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22444671
[ "Mutations", "in", "the", "glycosylphosphatidylinositol", "gene", "PIGL", "glycosylphosphatidylinositol", " ", "gene", "PIGL", "cause", "CHIME", "syndrome.", "CHIME", "syndrome", "is", "characterized", "by", "colobomas,", "heart", "defects,", "ichthyosiform", "dermatosis,", "mental", "retardation", "(intellectual", "disability),", "and", "ear", "anomalies,", "including", "conductive", "hearing", "loss.", "Whole-exome", "sequencing", "on", "five", "previously", "reported", "cases", "identified", "PIGL", ",", "the", "de-N-acetylase", "required", "for", "glycosylphosphatidylinositol", "(GPI)", "anchor", "formation,", "as", "a", "strong", "candidate.", "Furthermore,", "cell", "lines", "derived", "from", "these", "cases", "had", "significantly", "reduced", "levels", "of", "the", "two", "GPI", "anchor", "markers,", "CD59", " ", "and", "a", "GPI-binding", "toxin,", "aerolysin", "(FLAER),", "confirming", "the", "pathogenicity", "of", "the", "mutations." ]
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Mutations in the glycosylphosphatidylinositol gene PIGL glycosylphosphatidylinositol gene PIGL cause CHIME syndrome. CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL , the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations.
18252226
[ "Acetylcholine", "receptor", "pathway", "mutations", "explain", "various", "fetal", "akinesia", "deformation", "sequence", "disorders.", "Impaired", "fetal", "movement", "causes", "malformations,", "summarized", "as", "fetal", "akinesia", "deformation", "sequence", "(FADS),", "and", "is", "triggered", "by", "environmental", "and", "genetic", "factors.", "Acetylcholine", "receptor", " ", "(", "AChR", ")", "components", "are", "suspects", "because", "mutations", "in", "the", "fetally", "expressed", "gamma", "subunit", "(", "CHRNG", ")", "of", "AChR", " ", "were", "found", "in", "two", "FADS", "disorders,", "lethal", "multiple", "pterygium", "syndrome", "(LMPS)", "and", "Escobar", "syndrome.", "Other", "AChR", " ", "subunits", "alpha1,", "beta1,", "and", "delta", "(", "CHRNA1", ",", "CHRNB1", ",", "CHRND", ")", "as", "well", "as", "receptor-associated", "protein", "of", "the", "synapse", "(", "RAPSN", ")", "previously", "revealed", "missense", "or", "compound", "nonsense-missense", "mutations", "in", "viable", "congenital", "myasthenic", "syndrome;", "lethality", "of", "homozygous", "null", "mutations", "was", "predicted", "but", "never", "shown.", "We", "provide", "the", "first", "report", "to", "our", "knowledge", "of", "homozygous", "nonsense", "mutations", "in", "CHRNA1", " ", "and", "CHRND", " ", "and", "show", "that", "they", "were", "lethal,", "whereas", "novel", "recessive", "missense", "mutations", "in", "RAPSN", " ", "caused", "a", "severe", "but", "not", "necessarily", "lethal", "phenotype.", "To", "elucidate", "disease-associated", "malformations", "such", "as", "frequent", "abortions,", "fetal", "edema,", "cystic", "hygroma,", "or", "cardiac", "defects,", "we", "studied", "Chrna1", ",", "Chrnb1", ",", "Chrnd", ",", "Chrng", ",", "and", "Rapsn", " ", "in", "mouse", "embryos", "and", "found", "expression", "in", "skeletal", "muscles", "but", "also", "in", "early", "somite", "development.", "This", "indicates", "that", "early", "developmental", "defects", "might", "be", "due", "to", "somite", "expression", "in", "addition", "to", "solely", "muscle-specific", "effects.", "We", "conclude", "that", "complete", "or", "severe", "functional", "disruption", "of", "fetal", "AChR", " ", "causes", "lethal", "multiple", "pterygium", "syndrome", "whereas", "milder", "alterations", "result", "in", "fetal", "hypokinesia", "with", "inborn", "contractures", "or", "a", "myasthenic", "syndrome", "later", "in", "life." ]
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Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor ( AChR ) components are suspects because mutations in the fetally expressed gamma subunit ( CHRNG ) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta ( CHRNA1 , CHRNB1 , CHRND ) as well as receptor-associated protein of the synapse ( RAPSN ) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1 , Chrnb1 , Chrnd , Chrng , and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.
