy of 70% and a Matthews correlation coefficient of 0.45. It also showed a high specificity of 91.8%. Mutations in the 85 correctly identified important residues represented 81.7% of the total mutations recorded in the database. In addition, the method was able to correctly assign a probable functional or structural role to the residues. Such information could be critical for the interpretation and prediction of the effect of missense mutations, as it not only provided the fundamental explanation of the observed effect, but also helped design the most appropriate laboratory experiment to verify the prediction results.
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18179903
[ "Mutation", "analysis", "of", "CHRNA1", ",", "CHRNB1", ",", "CHRND", ",", "and", "RAPSN", " ", "genes", "in", "multiple", "pterygium", "syndrome/fetal", "akinesia", "patients.", "Multiple", "pterygium", "syndromes", "(MPS)", "comprise", "a", "group", "of", "multiple", "congenital", "anomaly", "disorders", "characterized", "by", "webbing", "(pterygia)", "of", "the", "neck,", "elbows,", "and/or", "knees", "and", "joint", "contractures", "(arthrogryposis).", "MPS", "are", "phenotypically", "and", "genetically", "heterogeneous", "but", "are", "traditionally", "divided", "into", "prenatally", "lethal", "and", "nonlethal", "(Escobar)", "types.", "Previously,", "we", "and", "others", "reported", "that", "recessive", "mutations", "in", "the", "embryonal", "acetylcholine", "receptor", "g", " ", "subunit", "(", "CHRNG", ")", "can", "cause", "both", "lethal", "and", "nonlethal", "MPS,", "thus", "demonstrating", "that", "pterygia", "resulted", "from", "fetal", "akinesia.", "We", "hypothesized", "that", "mutations", "in", "acetylcholine", "receptor-related", "genes", "might", "also", "result", "in", "a", "MPS/fetal", "akinesia", "phenotype", "and", "so", "we", "analyzed", "15", "cases", "of", "lethal", "MPS/fetal", "akinesia", "without", "CHRNG", " ", "mutations", "for", "mutations", "in", "the", "CHRNA1", ",", "CHRNB1", ",", "CHRND", ",", "and", "rapsyn", " ", "(", "RAPSN", ")", "genes.", "No", "CHRNA1", ",", "CHRNB1", ",", "or", "CHRND", " ", "mutations", "were", "detected,", "but", "a", "homozygous", "RAPSN", " ", "frameshift", "mutation,", "c.1177-1178delAA", ",", "was", "identified", "in", "a", "family", "with", "three", "children", "affected", "with", "lethal", "fetal", "akinesia", "sequence.", "Previously,", "RAPSN", " ", "mutations", "have", "been", "reported", "in", "congenital", "myasthenia.", "Functional", "studies", "were", "consistent", "with", "the", "hypothesis", "that", "whereas", "incomplete", "loss", "of", "rapsyn", "function", "may", "cause", "congenital", "myasthenia,", "more", "severe", "loss", "of", "function", "can", "result", "in", "a", "lethal", "fetal", "akinesia", "phenotype." ]
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Mutation analysis of CHRNA1 , CHRNB1 , CHRND , and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit ( CHRNG ) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1 , CHRNB1 , CHRND , and rapsyn ( RAPSN ) genes. No CHRNA1 , CHRNB1 , or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA , was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.
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1598916
[ "Uniparental", "disomy", "15", "resulting", "from", "\"correction\"", "of", "an", "initial", "trisomy", "15." ]
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Uniparental disomy 15 resulting from "correction" of an initial trisomy 15.
[ 2, 15943, 2768, 4905, 1923, 2054, 3542, 2461, 3864, 2037, 6, 6820, 6, 1927, 1925, 3754, 27477, 2461, 18, 3 ]
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15712269
[ "Identification", "and", "characterization", "of", "five", "novel", "MAN2B1", " ", "mutations", "in", "Italian", "patients", "with", "alpha-mannosidosis.", "Mutation", "analysis", "performed", "on", "six", "Italian", "families", "with", "alpha-mannosidosis", "type", "II", "allowed", "the", "identification", "of", "five", "new", "mutations", "in", "the", "MAN2B1", " ", "gene:", "c.157G>T", ",", "c.562C>T", ",", "c.599A>T", ",", "c.293dupA", ",", "c.2402G>A", " ", "(", "p.E53X", ",", "p.R188X", ",", "p.H200L", ",", "p.Y99VfsX61", ",", "p.G801D", ").", "Protein", "residues", "G801", "and", "H200", "are", "conserved", "among", "the", "four", "mammalian", "alpha-mannosidases", "cloned", "to", "date:", "human,", "cattle,", "cat", "and", "mouse.", "In", "vitro", "expression", "studies", "demonstrated", "that", "both", "missense", "mutations", "expressed", "no", "residual", "alpha-mannosidase", "activity", "indicating", "that", "they", "are", "disease-causing", "mutations.", "Modelling", "into", "the", "three-dimensional", "structure", "revealed", "that", "the", "p.H200L", " ", "could", "involve", "the", "catalytic", "mechanism,", "whereas", "p.G801D", " ", "would", "affect", "the", "correct", "folding", "of", "the", "enzyme." ]
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Identification and characterization of five novel MAN2B1 mutations in Italian patients with alpha-mannosidosis. Mutation analysis performed on six Italian families with alpha-mannosidosis type II allowed the identification of five new mutations in the MAN2B1 gene: c.157G>T , c.562C>T , c.599A>T , c.293dupA , c.2402G>A ( p.E53X , p.R188X , p.H200L , p.Y99VfsX61 , p.G801D ). Protein residues G801 and H200 are conserved among the four mammalian alpha-mannosidases cloned to date: human, cattle, cat and mouse. In vitro expression studies demonstrated that both missense mutations expressed no residual alpha-mannosidase activity indicating that they are disease-causing mutations. Modelling into the three-dimensional structure revealed that the p.H200L could involve the catalytic mechanism, whereas p.G801D would affect the correct folding of the enzyme.
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12632327
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Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Acrocapitofemoral dysplasia is a recently delineated autosomal recessive skeletal dysplasia, characterized clinically by short stature with short limbs and radiographically by cone-shaped epiphyses, mainly in hands and hips. Genomewide homozygosity mapping in two consanguineous families linked the locus to 2q35-q36 with a maximum two-point LOD score of 8.02 at marker D2S2248. Two recombination events defined the minimal critical region between markers D2S2248 and D2S2151 (3.74 cM). Using a candidate-gene approach, we identified two missense mutations in the amino-terminal signaling domain of the gene encoding Indian hedgehog ( IHH ). Both affected individuals of family 1 are homozygous for a 137C-->T transition ( P46L ), and the three patients in family 2 are homozygous for a 569T-->C transition ( V190A ). The two mutant amino acids are strongly conserved and predicted to be located outside the region where brachydactyly type A-1 mutations are clustered.
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16411177
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Masking selected sequence variation by incorporating mismatches into melting analysis probes. Hybridization probe melting analysis can be complicated by the presence of sequence variation (benign polymorphisms or other mutations) near the targeted mutation. We investigated the use of "masking" probes to differentiate alleles with similar probe melting temperatures. Selected sequence variation was masked by incorporating mismatches (deletion, unmatched nucleotide, or universal base) into hybridization probes at the polymorphic location. Such masking probes create a probe/target mismatch with all possible alleles at the selected polymorphic location. Any allele with additional variation at another site is identified by a lower probe melting temperature than alleles that vary only at the masked position. This "masking technique" was applied to RET protooncogene and HPA6 RET protooncogene and HPA6 mutation detection using unlabeled hybridization probes, a saturating dsDNA dye, and high-resolution melting analysis. Masking probes clearly distinguished all targeted mutations from polymorphisms when at least 1 base pair (bp) separated the mutation from the masked variation. We were able to mask polymorphisms immediately adjacent to mutations, except in certain cases, such as those involving single-base deletion probes when both adjacent positions had the same polymorphic nucleotides. The masking probes can also localize mutations to specific codons or nucleotide positions. Masking probes can simplify melting analysis of complex regions and eliminate the need for sequencing.
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7887433
[ "Prenatal", "genetic", "counseling", "for", "hemoglobinopathy", "carriers:", "a", "comparison", "of", "primary", "providers", "of", "prenatal", "care", "and", "professional", "genetic", "counselors.", "Health", "personnel", "trained", "in", "medical", "genetics", "are", "insufficient", "to", "meet", "the", "demand", "for", "genetic", "services.", "Methods", "must", "be", "found", "to", "enable", "primary", "care", "providers", "to", "offer", "commonly", "needed", "genetic", "services", "themselves.", "In", "our", "recently", "reported", "community-wide", "prenatal", "screening", "program", "for", "hemoglobinopathies,", "36%", "of", "women", "detected", "to", "have", "a", "hemoglobinopathy", "did", "not", "come", "to", "a", "tertiary", "center", "for", "counseling", "and", "thus", "may", "have", "not", "benefited", "from", "testing.", "To", "determine", "whether", "the", "efficiency", "of", "the", "program", "could", "be", "increased", "if", "counseling", "were", "provided", "by", "the", "prenatal", "care", "provider", "(obstetrician", "or", "family", "practitioner),", "we", "developed", "a", "pilot", "training", "program", "on", "the", "basis", "of", "our", "experience", "in", "offering", "such", "services", "and", "enlisted", "68%", "of", "regional", "prenatal", "care", "providers", "to", "participate.", "The", "proportion", "of", "patients", "detected", "to", "have", "a", "hemoglobinopathy", "who", "received", "counseling", "was", "similar", "in", "the", "primary", "and", "tertiary", "provider", "groups:", "59%", "versus", "50%,", "respectively,", "for", "sickle", "trait,", "and", "69%", "versus", "66%,", "respectively,", "for", "beta-thalassemia", "trait.", "Knowledge", "after", "counseling", "was", "also", "similar", "for", "the", "primary", "and", "tertiary", "provider", "groups:", "64%", "versus", "66%", "(mean", "%", "correct),", "respectively,", "for", "sickle", "trait,", "and", "79%", "versus", "78%,", "respectively,", "for", "beta-thalassemia", "trait.", "However,", "the", "two", "provider", "groups", "significantly", "differed", "with", "regard", "to", "whether", "or", "not", "the", "patient", "had", "her", "partner", "tested.", "For", "sickle", "trait,", "it", "was", "25%", "for", "the", "primary", "providers", "but", "49%", "for", "the", "tertiary", "providers", "(P", "<", ".001).", "For", "beta-thalassemia", "trait,", "it", "was", "47%", "for", "the", "primary", "providers", "but", "78%", "for", "the", "tertiary", "providers", "(P", "<", ".001).(ABSTRACT", "TRUNCATED", "AT", "250", "WORDS)" ]
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Prenatal genetic counseling for hemoglobinopathy carriers: a comparison of primary providers of prenatal care and professional genetic counselors. Health personnel trained in medical genetics are insufficient to meet the demand for genetic services. Methods must be found to enable primary care providers to offer commonly needed genetic services themselves. In our recently reported community-wide prenatal screening program for hemoglobinopathies, 36% of women detected to have a hemoglobinopathy did not come to a tertiary center for counseling and thus may have not benefited from testing. To determine whether the efficiency of the program could be increased if counseling were provided by the prenatal care provider (obstetrician or family practitioner), we developed a pilot training program on the basis of our experience in offering such services and enlisted 68% of regional prenatal care providers to participate. The proportion of patients detected to have a hemoglobinopathy who received counseling was similar in the primary and tertiary provider groups: 59% versus 50%, respectively, for sickle trait, and 69% versus 66%, respectively, for beta-thalassemia trait. Knowledge after counseling was also similar for the primary and tertiary provider groups: 64% versus 66% (mean % correct), respectively, for sickle trait, and 79% versus 78%, respectively, for beta-thalassemia trait. However, the two provider groups significantly differed with regard to whether or not the patient had her partner tested. For sickle trait, it was 25% for the primary providers but 49% for the tertiary providers (P < .001). For beta-thalassemia trait, it was 47% for the primary providers but 78% for the tertiary providers (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)
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8829645
[ "A", "66-basepair", "insertion", "in", "exon", "6", "of", "the", "alpha-L-fucosidase", " ", "gene", "of", "a", "fucosidosis", "patient." ]
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A 66-basepair insertion in exon 6 of the alpha-L-fucosidase gene of a fucosidosis patient.
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14722921
[ "Context", "of", "deletions", "and", "insertions", "in", "human", "coding", "sequences.", "We", "studied", "the", "dependence", "of", "the", "rate", "of", "short", "deletions", "and", "insertions", "on", "their", "contexts", "using", "the", "data", "on", "mutations", "within", "coding", "exons", "at", "19", "human", "loci", "that", "cause", "mendelian", "diseases.", "We", "confirm", "that", "periodic", "sequences", "consisting", "of", "three", "to", "five", "or", "more", "nucleotides", "are", "mutagenic.", "Mutability", "of", "sequences", "with", "strongly", "biased", "nucleotide", "composition", "is", "also", "elevated,", "even", "when", "mutations", "within", "homonucleotide", "runs", "longer", "than", "three", "nucleotides", "are", "ignored.", "In", "contrast,", "no", "elevated", "mutation", "rates", "have", "been", "detected", "for", "imperfect", "direct", "or", "inverted", "repeats.", "Among", "known", "candidate", "contexts,", "the", "indel", "context", "GTAAGT", "and", "regions", "with", "purine-pyrimidine", "imbalance", "between", "the", "two", "DNA", "strands", "are", "mutagenic", "in", "our", "sample,", "and", "many", "others", "are", "not", "mutagenic.", "Data", "on", "mutation", "hot", "spots", "suggest", "two", "novel", "contexts", "that", "increase", "the", "deletion", "rate.", "Comprehensive", "analysis", "of", "mutability", "of", "all", "possible", "contexts", "of", "lengths", "four,", "six,", "and", "eight", "indicates", "a", "substantially", "elevated", "deletion", "rate", "within", "YYYTG", "and", "similar", "sequences,", "which", "is", "one", "of", "the", "two", "contexts", "revealed", "by", "the", "hot", "spots.", "Possible", "contexts", "that", "increase", "the", "insertion", "rate", "(AT(A/C)(A/C)GCC", "and", "TACCRC)", "and", "decrease", "deletion", "(TATCGC)", "or", "insertion", "(GCGG)", "rates", "have", "also", "been", "identified.", "Two-thirds", "of", "deletions", "remove", "a", "repeat,", "and", "over", "80%", "of", "insertions", "create", "a", "repeat,", "i.e.,", "they", "are", "duplications." ]
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Context of deletions and insertions in human coding sequences. We studied the dependence of the rate of short deletions and insertions on their contexts using the data on mutations within coding exons at 19 human loci that cause mendelian diseases. We confirm that periodic sequences consisting of three to five or more nucleotides are mutagenic. Mutability of sequences with strongly biased nucleotide composition is also elevated, even when mutations within homonucleotide runs longer than three nucleotides are ignored. In contrast, no elevated mutation rates have been detected for imperfect direct or inverted repeats. Among known candidate contexts, the indel context GTAAGT and regions with purine-pyrimidine imbalance between the two DNA strands are mutagenic in our sample, and many others are not mutagenic. Data on mutation hot spots suggest two novel contexts that increase the deletion rate. Comprehensive analysis of mutability of all possible contexts of lengths four, six, and eight indicates a substantially elevated deletion rate within YYYTG and similar sequences, which is one of the two contexts revealed by the hot spots. Possible contexts that increase the insertion rate (AT(A/C)(A/C)GCC and TACCRC) and decrease deletion (TATCGC) or insertion (GCGG) rates have also been identified. Two-thirds of deletions remove a repeat, and over 80% of insertions create a repeat, i.e., they are duplications.
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8328452
[ "Molecular", "analysis", "of", "Hurler", "syndrome", "in", "Druze", "and", "Muslim", "Arab", "patients", "in", "Israel:", "multiple", "allelic", "mutations", "of", "the", "IDUA", " ", "gene", "in", "a", "small", "geographic", "area.", "The", "mutations", "underlying", "Hurler", "syndrome", "(mucopolysaccharidosis", "IH)", "in", "Druze", "and", "Muslim", "Israeli", "Arab", "patients", "have", "been", "characterized.", "Four", "alleles", "were", "identified,", "using", "a", "combination", "of", "(a)", "PCR", "amplification", "of", "reverse-transcribed", "RNA", "or", "genomic", "DNA", "segments,", "(b)", "cycle", "sequencing", "of", "PCR", "products,", "and", "(c)", "restriction-enzyme", "analysis.", "One", "allele", "has", "two", "amino", "acid", "substitutions,", "Gly409-->Arg", " ", "in", "exon", "9", "and", "Ter-->Cys", "in", "exon", "14.", "The", "other", "three", "alleles", "have", "mutations", "in", "exon", "2", "(", "Tyr64-->Ter", "),", "exon", "7", "(", "Gln310-->Ter", "),", "or", "exon", "8", "(", "Thr366-->Pro", ").", "Transfection", "of", "mutagenized", "cDNAs", "into", "Cos-1", "cells", "showed", "that", "two", "missense", "mutations,", "Thr366-->Pro", " ", "and", "Ter-->Cys,", "permitted", "the", "expression", "of", "only", "trace", "amounts", "of", "alpha-L-iduronidase", "activity,", "whereas", "Gly409-->Arg", " ", "permitted", "the", "expression", "of", "60%", "as", "much", "enzyme", "as", "did", "the", "normal", "cDNA.", "The", "nonsense", "mutations", "were", "associated", "with", "abnormalities", "of", "RNA", "processing:", "(1)", "both", "a", "very", "low", "level", "of", "mRNA", "and", "skipping", "of", "exon", "2", "for", "Tyr64-->Ter", " ", "and", "(2)", "utilization", "of", "a", "cryptic", "splice", "site", "for", "Gln310-->Ter", ".", "In", "all", "instances,", "the", "probands", "were", "found", "homozygous,", "and", "the", "parents", "heterozygous,", "for", "the", "mutant", "alleles,", "as", "anticipated", "from", "the", "consanguinity", "in", "each", "family.", "The", "two-mutation", "allele", "was", "identified", "in", "a", "family", "from", "Gaza;", "the", "other", "three", "alleles", "were", "found", "in", "seven", "families,", "five", "of", "them", "Druze,", "residing", "in", "a", "very", "small", "area", "of", "northern", "Israel.", "Since", "such", "clustering", "suggests", "a", "classic", "founder", "effect,", "the", "presence", "of", "three", "mutant", "alleles", "of", "the", "IDUA", " ", "gene", "was", "unexpected." ]
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Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. The mutations underlying Hurler syndrome (mucopolysaccharidosis IH) in Druze and Muslim Israeli Arab patients have been characterized. Four alleles were identified, using a combination of (a) PCR amplification of reverse-transcribed RNA or genomic DNA segments, (b) cycle sequencing of PCR products, and (c) restriction-enzyme analysis. One allele has two amino acid substitutions, Gly409-->Arg in exon 9 and Ter-->Cys in exon 14. The other three alleles have mutations in exon 2 ( Tyr64-->Ter ), exon 7 ( Gln310-->Ter ), or exon 8 ( Thr366-->Pro ). Transfection of mutagenized cDNAs into Cos-1 cells showed that two missense mutations, Thr366-->Pro and Ter-->Cys, permitted the expression of only trace amounts of alpha-L-iduronidase activity, whereas Gly409-->Arg permitted the expression of 60% as much enzyme as did the normal cDNA. The nonsense mutations were associated with abnormalities of RNA processing: (1) both a very low level of mRNA and skipping of exon 2 for Tyr64-->Ter and (2) utilization of a cryptic splice site for Gln310-->Ter . In all instances, the probands were found homozygous, and the parents heterozygous, for the mutant alleles, as anticipated from the consanguinity in each family. The two-mutation allele was identified in a family from Gaza; the other three alleles were found in seven families, five of them Druze, residing in a very small area of northern Israel. Since such clustering suggests a classic founder effect, the presence of three mutant alleles of the IDUA gene was unexpected.