8328456
[ "Anticipation", "in", "bipolar", "affective", "disorder.", "Anticipation", "refers", "to", "the", "increase", "in", "disease", "severity", "or", "decrease", "in", "age", "at", "onset", "in", "succeeding", "generations.", "This", "phenomenon,", "formerly", "ascribed", "to", "observation", "biases,", "correlates", "with", "the", "expansion", "of", "trinucleotide", "repeat", "sequences", "(TNRs)", "in", "some", "disorders.", "If", "present", "in", "bipolar", "affective", "disorder", "(", "BPAD", "),", "anticipation", "could", "provide", "clues", "to", "its", "genetic", "etiology.", "We", "compared", "age", "at", "onset", "and", "disease", "severity", "between", "two", "generations", "of", "34", "unilineal", "families", "ascertained", "for", "a", "genetic", "linkage", "study", "of", "BPAD", ".", "Life-table", "analyses", "showed", "a", "significant", "decrease", "in", "survival", "to", "first", "mania", "or", "depression", "from", "the", "first", "to", "the", "second", "generation", "(P", "<", ".001).", "Intergenerational", "pairwise", "comparisons", "showed", "both", "a", "significantly", "earlier", "age", "at", "onset", "(P", "<", ".001)", "and", "a", "significantly", "increased", "disease", "severity", "(P", "<", ".001)", "in", "the", "second", "generation.", "This", "difference", "was", "significant", "under", "each", "of", "four", "data-sampling", "schemes", "which", "excluded", "probands", "in", "the", "second", "generation.", "The", "second", "generation", "experienced", "onset", "8.9-13.5", "years", "earlier", "and", "illness", "1.8-3.4", "times", "more", "severe", "than", "did", "the", "first", "generation.", "In", "additional", "analyses,", "drug", "abuse,", "deaths", "of", "affected", "individuals", "prior", "to", "interview,", "decreased", "fertility,", "censoring", "of", "age", "at", "onset,", "and", "the", "cohort", "effect", "did", "not", "affect", "our", "results.", "We", "conclude", "that", "genetic", "anticipation", "occurs", "in", "this", "sample", "of", "unilineal", "BPAD", " ", "families.", "These", "findings", "may", "implicate", "genes", "with", "expanding", "TNRs", "in", "the", "genetic", "etiology", "of", "BPAD", "." ]
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Anticipation in bipolar affective disorder. Anticipation refers to the increase in disease severity or decrease in age at onset in succeeding generations. This phenomenon, formerly ascribed to observation biases, correlates with the expansion of trinucleotide repeat sequences (TNRs) in some disorders. If present in bipolar affective disorder ( BPAD ), anticipation could provide clues to its genetic etiology. We compared age at onset and disease severity between two generations of 34 unilineal families ascertained for a genetic linkage study of BPAD . Life-table analyses showed a significant decrease in survival to first mania or depression from the first to the second generation (P < .001). Intergenerational pairwise comparisons showed both a significantly earlier age at onset (P < .001) and a significantly increased disease severity (P < .001) in the second generation. This difference was significant under each of four data-sampling schemes which excluded probands in the second generation. The second generation experienced onset 8.9-13.5 years earlier and illness 1.8-3.4 times more severe than did the first generation. In additional analyses, drug abuse, deaths of affected individuals prior to interview, decreased fertility, censoring of age at onset, and the cohort effect did not affect our results. We conclude that genetic anticipation occurs in this sample of unilineal BPAD families. These findings may implicate genes with expanding TNRs in the genetic etiology of BPAD .