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22036171
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Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Congenital hypomyelinating disorders are a heterogeneous group of inherited leukoencephalopathies characterized by abnormal myelin formation. We have recently reported a hypomyelinating syndrome characterized by diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). We performed whole-exome sequencing of three unrelated individuals with HCAHC and identified compound heterozygous mutations in POLR3B in two individuals. The mutations include a nonsense mutation, a splice-site mutation, and two missense mutations at evolutionally conserved amino acids. Using reverse transcription-PCR and sequencing, we demonstrated that the splice-site mutation caused deletion of exon 18 from POLR3B mRNA and that the transcript harboring the nonsense mutation underwent nonsense-mediated mRNA decay. We also identified compound heterozygous missense mutations in POLR3A in the remaining individual. POLR3A and POLR3B encode the largest and second largest subunits of RNA Polymerase III (Pol III), RPC1 and RPC2 POLR3A and POLR3B encode the largest and second largest subunits of RNA Polymerase III (Pol III), RPC1 and RPC2, respectively. RPC1 and RPC2 together form the active center of the polymerase and contribute to the catalytic activity of the polymerase. Pol III is involved in the transcription of small noncoding RNAs, such as 5S ribosomal RNA and all transfer RNAs (tRNA). We hypothesize that perturbation of Pol III target transcription, especially of tRNAs, could be a common pathological mechanism underlying POLR3A and POLR3B mutations.
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21922597
[ "Fine-tiling", "array", "CGH", "to", "improve", "diagnostics", "for", "α-", "and", "β-thalassemia", "rearrangements.", "Implementation", "of", "multiplex", "ligation-dependent", "probe", "amplification", "(MLPA)", "for", "thalassemia", "causing", "deletions", "has", "lead", "to", "the", "detection", "of", "new", "rearrangements.", "Knowledge", "of", "the", "exact", "breakpoint", "sequences", "should", "give", "more", "insight", "into", "the", "molecular", "mechanisms", "underlying", "these", "rearrangements,", "and", "would", "facilitate", "the", "design", "of", "gap-PCRs.", "We", "have", "designed", "a", "custom", "fine-tiling", "array", "with", "oligonucleotides", "covering", "the", "complete", "globin", "gene", "clusters.", "We", "hybridized", "27", "DNA", "samples", "containing", "newly", "identified", "deletions", "and", "nine", "positive", "controls.", "We", "designed", "specific", "primers", "to", "amplify", "relatively", "short", "fragments", "containing", "the", "breakpoint", "sequence", "and", "analyzed", "these", "by", "direct", "sequencing.", "Results", "from", "nine", "positive", "controls", "showed", "that", "array", "comparative", "genomic", "hybridization", "(aCGH)", "is", "suitable", "to", "detect", "small", "and", "large", "rearrangements.", "We", "were", "able", "to", "locate", "all", "breakpoints", "to", "a", "region", "of", "approximately", "2", "kb.", "We", "designed", "breakpoint", "primers", "for", "22", "cases", "and", "amplification", "was", "successful", "in", "19", "cases.", "For", "12", "of", "these,", "the", "exact", "locations", "of", "the", "breakpoints", "were", "determined.", "Seven", "of", "these", "deletions", "have", "not", "been", "reported", "before.", "aCGH", "is", "a", "valuable", "tool", "for", "high-resolution", "breakpoint", "characterization.", "The", "combination", "of", "MLPA", "and", "aCGH", "has", "lead", "to", "relatively", "cheap", "and", "easy", "to", "perform", "PCR", "assays,", "which", "might", "be", "of", "use", "for", "laboratories", "as", "an", "alternative", "for", "MLPA", "in", "populations", "where", "only", "a", "limited", "number", "of", "specific", "deletions", "occur", "with", "high", "frequency." ]
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Fine-tiling array CGH to improve diagnostics for α- and β-thalassemia rearrangements. Implementation of multiplex ligation-dependent probe amplification (MLPA) for thalassemia causing deletions has lead to the detection of new rearrangements. Knowledge of the exact breakpoint sequences should give more insight into the molecular mechanisms underlying these rearrangements, and would facilitate the design of gap-PCRs. We have designed a custom fine-tiling array with oligonucleotides covering the complete globin gene clusters. We hybridized 27 DNA samples containing newly identified deletions and nine positive controls. We designed specific primers to amplify relatively short fragments containing the breakpoint sequence and analyzed these by direct sequencing. Results from nine positive controls showed that array comparative genomic hybridization (aCGH) is suitable to detect small and large rearrangements. We were able to locate all breakpoints to a region of approximately 2 kb. We designed breakpoint primers for 22 cases and amplification was successful in 19 cases. For 12 of these, the exact locations of the breakpoints were determined. Seven of these deletions have not been reported before. aCGH is a valuable tool for high-resolution breakpoint characterization. The combination of MLPA and aCGH has lead to relatively cheap and easy to perform PCR assays, which might be of use for laboratories as an alternative for MLPA in populations where only a limited number of specific deletions occur with high frequency.
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7599639
[ "Novel", "(", "cys152", ">", "arg", ")", "missense", "mutation", "in", "an", "Arab", "patient", "with", "Canavan", "disease." ]
[ 0, 0, 3, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Novel ( cys152 > arg ) missense mutation in an Arab patient with Canavan disease.
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13680528
[ "A", "genomewide", "screen", "of", "345", "families", "for", "autism-susceptibility", "loci.", "We", "previously", "reported", "a", "genomewide", "scan", "to", "identify", "autism-susceptibility", "loci", "in", "110", "multiplex", "families,", "showing", "suggestive", "evidence", "(P", "<.01)", "for", "linkage", "to", "autism-spectrum", "disorders", "(ASD)", "on", "chromosomes", "5,", "8,", "16,", "19,", "and", "X", "and", "showing", "nominal", "evidence", "(P", "<.05)", "on", "several", "additional", "chromosomes", "(2,", "3,", "4,", "10,", "11,", "12,", "15,", "18,", "and", "20).", "In", "this", "follow-up", "analysis", "we", "have", "increased", "the", "sample", "size", "threefold,", "while", "holding", "the", "study", "design", "constant,", "so", "that", "we", "now", "report", "345", "multiplex", "families,", "each", "with", "at", "least", "two", "siblings", "affected", "with", "autism", "or", "ASD", "phenotype.", "Along", "with", "235", "new", "multiplex", "families,", "73", "new", "microsatellite", "markers", "were", "also", "added", "in", "10", "regions,", "thereby", "increasing", "the", "marker", "density", "at", "these", "strategic", "locations", "from", "10", "cM", "to", "approximately", "2", "cM", "and", "bringing", "the", "total", "number", "of", "markers", "to", "408", "over", "the", "entire", "genome.", "Multipoint", "maximum", "LOD", "scores", "(MLS)", "obtained", "from", "affected-sib-pair", "analysis", "of", "all", "345", "families", "yielded", "suggestive", "evidence", "for", "linkage", "on", "chromosomes", "17,", "5,", "11,", "4,", "and", "8", "(listed", "in", "order", "by", "MLS)", "(P", "<.01).", "The", "most", "significant", "findings", "were", "an", "MLS", "of", "2.83", "(P", "=.00029)", "on", "chromosome", "17q,", "near", "the", "serotonin", "transporter", "(5-hydroxytryptamine", "transporter", "[5-HTT]),", "and", "an", "MLS", "of", "2.54", "(P", "=.00059)", "on", "5p.", "The", "present", "follow-up", "genome", "scan,", "which", "used", "a", "consistent", "research", "design", "across", "studies", "and", "examined", "the", "largest", "ASD", "sample", "collection", "reported", "to", "date,", "gave", "either", "equivalent", "or", "marginally", "increased", "evidence", "for", "linkage", "at", "several", "chromosomal", "regions", "implicated", "in", "our", "previous", "scan", "but", "eliminated", "evidence", "for", "linkage", "at", "other", "regions." ]
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A genomewide screen of 345 families for autism-susceptibility loci. We previously reported a genomewide scan to identify autism-susceptibility loci in 110 multiplex families, showing suggestive evidence (P <.01) for linkage to autism-spectrum disorders (ASD) on chromosomes 5, 8, 16, 19, and X and showing nominal evidence (P <.05) on several additional chromosomes (2, 3, 4, 10, 11, 12, 15, 18, and 20). In this follow-up analysis we have increased the sample size threefold, while holding the study design constant, so that we now report 345 multiplex families, each with at least two siblings affected with autism or ASD phenotype. Along with 235 new multiplex families, 73 new microsatellite markers were also added in 10 regions, thereby increasing the marker density at these strategic locations from 10 cM to approximately 2 cM and bringing the total number of markers to 408 over the entire genome. Multipoint maximum LOD scores (MLS) obtained from affected-sib-pair analysis of all 345 families yielded suggestive evidence for linkage on chromosomes 17, 5, 11, 4, and 8 (listed in order by MLS) (P <.01). The most significant findings were an MLS of 2.83 (P =.00029) on chromosome 17q, near the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), and an MLS of 2.54 (P =.00059) on 5p. The present follow-up genome scan, which used a consistent research design across studies and examined the largest ASD sample collection reported to date, gave either equivalent or marginally increased evidence for linkage at several chromosomal regions implicated in our previous scan but eliminated evidence for linkage at other regions.
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8651286
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Finding genes on the X chromosome by which homo may have become sapiens.
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18674750
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WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels. Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase ( WWOX ) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX . Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.
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22405088
[ "Exome", "sequencing", "reveals", "mutations", "in", "TRPV3", " ", "as", "a", "cause", "of", "Olmsted", "syndrome.", "Olmsted", "syndrome", "(OS)", "is", "a", "rare", "congenital", "disorder", "characterized", "by", "palmoplantar", "and", "periorificial", "keratoderma,", "alopecia", "in", "most", "cases,", "and", "severe", "itching.", "The", "genetic", "basis", "for", "OS", "remained", "unidentified.", "Using", "whole-exome", "sequencing", "of", "case-parents", "trios,", "we", "have", "identified", "a", "de", "novo", "missense", "mutation", "in", "TRPV3", " ", "that", "produces", "p.Gly573Ser", " ", "in", "an", "individual", "with", "OS.", "Nucleotide", "sequencing", "of", "five", "additional", "affected", "individuals", "also", "revealed", "missense", "mutations", "in", "TRPV3", " ", "(which", "produced", "p.Gly573Ser", " ", "in", "three", "cases", "and", "p.Gly573Cys", " ", "and", "p.Trp692Gly", " ", "in", "one", "case", "each).", "Encoding", "a", "transient", "receptor", "potential", "vanilloid-3", "cation", "channel", ",", "TRPV3", " ", "is", "primarily", "expressed", "in", "the", "skin,", "hair", "follicles,", "brain,", "and", "spinal", "cord.", "In", "transfected", "HEK293", "cells", "expressing", "TRPV3", " ", "mutants,", "much", "larger", "inward", "currents", "were", "recorded,", "probably", "because", "of", "the", "constitutive", "opening", "of", "the", "mutants.", "These", "gain-of-function", "mutations", "might", "lead", "to", "elevated", "apoptosis", "of", "keratinocytes", "and", "consequent", "skin", "hyperkeratosis", "in", "the", "affected", "individuals.", "Our", "findings", "suggest", "that", "TRPV3", " ", "plays", "essential", "roles", "in", "skin", "keratinization,", "hair", "growth,", "and", "possibly", "itching", "sensation", "in", "humans", "and", "selectively", "targeting", "TRPV3", " ", "could", "provide", "therapeutic", "potential", "for", "keratinization", "or", "itching-related", "skin", "disorders." ]
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Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching. The genetic basis for OS remained unidentified. Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS. Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each). Encoding a transient receptor potential vanilloid-3 cation channel , TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord. In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants. These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals. Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders.
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19842213
[ "Shadow", "autozygosity", "mapping", "by", "linkage", "exclusion", "(SAMPLE):", "a", "simple", "strategy", "to", "identify", "the", "genetic", "basis", "of", "lethal", "autosomal", "recessive", "disorders.", "Autozygosity", "mapping", "has", "been", "invaluable", "for", "determining", "the", "genetic", "basis", "of", "lethal", "autosomal", "recessive", "disorders,", "but", "this", "approach", "remains", "challenging", "because", "DNA", "from", "affected", "individuals", "may", "often", "be", "unavailable", "or", "of", "insufficient", "quality", "for", "extensive", "molecular", "genetic", "studies.", "To", "circumvent", "these", "difficulties,", "we", "developed", "a", "computer", "program", "called", "\"SAMPLE\"", "(for", "shadow", "autozygosity", "mapping", "by", "linkage", "exclusion)", "to", "enhance", "autozygosity", "mapping", "through", "the", "empirical", "analysis", "of", "haplotypes", "of", "unaffected", "individuals", "in", "consanguineous", "families.", "Single", "nucleotide", "polymorphism", "(SNP)", "genotyping", "of", "unaffected", "individuals", "in", "complex", "consanguineous", "pedigrees", "is", "used", "to", "infer", "limited", "chromosomal", "regions", "compatible", "with", "linkage", "to", "a", "potential", "disease", "locus,", "and", "to", "allow", "the", "immediate", "prioritization", "of", "potential", "regions", "of", "interest.", "Further", "limited", "genotyping", "then", "enables", "the", "rapid", "confirmation", "and", "fine", "mapping", "of", "a", "disease", "locus.", "We", "demonstrate", "the", "utility", "of", "this", "strategy", "by", "using", "genotyping", "data", "from", "only", "parents", "and", "unaffected", "siblings,", "in", "three", "consanguineous", "families", "affected", "with", "Meckel-Gruber", "syndrome,", "to", "correctly", "infer", "the", "location", "of", "the", "MKS3", "/", "TMEM67", " ", "locus", "on", "chromosome", "8q22.1.", "This", "strategy", "is", "practicable", "only", "with", "the", "recent", "advances", "in", "whole", "genome", "genotyping", "by", "high-density", "SNP", "microarrays,", "and", "could", "not", "be", "easily", "implemented", "in", "approaches", "that", "rely", "on", "microsatellite", "markers.", "SAMPLE", "is", "available", "at", "http://dna.leeds.ac.uk/sample/." ]
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Shadow autozygosity mapping by linkage exclusion (SAMPLE): a simple strategy to identify the genetic basis of lethal autosomal recessive disorders. Autozygosity mapping has been invaluable for determining the genetic basis of lethal autosomal recessive disorders, but this approach remains challenging because DNA from affected individuals may often be unavailable or of insufficient quality for extensive molecular genetic studies. To circumvent these difficulties, we developed a computer program called "SAMPLE" (for shadow autozygosity mapping by linkage exclusion) to enhance autozygosity mapping through the empirical analysis of haplotypes of unaffected individuals in consanguineous families. Single nucleotide polymorphism (SNP) genotyping of unaffected individuals in complex consanguineous pedigrees is used to infer limited chromosomal regions compatible with linkage to a potential disease locus, and to allow the immediate prioritization of potential regions of interest. Further limited genotyping then enables the rapid confirmation and fine mapping of a disease locus. We demonstrate the utility of this strategy by using genotyping data from only parents and unaffected siblings, in three consanguineous families affected with Meckel-Gruber syndrome, to correctly infer the location of the MKS3 / TMEM67 locus on chromosome 8q22.1. This strategy is practicable only with the recent advances in whole genome genotyping by high-density SNP microarrays, and could not be easily implemented in approaches that rely on microsatellite markers. SAMPLE is available at http://dna.leeds.ac.uk/sample/.
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10739764
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Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.
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1570829
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Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. The human Y chromosome encodes a testis-determining factor ( TDF testis-determining factor (TDF) which is responsible for initiating male sex determination. Recently a region of the Y chromosome ( SRY ) was identified as part of the TDF gene. We have identified a three-generation family (N) in which all XY individuals have a single base-pair substitution resulting in a conservative amino acid change in the conserved domain of the SRY open reading frame. Three individuals are XY sex-reversed females, and two are XY males. Several models are proposed to explain association between a sequence variant in SRY and two sex phenotypes.
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16941471
[ "Comprehensive", "NF1", "screening", "on", "cultured", "Schwann", "cells", "from", "neurofibromas.", "Neurofibromatosis", "type", "1", "(NF1)", "is", "mainly", "characterized", "by", "the", "occurrence", "of", "benign", "peripheral", "nerve", "sheath", "tumors", "or", "neurofibromas.", "Thorough", "investigation", "of", "the", "somatic", "mutation", "spectrum", "has", "thus", "far", "been", "hampered", "by", "the", "large", "size", "of", "the", "NF1", "gene", "and", "the", "considerable", "proportion", "of", "NF1", "heterozygous", "cells", "within", "the", "tumors.", "We", "developed", "an", "improved", "somatic", "mutation", "detection", "strategy", "on", "cultured", "Schwann", "cells", "derived", "from", "neurofibromas", "and", "investigated", "38", "tumors", "from", "nine", "NF1", "patients.", "Twenty-nine", "somatic", "NF1", "lesions", "were", "detected", "which", "represents", "the", "highest", "NF1", "somatic", "mutation", "detection", "rate", "described", "so", "far", "(76%).", "Furthermore,", "our", "data", "strongly", "suggest", "that", "the", "acquired", "second", "hit", "underlies", "reduced", "NF1", "expression", "in", "Schwann", "cell", "cultures.", "Together,", "these", "data", "clearly", "illustrate", "that", "two", "inactivating", "NF1", "mutations,", "in", "a", "subpopulation", "of", "the", "Schwann", "cells,", "are", "required", "for", "neurofibroma", "formation", "in", "NF1", "tumorigenesis.", "The", "observed", "somatic", "mutation", "spectrum", "shows", "that", "intragenic", "NF1", "mutations", "(26/29)", "are", "most", "prevalent,", "particularly", "frameshift", "mutations", "(12/29,", "41%).", "We", "hypothesize", "that", "this", "mutation", "signature", "might", "reflect", "slightly", "reduced", "DNA", "repair", "efficiency", "as", "a", "trigger", "for", "NF1", "somatic", "inactivation", "preceding", "tumorigenesis.", "Joint", "analysis", "of", "the", "current", "and", "previously", "published", "NF1", "mutation", "data", "revealed", "a", "significant", "difference", "in", "the", "somatic", "mutation", "spectrum", "in", "patients", "with", "a", "NF1", "microdeletion", "vs.", "non-microdeletion", "patients", "with", "respect", "to", "the", "prevalence", "of", "loss", "of", "heterozygosity", "events", "(0/15", "vs.", "41/81).", "Differences", "in", "somatic", "inactivation", "mechanism", "might", "therefore", "exist", "between", "NF1", "microdeletion", "patients", "and", "the", "general", "NF1", "population." ]
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Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Neurofibromatosis type 1 (NF1) is mainly characterized by the occurrence of benign peripheral nerve sheath tumors or neurofibromas. Thorough investigation of the somatic mutation spectrum has thus far been hampered by the large size of the NF1 gene and the considerable proportion of NF1 heterozygous cells within the tumors. We developed an improved somatic mutation detection strategy on cultured Schwann cells derived from neurofibromas and investigated 38 tumors from nine NF1 patients. Twenty-nine somatic NF1 lesions were detected which represents the highest NF1 somatic mutation detection rate described so far (76%). Furthermore, our data strongly suggest that the acquired second hit underlies reduced NF1 expression in Schwann cell cultures. Together, these data clearly illustrate that two inactivating NF1 mutations, in a subpopulation of the Schwann cells, are required for neurofibroma formation in NF1 tumorigenesis. The observed somatic mutation spectrum shows that intragenic NF1 mutations (26/29) are most prevalent, particularly frameshift mutations (12/29, 41%). We hypothesize that this mutation signature might reflect slightly reduced DNA repair efficiency as a trigger for NF1 somatic inactivation preceding tumorigenesis. Joint analysis of the current and previously published NF1 mutation data revealed a significant difference in the somatic mutation spectrum in patients with a NF1 microdeletion vs. non-microdeletion patients with respect to the prevalence of loss of heterozygosity events (0/15 vs. 41/81). Differences in somatic inactivation mechanism might therefore exist between NF1 microdeletion patients and the general NF1 population.
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10205286
[ "Genomewide", "Transmission/Disequilibrium", "testing:", "a", "correction." ]
[ 0, 0, 0, 0, 0 ]
Genomewide Transmission/Disequilibrium testing: a correction.
[ 2, 3843, 7641, 5303, 19, 19264, 4213, 30, 43, 6820, 18, 3 ]
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8328462
[ "beta-Hexosaminidase", " ", "isozymes", "from", "cells", "cotransfected", "with", "alpha", "and", "beta", "cDNA", "constructs:", "analysis", "of", "the", "alpha-subunit", "missense", "mutation", "associated", "with", "the", "adult", "form", "of", "Tay-Sachs", "disease.", "In", "vitro", "mutagenesis", "and", "transient", "expression", "in", "COS", "cells", "has", "been", "used", "to", "associate", "a", "missense", "mutation", "with", "a", "clinical", "or", "biochemical", "phenotype.", "Mutations", "affecting", "the", "alpha-subunit", "of", "beta-hexosaminidase", "A", " ", "(alpha", "beta)", "(E.C.3.2.1.52)", "result", "in", "Tay-Sachs", "disease.", "Because", "hexosaminidase", "A", " ", "is", "heterodimeric,", "analysis", "of", "alpha-chain", "mutations", "is", "not", "straightforward.", "We", "examine", "three", "approaches", "utilizing", "previously", "identified", "mutations", "affecting", "alpha-chain", "folding.", "These", "involve", "transfection", "of", "(1)", "the", "alpha", "cDNA", "alone;", "(2)", "a", "beta", "cDNA", "construct", "encoding", "a", "beta-subunit", "substituted", "at", "a", "position", "homologous", "to", "that", "of", "the", "alpha-subunit,", "and", "(3)", "both", "alpha", "and", "beta", "cDNAs.", "The", "latter", "two", "procedures", "amplified", "residual", "activity", "levels", "over", "that", "of", "patient", "samples,", "an", "effect", "not", "previously", "found", "with", "mutations", "affecting", "an", "\"active\"", "alpha", "Arg", "residue.", "This", "effect", "may", "help", "to", "discriminate", "between", "protein-folding", "and", "active-site", "mutations.", "We", "conclude", "that,", "with", "proper", "controls,", "the", "latter", "method", "of", "cotransfection", "can", "be", "used", "to", "evaluate", "the", "effects", "and", "perhaps", "to", "predict", "the", "clinical", "course", "of", "some", "alpha-chain", "mutations.", "Using", "this", "technique,", "we", "demonstrate", "that", "the", "adult-onset", "Tay-Sachs", "mutation,", "alpha", "Gly", "-->", "Ser269", ",", "does", "not", "directly", "affect", "alpha", "beta", "dimerization", "but", "exerts", "an", "indirect", "effect", "on", "the", "dimer", "through", "destabilizing", "the", "folded", "alpha-subunit", "at", "physiological", "temperatures.", "Two", "other", "alpha", "mutations", "linked", "to", "more", "severe", "phenotypes", "appear", "to", "inhibit", "the", "initial", "folding", "of", "the", "subunit." ]
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beta-Hexosaminidase isozymes from cells cotransfected with alpha and beta cDNA constructs: analysis of the alpha-subunit missense mutation associated with the adult form of Tay-Sachs disease. In vitro mutagenesis and transient expression in COS cells has been used to associate a missense mutation with a clinical or biochemical phenotype. Mutations affecting the alpha-subunit of beta-hexosaminidase A (alpha beta) (E.C.3.2.1.52) result in Tay-Sachs disease. Because hexosaminidase A is heterodimeric, analysis of alpha-chain mutations is not straightforward. We examine three approaches utilizing previously identified mutations affecting alpha-chain folding. These involve transfection of (1) the alpha cDNA alone; (2) a beta cDNA construct encoding a beta-subunit substituted at a position homologous to that of the alpha-subunit, and (3) both alpha and beta cDNAs. The latter two procedures amplified residual activity levels over that of patient samples, an effect not previously found with mutations affecting an "active" alpha Arg residue. This effect may help to discriminate between protein-folding and active-site mutations. We conclude that, with proper controls, the latter method of cotransfection can be used to evaluate the effects and perhaps to predict the clinical course of some alpha-chain mutations. Using this technique, we demonstrate that the adult-onset Tay-Sachs mutation, alpha Gly --> Ser269 , does not directly affect alpha beta dimerization but exerts an indirect effect on the dimer through destabilizing the folded alpha-subunit at physiological temperatures. Two other alpha mutations linked to more severe phenotypes appear to inhibit the initial folding of the subunit.
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11139269
[ "A", "novel", "polymorphism", "(-88", "C>A)", "in", "the", "5'", "UTR", "of", "the", "p53R2", "-88", "C>A", ")", "in", "the", "5'", "UTR", "of", "the", "p53R2", "gene." ]
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A novel polymorphism (-88 C>A) in the 5' UTR of the p53R2 -88 C>A ) in the 5' UTR of the p53R2 gene.
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9497249
[ "Assignment", "of", "the", "tibial", "muscular", "dystrophy", "locus", "to", "chromosome", "2q31.", "Tibial", "muscular", "dystrophy", "(TMD)", "is", "a", "rare", "autosomal", "dominant", "distal", "myopathy", "with", "late", "adult", "onset.", "The", "phenotype", "is", "relatively", "mild:", "muscle", "weakness", "manifests", "in", "the", "patient's", "early", "40s", "and", "remains", "confined", "to", "the", "tibial", "anterior", "muscles.", "Histopathological", "changes", "in", "muscle", "are", "compatible", "with", "muscular", "dystrophy,", "with", "the", "exception", "that", "rimmed", "vacuoles", "are", "a", "rather", "common", "finding.", "We", "performed", "a", "genomewide", "scan,", "with", "279", "highly", "polymorphic", "Cooperative", "Human", "Linkage", "Center", "microsatellite", "markers,", "on", "11", "affected", "individuals", "of", "one", "Finnish", "TMD", "family.", "The", "only", "evidence", "for", "linkage", "emerged", "from", "markers", "in", "a", "43-cM", "region", "on", "chromosome", "2q.", "In", "further", "linkage", "analyses,", "which", "included", "three", "other", "Finnish", "TMD", "families", "and", "which", "used", "a", "denser", "set", "of", "markers,", "a", "maximum", "two-point", "LOD", "score", "of", "10.14", "(recombination", "fraction", "of", ".05)", "was", "obtained", "with", "marker", "D2S364.", "Multipoint", "likelihood", "calculations,", "combined", "with", "the", "haplotype", "and", "recombination", "analyses,", "restricted", "the", "TMD", "locus", "to", "an", "approximately", "1-cM", "critical", "chromosomal", "region", "without", "any", "evidence", "of", "heterogeneity.", "Since", "all", "the", "affecteds", "share", "one", "core", "haplotype,", "the", "dominance", "of", "one", "ancestor", "mutation", "is", "obvious", "in", "the", "Finnish", "TMD", "families.", "The", "disease", "locus", "that", "was", "found", "represents", "a", "novel", "muscular", "dystrophy", "locus,", "providing", "evidence", "for", "the", "involvement", "of", "one", "additional", "gene", "in", "the", "distal", "myopathy", "group", "of", "muscle", "disorders." ]
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Assignment of the tibial muscular dystrophy locus to chromosome 2q31. Tibial muscular dystrophy (TMD) is a rare autosomal dominant distal myopathy with late adult onset. The phenotype is relatively mild: muscle weakness manifests in the patient's early 40s and remains confined to the tibial anterior muscles. Histopathological changes in muscle are compatible with muscular dystrophy, with the exception that rimmed vacuoles are a rather common finding. We performed a genomewide scan, with 279 highly polymorphic Cooperative Human Linkage Center microsatellite markers, on 11 affected individuals of one Finnish TMD family. The only evidence for linkage emerged from markers in a 43-cM region on chromosome 2q. In further linkage analyses, which included three other Finnish TMD families and which used a denser set of markers, a maximum two-point LOD score of 10.14 (recombination fraction of .05) was obtained with marker D2S364. Multipoint likelihood calculations, combined with the haplotype and recombination analyses, restricted the TMD locus to an approximately 1-cM critical chromosomal region without any evidence of heterogeneity. Since all the affecteds share one core haplotype, the dominance of one ancestor mutation is obvious in the Finnish TMD families. The disease locus that was found represents a novel muscular dystrophy locus, providing evidence for the involvement of one additional gene in the distal myopathy group of muscle disorders.
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11156534
[ "A", "novel", "syndrome", "affecting", "multiple", "mitochondrial", "functions,", "located", "by", "microcell-mediated", "transfer", "to", "chromosome", "2p14-2p13.", "We", "have", "studied", "cultured", "skin", "fibroblasts", "from", "three", "siblings", "and", "one", "unrelated", "individual,", "all", "of", "whom", "had", "fatal", "mitochondrial", "disease", "manifesting", "soon", "after", "birth.", "After", "incubation", "with", "1", "mM", "glucose,", "these", "four", "cell", "strains", "exhibited", "lactate/pyruvate", "ratios", "that", "were", "six", "times", "greater", "than", "those", "of", "controls.", "On", "further", "analysis,", "enzymatic", "activities", "of", "the", "pyruvate", "dehydrogenase", "complex,", "the", "2-oxoglutarate", "dehydrogenase", "complex,", "NADH", "cytochrome", "c", "reductase,", "succinate", "dehydrogenase,", "and", "succinate", "cytochrome", "c", "reductase", "were", "severely", "deficient.", "In", "two", "of", "the", "siblings", "the", "enzymatic", "activity", "of", "cytochrome", "oxidase", "was", "mildly", "decreased", "(by", "approximately", "50%).", "Metabolite", "analysis", "performed", "on", "urine", "samples", "taken", "from", "these", "patients", "revealed", "high", "levels", "of", "glycine,", "leucine,", "valine,", "and", "isoleucine,", "indicating", "abnormalities", "of", "both", "the", "glycine-cleavage", "system", "and", "branched-chain", "alpha-ketoacid", "dehydrogenase.", "In", "contrast,", "the", "activities", "of", "fibroblast", "pyruvate", "carboxylase,", "mitochondrial", "aconitase,", "and", "citrate", "synthase", "were", "normal.", "Immunoblot", "analysis", "of", "selected", "complex", "III", "subunits", "(core", "1,", "cyt", "c(1),", "and", "iron-sulfur", "protein)", "and", "of", "the", "pyruvate", "dehydrogenase", "complex", "subunits", "revealed", "no", "visible", "changes", "in", "the", "levels", "of", "all", "examined", "proteins,", "decreasing", "the", "possibility", "that", "an", "import", "and/or", "assembly", "factor", "is", "involved.", "To", "elucidate", "the", "underlying", "molecular", "defect,", "analysis", "of", "microcell-mediated", "chromosome-fusion", "was", "performed", "between", "the", "present", "study's", "fibroblasts", "(recipients)", "and", "a", "panel", "of", "A9", "mouse:human", "hybrids", "(donors)", "developed", "by", "Cuthbert", "et", "al.", "(1995).", "Complementation", "was", "observed", "between", "the", "recipient", "cells", "from", "both", "families", "and", "the", "mouse:human", "hybrid", "clone", "carrying", "human", "chromosome", "2.", "These", "results", "indicate", "that", "the", "underlying", "defect", "in", "our", "patients", "is", "under", "the", "control", "of", "a", "nuclear", "gene,", "the", "locus", "of", "which", "is", "on", "chromosome", "2.", "A", "5-cM", "interval", "has", "been", "identified", "as", "potentially", "containing", "the", "critical", "region", "for", "the", "unknown", "gene.", "This", "interval", "maps", "to", "region", "2p14-2p13." ]
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A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. We have studied cultured skin fibroblasts from three siblings and one unrelated individual, all of whom had fatal mitochondrial disease manifesting soon after birth. After incubation with 1 mM glucose, these four cell strains exhibited lactate/pyruvate ratios that were six times greater than those of controls. On further analysis, enzymatic activities of the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, NADH cytochrome c reductase, succinate dehydrogenase, and succinate cytochrome c reductase were severely deficient. In two of the siblings the enzymatic activity of cytochrome oxidase was mildly decreased (by approximately 50%). Metabolite analysis performed on urine samples taken from these patients revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of both the glycine-cleavage system and branched-chain alpha-ketoacid dehydrogenase. In contrast, the activities of fibroblast pyruvate carboxylase, mitochondrial aconitase, and citrate synthase were normal. Immunoblot analysis of selected complex III subunits (core 1, cyt c(1), and iron-sulfur protein) and of the pyruvate dehydrogenase complex subunits revealed no visible changes in the levels of all examined proteins, decreasing the possibility that an import and/or assembly factor is involved. To elucidate the underlying molecular defect, analysis of microcell-mediated chromosome-fusion was performed between the present study's fibroblasts (recipients) and a panel of A9 mouse:human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells from both families and the mouse:human hybrid clone carrying human chromosome 2. These results indicate that the underlying defect in our patients is under the control of a nuclear gene, the locus of which is on chromosome 2. A 5-cM interval has been identified as potentially containing the critical region for the unknown gene. This interval maps to region 2p14-2p13.
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8755932
[ "mtDNA", "sequence", "diversity", "in", "Africa.", "mtDNA", "sequences", "were", "determined", "from", "241", "individuals", "from", "nine", "ethnic", "groups", "in", "Africa.", "When", "they", "were", "compared", "with", "published", "data", "from", "other", "groups,", "it", "was", "found", "that", "the", "!Kung,", "Mbuti,", "and", "Biaka", "show", "on", "the", "order", "of", "10", "times", "more", "sequence", "differences", "between", "the", "three", "groups,", "as", "well", "as", "between", "those", "and", "the", "other", "groups", "(the", "Fulbe,", "Hausa,", "Tuareg,", "Songhai,", "Kanuri,", "Yoruba,", "Mandenka,", "Somali,", "Tukana,", "and", "Kikuyu),", "than", "these", "other", "groups", "do", "between", "one", "other.", "Furthermore,", "the", "pairwise", "sequence", "distributions,", "patterns", "of", "coalescence", "events,", "and", "numbers", "of", "variable", "positions", "relative", "to", "the", "mean", "sequence", "difference", "indicate", "that", "the", "former", "three", "groups", "have", "been", "of", "constant", "size", "over", "time,", "whereas", "the", "latter", "have", "expanded", "in", "size.", "We", "suggest", "that", "this", "reflects", "subsistence", "patterns", "in", "that", "the", "populations", "that", "have", "expanded", "in", "size", "are", "food", "producers", "whereas", "those", "that", "have", "not", "are", "hunters", "and", "gatherers." ]
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mtDNA sequence diversity in Africa. mtDNA sequences were determined from 241 individuals from nine ethnic groups in Africa. When they were compared with published data from other groups, it was found that the !Kung, Mbuti, and Biaka show on the order of 10 times more sequence differences between the three groups, as well as between those and the other groups (the Fulbe, Hausa, Tuareg, Songhai, Kanuri, Yoruba, Mandenka, Somali, Tukana, and Kikuyu), than these other groups do between one other. Furthermore, the pairwise sequence distributions, patterns of coalescence events, and numbers of variable positions relative to the mean sequence difference indicate that the former three groups have been of constant size over time, whereas the latter have expanded in size. We suggest that this reflects subsistence patterns in that the populations that have expanded in size are food producers whereas those that have not are hunters and gatherers.
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10738004
[ "A", "novel", "mutation", "(", "Q239R", ")", "identified", "in", "a", "Taiwan", "Chinese", "patient", "with", "type", "VI", "mucopolysaccharidosis", "(Maroteaux-Lamy", "syndrome)." ]
[ 0, 0, 0, 0, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
A novel mutation ( Q239R ) identified in a Taiwan Chinese patient with type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome).
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7825583
[ "Mapping", "of", "the", "gene", "for", "Machado-Joseph", "disease", "within", "a", "3.6-cM", "interval", "flanked", "by", "D14S291/D14S280", "and", "D14S81,", "on", "the", "basis", "of", "studies", "of", "linkage", "and", "linkage", "disequilibrium", "in", "24", "Japanese", "families.", "The", "gene", "locus", "of", "Machado-Joseph", "disease", "(MJD)", "has", "recently", "been", "mapped", "within", "a", "29-cM", "subregion", "of", "14q", "chromosome.", "We", "did", "a", "linkage", "study", "of", "24", "multigenerational", "MJD", "Japanese", "pedigrees,", "in", "an", "attempt", "to", "narrow", "the", "candidate", "region", "of", "this", "gene.", "Pairwise", "and", "multipoint", "linkage", "analysis,", "together", "with", "haplotype", "segregation", "analysis,", "led", "to", "the", "conclusion", "that", "the", "MJD", " ", "gene", "is", "located", "at", "the", "6.8-cM", "interval", "between", "D14S256", "and", "D14S81", "(Zmax", "=", "24.78,", "multipoint", "linkage", "analysis).", "D14S291", "and", "D14S280,", "located", "at", "the", "center", "of", "this", "interval,", "showed", "no", "obligate", "recombination", "with", "the", "MJD", " ", "gene", "(Zmax", "=", "5.93", "for", "D14S291", "and", "9.99", "for", "D14S280).", "A", "weak,", "but", "significant,", "linkage", "disequilibrium", "of", "MJD", " ", "gene", "was", "noted", "with", "D14S81", "(P", "<", ".05)", "but", "not", "with", "D14S291", "or", "D14S280.", "These", "results", "suggest", "that", "a", "3.6-cM", "interval", "flanked", "by", "D14S291/D14S280", "and", "D14S81", "is", "the", "most", "likely", "location", "of", "the", "MJD", " ", "gene", "and", "that", "it", "is", "closest", "to", "D14S81." ]
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Mapping of the gene for Machado-Joseph disease within a 3.6-cM interval flanked by D14S291/D14S280 and D14S81, on the basis of studies of linkage and linkage disequilibrium in 24 Japanese families. The gene locus of Machado-Joseph disease (MJD) has recently been mapped within a 29-cM subregion of 14q chromosome. We did a linkage study of 24 multigenerational MJD Japanese pedigrees, in an attempt to narrow the candidate region of this gene. Pairwise and multipoint linkage analysis, together with haplotype segregation analysis, led to the conclusion that the MJD gene is located at the 6.8-cM interval between D14S256 and D14S81 (Zmax = 24.78, multipoint linkage analysis). D14S291 and D14S280, located at the center of this interval, showed no obligate recombination with the MJD gene (Zmax = 5.93 for D14S291 and 9.99 for D14S280). A weak, but significant, linkage disequilibrium of MJD gene was noted with D14S81 (P < .05) but not with D14S291 or D14S280. These results suggest that a 3.6-cM interval flanked by D14S291/D14S280 and D14S81 is the most likely location of the MJD gene and that it is closest to D14S81.
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10408772
[ "Insertion", "of", "Alu", "element", "responsible", "for", "acute", "intermittent", "porphyria.", "In", "this", "study,", "we", "report", "a", "large", "Finnish", "family", "in", "which", "an", "Alu", "element", "interferes", "with", "the", "coding", "region", "of", "the", "porphobilinogen", "deaminase", " ", "(", "PBGD", ")", "gene", "resulting", "in", "acute", "intermittent", "porphyria", "(AIP).", "Polymerase", "chain", "reaction", "(PCR)", "and", "single-strand", "conformation", "polymorphism", "(SSCP)", "analysis", "of", "exon", "5", "among", "patients", "showed", "an", "abnormal", "band", "around", "350", "bp", "apart", "from", "the", "normal", "bands.", "Subcloning", "and", "sequencing", "of", "the", "fragment", "revealed", "a", "333-bp", "Alu", "sequence", "that", "was", "directly", "inserted", "into", "exon", "5", "in", "antisense", "orientation.", "The", "junction", "sequences", "included", "a", "13-bp", "target", "site", "duplication.", "This", "Alu", "cassette", "belongs", "to", "a", "Ya5", "subfamily,", "one", "of", "the", "youngest", "and", "currently", "most", "active", "Alu", "subfamilies", "in", "evolution.", "The", "Alu", "insertion", "resulted", "in", "a", "dramatically", "decreased", "steady-state", "level", "of", "the", "allelic", "transcript,", "as", "this", "Alu", "sequence", "could", "not", "be", "demonstrated", "by", "direct", "sequencing", "of", "the", "amplified", "cDNA", "synthesized", "from", "total", "RNA", "extracted", "from", "the", "patients'", "lymphoblast", "cell", "lines.", "A", "stop", "codon", "present", "in", "the", "reading", "frame", "causes", "premature", "termination", "of", "PBGD", " ", "synthesis.", "The", "predicted", "polypeptide", "contains", "64", "of", "the", "361", "amino", "acids", "of", "PBGD", ",", "followed", "by", "13", "amino", "acids", "that", "are", "not", "identical", "to", "the", "PBGD", " ", "polypeptide.", "To", "further", "characterize", "the", "consequences", "of", "the", "insertion,", "the", "Alu", "sequence", "was", "inserted", "into", "exon", "5", "of", "the", "PBGD", " ", "cDNA", "and", "expressed", "in", "the", "eukaryotic", "COS-1", "cell", "line.", "The", "mutated", "construct", "expressed", "no", "enzyme", "activity", "comparable", "to", "that", "of", "the", "wild-type", "PBGD", ";", "furthermore,", "no", "mutant", "protein", "could", "be", "detected", "by", "Western", "blot", "analysis." ]
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Insertion of Alu element responsible for acute intermittent porphyria. In this study, we report a large Finnish family in which an Alu element interferes with the coding region of the porphobilinogen deaminase ( PBGD ) gene resulting in acute intermittent porphyria (AIP). Polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis of exon 5 among patients showed an abnormal band around 350 bp apart from the normal bands. Subcloning and sequencing of the fragment revealed a 333-bp Alu sequence that was directly inserted into exon 5 in antisense orientation. The junction sequences included a 13-bp target site duplication. This Alu cassette belongs to a Ya5 subfamily, one of the youngest and currently most active Alu subfamilies in evolution. The Alu insertion resulted in a dramatically decreased steady-state level of the allelic transcript, as this Alu sequence could not be demonstrated by direct sequencing of the amplified cDNA synthesized from total RNA extracted from the patients' lymphoblast cell lines. A stop codon present in the reading frame causes premature termination of PBGD synthesis. The predicted polypeptide contains 64 of the 361 amino acids of PBGD , followed by 13 amino acids that are not identical to the PBGD polypeptide. To further characterize the consequences of the insertion, the Alu sequence was inserted into exon 5 of the PBGD cDNA and expressed in the eukaryotic COS-1 cell line. The mutated construct expressed no enzyme activity comparable to that of the wild-type PBGD ; furthermore, no mutant protein could be detected by Western blot analysis.
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15272417
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A major lung cancer susceptibility locus maps to chromosome 6q23-25. Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.
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21129725
[ "Replication", "strategies", "for", "rare", "variant", "complex", "trait", "association", "studies", "via", "next-generation", "sequencing.", "There", "is", "solid", "evidence", "that", "complex", "traits", "can", "be", "caused", "by", "rare", "variants.", "Next-generation", "sequencing", "technologies", "are", "powerful", "tools", "for", "mapping", "rare", "variants.", "Confirmation", "of", "significant", "findings", "in", "stage", "1", "through", "replication", "in", "an", "independent", "stage", "2", "sample", "is", "necessary", "for", "association", "studies.", "For", "gene-based", "mapping", "of", "rare", "variants,", "two", "replication", "strategies", "are", "possible:", "(1)", "variant-based", "replication,", "wherein", "only", "variants", "from", "nucleotide", "sites", "uncovered", "in", "stage", "1", "are", "genotyped", "and", "followed-up", "and", "(2)", "sequence-based", "replication,", "wherein", "the", "gene", "region", "is", "sequenced", "in", "the", "replication", "sample", "and", "both", "known", "and", "novel", "variants", "are", "tested.", "The", "efficiency", "of", "the", "two", "strategies", "is", "dependent", "on", "the", "proportions", "of", "causative", "variants", "discovered", "in", "stage", "1", "and", "sequencing/genotyping", "errors.", "With", "rigorous", "population", "genetic", "and", "phenotypic", "models,", "it", "is", "demonstrated", "that", "sequence-based", "replication", "is", "consistently", "more", "powerful.", "However,", "the", "power", "gain", "is", "small", "(1)", "for", "large-scale", "studies", "with", "thousands", "of", "individuals,", "because", "a", "large", "fraction", "of", "causative", "variant", "sites", "can", "be", "observed", "and", "(2)", "for", "small-", "to", "medium-scale", "studies", "with", "a", "few", "hundred", "samples,", "because", "a", "large", "proportion", "of", "the", "locus", "population", "attributable", "risk", "can", "be", "explained", "by", "the", "uncovered", "variants.", "Therefore,", "genotyping", "can", "be", "a", "temporal", "solution", "for", "replicating", "genetic", "studies", "if", "stage", "1", "and", "2", "samples", "are", "drawn", "from", "the", "same", "population.", "However,", "sequence-based", "replication", "is", "advantageous", "if", "the", "stage", "1", "sample", "is", "small", "or", "novel", "variants", "discovery", "is", "also", "of", "interest.", "It", "is", "shown", "that", "currently", "attainable", "levels", "of", "sequencing", "error", "only", "minimally", "affect", "the", "comparison,", "and", "the", "advantage", "of", "sequence-based", "replication", "remains." ]
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Replication strategies for rare variant complex trait association studies via next-generation sequencing. There is solid evidence that complex traits can be caused by rare variants. Next-generation sequencing technologies are powerful tools for mapping rare variants. Confirmation of significant findings in stage 1 through replication in an independent stage 2 sample is necessary for association studies. For gene-based mapping of rare variants, two replication strategies are possible: (1) variant-based replication, wherein only variants from nucleotide sites uncovered in stage 1 are genotyped and followed-up and (2) sequence-based replication, wherein the gene region is sequenced in the replication sample and both known and novel variants are tested. The efficiency of the two strategies is dependent on the proportions of causative variants discovered in stage 1 and sequencing/genotyping errors. With rigorous population genetic and phenotypic models, it is demonstrated that sequence-based replication is consistently more powerful. However, the power gain is small (1) for large-scale studies with thousands of individuals, because a large fraction of causative variant sites can be observed and (2) for small- to medium-scale studies with a few hundred samples, because a large proportion of the locus population attributable risk can be explained by the uncovered variants. Therefore, genotyping can be a temporal solution for replicating genetic studies if stage 1 and 2 samples are drawn from the same population. However, sequence-based replication is advantageous if the stage 1 sample is small or novel variants discovery is also of interest. It is shown that currently attainable levels of sequencing error only minimally affect the comparison, and the advantage of sequence-based replication remains.
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20672374
[ "Experience", "with", "carrier", "screening", "and", "prenatal", "diagnosis", "for", "16", "Ashkenazi", "Jewish", "genetic", "diseases.", "The", "success", "of", "prenatal", "carrier", "screening", "as", "a", "disease", "prevention", "strategy", "in", "the", "Ashkenazi", "Jewish", "(AJ)", "population", "has", "driven", "the", "expansion", "of", "screening", "panels", "as", "disease-causing", "founder", "mutations", "have", "been", "identified.", "However,", "the", "carrier", "frequencies", "of", "many", "of", "these", "mutations", "have", "not", "been", "reported", "in", "large", "AJ", "cohorts.", "We", "determined", "the", "carrier", "frequencies", "of", "over", "100", "mutations", "for", "16", "recessive", "disorders", "in", "the", "New", "York", "metropolitan", "area", "AJ", "population.", "Among", "the", "100%", "AJ-descended", "individuals,", "screening", "for", "16", "disorders", "resulted", "in", "∼1", "in", "3.3", "being", "a", "carrier", "for", "one", "disease", "and", "∼1", "in", "24", "for", "two", "diseases.", "The", "carrier", "frequencies", "ranged", "from", "0.066", "(1", "in", "15.2;", "Gaucher", "disease)", "to", "0.006", "(1", "in", "168;", "nemaline", "myopathy),", "which", "averaged", "∼15%", "higher", "than", "those", "for", "all", "screenees.", "Importantly,", "over", "95%", "of", "screenees", "chose", "to", "be", "screened", "for", "all", "possible", "AJ", "diseases,", "including", "disorders", "with", "lower", "carrier", "frequencies", "and/or", "detectability.", "Carrier", "screening", "also", "identified", "rare", "individuals", "homozygous", "for", "disease-causing", "mutations", "who", "had", "previously", "unrecognized", "clinical", "manifestations.", "Additionally,", "prenatal", "testing", "results", "and", "experience", "for", "all", "16", "disorders", "(n", "=", "574)", "are", "reported.", "Together,", "these", "data", "indicate", "the", "general", "acceptance,", "carrier", "frequencies,", "and", "prenatal", "testing", "results", "for", "an", "expanded", "panel", "of", "16", "diseases", "in", "the", "AJ", "population." ]
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Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases. The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease-causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ-descended individuals, screening for 16 disorders resulted in ∼1 in 3.3 being a carrier for one disease and ∼1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ∼15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease-causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population.
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19268277
[ "Mutations", "in", "SPATA7", " ", "cause", "Leber", "congenital", "amaurosis", "and", "juvenile", "retinitis", "pigmentosa.", "Leber", "congenital", "amaurosis", "(LCA)", "and", "juvenile", "retinitis", "pigmentosa", "(RP)", "are", "the", "most", "common", "hereditary", "causes", "of", "visual", "impairment", "in", "infants", "and", "children.", "Using", "homozygosity", "mapping,", "we", "narrowed", "down", "the", "critical", "region", "of", "the", "LCA3", " ", "locus", "to", "3.8", "Mb", "between", "markers", "D14S1022", "and", "D14S1005.", "By", "direct", "Sanger", "sequencing", "of", "all", "genes", "within", "this", "region,", "we", "found", "a", "homozygous", "nonsense", "mutation", "in", "the", "SPATA7", " ", "gene", "in", "Saudi", "Arabian", "family", "KKESH-060.", "Three", "other", "loss-of-function", "mutations", "were", "subsequently", "discovered", "in", "patients", "with", "LCA", "or", "juvenile", "RP", "from", "distinct", "populations.", "Furthermore,", "we", "determined", "that", "Spata7", " ", "is", "expressed", "in", "the", "mature", "mouse", "retina.", "Our", "findings", "reveal", "another", "human", "visual-disease", "gene", "that", "causes", "LCA", "and", "juvenile", "RP." ]
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Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa. Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are the most common hereditary causes of visual impairment in infants and children. Using homozygosity mapping, we narrowed down the critical region of the LCA3 locus to 3.8 Mb between markers D14S1022 and D14S1005. By direct Sanger sequencing of all genes within this region, we found a homozygous nonsense mutation in the SPATA7 gene in Saudi Arabian family KKESH-060. Three other loss-of-function mutations were subsequently discovered in patients with LCA or juvenile RP from distinct populations. Furthermore, we determined that Spata7 is expressed in the mature mouse retina. Our findings reveal another human visual-disease gene that causes LCA and juvenile RP.
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22623374
[ "Gaucher", "disease", "paradigm:", "From", "ERAD", "to", "comorbidity.", "Mutations", "in", "the", "GBA", "gene,", "encoding", "the", "lysosomal", "acid", "beta-glucocerebrosidase", "(GCase),", "lead", "to", "deficient", "activity", "of", "the", "enzyme", "in", "the", "lysosomes,", "to", "glucosylceramide", "accumulation", "and", "to", "development", "of", "Gaucher", "disease", "(GD).", "More", "than", "280", "mutations", "in", "the", "GBA", "GBA", " ", "gene,", "encoding", "the", "lysosomal", "acid", "beta-glucocerebrosidase", "(", "GCase", "ysosomal", "acid", "beta-glucocerebrosidase", " ", "(GCase),", "lead", "to", "deficient", "activity", "of", "the", "enzyme", "in", "the", "lysosomes,", "to", "glucosylceramide", "accumulation", "and", "to", "development", "of", "Gaucher", "disease", "(GD).", "More", "than", "280", "mutations", "in", "the", "GBA", "gene", "have", "been", "directly", "associated", "with", "GD.", "Mutant", "GCase", "variants", "present", "variable", "levels", "of", "endoplasmic", "reticulum", "(ER)", "retention,", "due", "to", "their", "inability", "to", "correctly", "fold,", "and", "undergo", "ER-associated", "degradation", "(ERAD)", "in", "the", "proteasomes.", "The", "degree", "of", "ER", "retention", "and", "proteasomal", "degradation", "is", "one", "of", "the", "factors", "that", "determine", "GD", "severity.", "In", "the", "present", "review,", "we", "discuss", "ERAD", "of", "mutant", "GCase", "variants", "and", "its", "possible", "consequences", "in", "GD", "patients", "and", "in", "carriers", "of", "GD", "mutations.", "Hum", "Mutat", "33:1398-1407,", "2012.", "©", "2012", "Wiley", "Periodicals,", "Inc." ]
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Gaucher disease paradigm: From ERAD to comorbidity. Mutations in the GBA gene, encoding the lysosomal acid beta-glucocerebrosidase (GCase), lead to deficient activity of the enzyme in the lysosomes, to glucosylceramide accumulation and to development of Gaucher disease (GD). More than 280 mutations in the GBA GBA gene, encoding the lysosomal acid beta-glucocerebrosidase ( GCase ysosomal acid beta-glucocerebrosidase (GCase), lead to deficient activity of the enzyme in the lysosomes, to glucosylceramide accumulation and to development of Gaucher disease (GD). More than 280 mutations in the GBA gene have been directly associated with GD. Mutant GCase variants present variable levels of endoplasmic reticulum (ER) retention, due to their inability to correctly fold, and undergo ER-associated degradation (ERAD) in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity. In the present review, we discuss ERAD of mutant GCase variants and its possible consequences in GD patients and in carriers of GD mutations. Hum Mutat 33:1398-1407, 2012. © 2012 Wiley Periodicals, Inc.
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10577941
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Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia.
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15195659
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Modes of action of HLA-DR susceptibility specificities in multiple sclerosis.
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Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome. The receptors for follitropin ( FSHR follitropin (FSHR), thyrotropin ( TSHR ), and lutropin/chorionic gonadotropin ( LHCGR ) are the members of the glycoprotein hormone ( GPH ) receptors ( GPHR ) family. They present a bipartite structure with a large extracellular amino-terminal domain (ECD), responsible for high-affinity hormone binding, and a carboxyl-terminal serpentine region, implicated in transduction of the activation signal. Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare genetic condition in which human chorionic gonadotropin (hCG) promiscuously stimulates the FSHR during the first trimester of pregnancy. Surprisingly, germline FSHR mutations responsible for the disease have so far been found only in the transmembrane helices of the serpentine region of the FSHR , outside the hormone binding domain. When tested functionally, all mutants were abnormally sensitive to both hCG and thyrotropin (TSH) while displaying constitutive activity. This loss of ligand specificity was attributed to the lowering of an intramolecular barrier of activation rather than to an increase of binding affinity. Here we report the first germline mutation responsible for sOHSS ( c.383C>A , p.Ser128Tyr ), located in the ECD of the FSHR. Contrary to the mutations described previously, the p.Ser128Tyr FSHR . Contrary to the mutations described previously, the p.Ser128Tyr FSHR mutant displayed increase in affinity and sensitivity toward hCG and did not show any constitutive activity, nor promiscuous activation by TSH. Thus, sOHSS can be achieved from different molecular mechanisms involving each functional domains of the FSHR . Based on the structure of the FSHR / FSH complex and site-directed mutagenesis studies, we provide robust molecular models for the GPH / GPHR complexes and we propose a molecular explanation to the binding characteristics of the p.Ser128Tyr mutant.
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11317353
[ "Variable", "expressivity", "and", "mutation", "databases:", "The", "androgen", "receptor", "gene", "mutations", "database.", "For", "over", "50", "years", "genetics", "has", "presumed", "that", "variations", "in", "phenotypic", "expression", "have,", "for", "the", "most", "part,", "been", "the", "result", "of", "alterations", "in", "genotype.", "The", "importance", "and", "value", "of", "mutation", "databases", "has", "been", "based", "on", "the", "premise", "that", "the", "same", "gene", "or", "allelic", "variation", "in", "a", "specific", "gene", "that", "has", "been", "proven", "to", "determine", "a", "specific", "phenotype,", "will", "always", "produce", "the", "same", "phenotype.", "However,", "recent", "evidence", "has", "shown", "that", "so", "called", "\"simple\"", "Mendelian", "disorders", "or", "monogenic", "traits", "are", "often", "far", "from", "simple,", "exhibiting", "phenotypic", "variation", "(variable", "expressivity)", "that", "cannot", "be", "explained", "solely", "by", "a", "gene", "or", "allelic", "alteration.", "The", "AR", " ", "gene", "mutations", "database", "now", "lists", "25", "cases", "where", "different", "degrees", "of", "androgen", "insensitivity", "are", "caused", "by", "identical", "mutations", "in", "the", "androgen", "receptor", "gene", ".", "In", "five", "of", "these", "cases", "the", "phenotypic", "variability", "is", "due", "to", "somatic", "mosaicism,", "that", "is,", "somatic", "mutations", "that", "occur", "in", "only", "certain", "cells", "of", "androgen-sensitive", "tissue.", "Recently,", "a", "number", "of", "other", "cases", "of", "variable", "expressivity", "have", "also", "been", "linked", "to", "somatic", "mosaicism.", "The", "impact", "of", "variable", "expressivity", "due", "to", "somatic", "mutations", "and", "mosaicism", "on", "mutation", "databases", "is", "discussed.", "In", "particular,", "the", "effect", "of", "an", "organism", "exhibiting", "genetic", "heterogeneity", "within", "its", "tissues,", "and", "the", "possibility", "of", "an", "organism's", "genotype", "changing", "over", "its", "lifetime,", "are", "considered", "to", "have", "important", "implications", "for", "mutation", "databases", "in", "the", "future." ]
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Variable expressivity and mutation databases: The androgen receptor gene mutations database. For over 50 years genetics has presumed that variations in phenotypic expression have, for the most part, been the result of alterations in genotype. The importance and value of mutation databases has been based on the premise that the same gene or allelic variation in a specific gene that has been proven to determine a specific phenotype, will always produce the same phenotype. However, recent evidence has shown that so called "simple" Mendelian disorders or monogenic traits are often far from simple, exhibiting phenotypic variation (variable expressivity) that cannot be explained solely by a gene or allelic alteration. The AR gene mutations database now lists 25 cases where different degrees of androgen insensitivity are caused by identical mutations in the androgen receptor gene . In five of these cases the phenotypic variability is due to somatic mosaicism, that is, somatic mutations that occur in only certain cells of androgen-sensitive tissue. Recently, a number of other cases of variable expressivity have also been linked to somatic mosaicism. The impact of variable expressivity due to somatic mutations and mosaicism on mutation databases is discussed. In particular, the effect of an organism exhibiting genetic heterogeneity within its tissues, and the possibility of an organism's genotype changing over its lifetime, are considered to have important implications for mutation databases in the future.
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9452048
[ "Identification", "of", "three", "novel", "mutations", "in", "the", "CFTR", " ", "gene,", "R117P", ",", "deltaD192", ",", "and", "3121-1G-->A", " ", "in", "four", "French", "patients." ]
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Identification of three novel mutations in the CFTR gene, R117P , deltaD192 , and 3121-1G-->A in four French patients.
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9222768
[ "Novel", "mutation", "(", "A141D", ")", "in", "exon", "4", "of", "the", "CFTR", " ", "gene", "identified", "in", "an", "Algerian", "patient." ]
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Novel mutation ( A141D ) in exon 4 of the CFTR gene identified in an Algerian patient.
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17503325
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Red-green color vision impairment in Duchenne muscular dystrophy. The present study evaluated the color vision of 44 patients with Duchenne muscular dystrophy (DMD) (mean age 14.8 years; SD 4.9) who were submitted to a battery of four different color tests: Cambridge Colour Test (CCT), Neitz Anomaloscope, Ishihara, and American Optical Hardy-Rand-Rittler (AO H-R-R). Patients were divided into two groups according to the region of deletion in the dystrophin gene: upstream of exon 30 (n=12) and downstream of exon 30 (n=32). The control group was composed of 70 age-matched healthy male subjects with no ophthalmological complaints. Of the patients with DMD, 47% (21/44) had a red-green color vision defect in the CCT, confirmed by the Neitz Anomaloscope with statistical agreement (P<.001). The Ishihara and the AO H-R-R had a lower capacity to detect color defects--5% and 7%, respectively, with no statistical similarity between the results of these two tests nor between CCT and Anomaloscope results (P>.05). Of the patients with deletion downstream of exon 30, 66% had a red-green color defect. No color defect was found in the patients with deletion upstream of exon 30. A negative correlation between the color thresholds and age was found for the controls and patients with DMD, suggesting a nonprogressive color defect. The percentage (66%) of patients with a red-green defect was significantly higher than the expected <10% for the normal male population (P<.001). In contrast, patients with DMD with deletion upstream of exon 30 had normal color vision. This color defect might be partially explained by a retina impairment related to dystrophin isoform Dp260.
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