9718346
[ "A", "gene", "involved", "in", "XY", "sex", "reversal", "is", "located", "on", "chromosome", "9,", "distal", "to", "marker", "D9S1779.", "The", "genetic", "mechanisms", "involved", "in", "sex", "differentiation", "are", "poorly", "understood,", "and", "progress", "in", "identification", "of", "the", "genes", "involved", "has", "been", "slow.", "The", "fortuitous", "finding", "of", "chromosomal", "rearrangements", "in", "association", "with", "a", "sex-reversed", "phenotype", "has", "led", "to", "the", "isolation", "of", "SRY", " ", "and", "SOX9,", " ", "both", "shown", "to", "be", "involved", "in", "the", "sex-determining", "pathway.", "In", "addition,", "duplications", "of", "the", "X", "chromosome,", "deletions", "of", "chromosomes", "9", "and", "10,", "and", "translocations", "involving", "chromosome", "17", "have", "been", "reported", "to", "be", "associated", "with", "abnormal", "testicular", "differentiation,", "leading", "to", "male-to-female", "sex", "reversal", "in", "46,XY", "individuals.", "We", "present", "the", "cytogenetic", "and", "molecular", "analyses", "of", "four", "sex-reversed", "XY", "females,", "each", "with", "gonadal", "dysgenesis", "and", "other", "variable", "malformations,", "and", "with", "terminal", "deletions", "of", "distal", "chromosome", "9p,", "resulting", "from", "unbalanced", "autosomal", "translocations.", "PCR", "amplification", "and", "DNA", "sequence", "analysis", "of", "SRY", " ", "revealed", "no", "mutations", "in", "the", "high-mobility-group", "domain", "(i.e.,", "HMG", "box)", "in", "any", "of", "the", "four", "patients.", "Conventional", "and", "molecular", "cytogenetic", "analyses", "of", "metaphase", "chromosomes", "from", "each", "patient", "suggest", "that", "the", "smallest", "region", "of", "overlap", "(SRO)", "of", "deletions", "involves", "a", "very", "small", "region", "of", "distal", "band", "9p24.", "Loss-of-heterozygosity", "studies", "using", "17", "highly", "polymorphic", "microsatellite", "markers,", "as", "well", "as", "FISH", "using", "YAC", "clones", "corresponding", "to", "the", "most", "distal", "markers", "on", "9p,", "showed", "that", "the", "SRO", "lies", "distal", "to", "marker", "D9S1779.", "These", "results", "significantly", "narrow", "the", "putative", "sex-determining", "gene", "to", "the", "very", "terminal", "region", "of", "the", "short", "arm", "of", "chromosome", "9." ]
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A gene involved in XY sex reversal is located on chromosome 9, distal to marker D9S1779. The genetic mechanisms involved in sex differentiation are poorly understood, and progress in identification of the genes involved has been slow. The fortuitous finding of chromosomal rearrangements in association with a sex-reversed phenotype has led to the isolation of SRY and SOX9, both shown to be involved in the sex-determining pathway. In addition, duplications of the X chromosome, deletions of chromosomes 9 and 10, and translocations involving chromosome 17 have been reported to be associated with abnormal testicular differentiation, leading to male-to-female sex reversal in 46,XY individuals. We present the cytogenetic and molecular analyses of four sex-reversed XY females, each with gonadal dysgenesis and other variable malformations, and with terminal deletions of distal chromosome 9p, resulting from unbalanced autosomal translocations. PCR amplification and DNA sequence analysis of SRY revealed no mutations in the high-mobility-group domain (i.e., HMG box) in any of the four patients. Conventional and molecular cytogenetic analyses of metaphase chromosomes from each patient suggest that the smallest region of overlap (SRO) of deletions involves a very small region of distal band 9p24. Loss-of-heterozygosity studies using 17 highly polymorphic microsatellite markers, as well as FISH using YAC clones corresponding to the most distal markers on 9p, showed that the SRO lies distal to marker D9S1779. These results significantly narrow the putative sex-determining gene to the very terminal region of the short arm of chromosome 9.
7977348
[ "Familial", "site-specific", "ovarian", "cancer", "is", "linked", "to", "BRCA1", " ", "on", "17q12-21.", "In", "a", "study", "of", "nine", "families", "with", "\"site-specific\"", "ovarian", "cancer", "(criterion:", "three", "or", "more", "cases", "of", "epithelial", "ovarian", "cancer", "and", "no", "cases", "of", "breast", "cancer", "diagnosed", "at", "age", "<", "50", "years)", "we", "have", "obtained", "evidence", "of", "linkage", "to", "the", "breast-ovarian", "cancer", "susceptibility", "gene,", "BRCA1", " ", "on", "17q12-21.", "If", "the", "risk", "of", "cancer", "in", "these", "families", "is", "assumed", "to", "be", "restricted", "to", "the", "ovary,", "the", "best", "estimate", "of", "the", "proportion", "of", "families", "linked", "to", "BRCA1", " ", "is", ".78", "(95%", "confidence", "interval", ".32-1.0).", "If", "predisposition", "to", "both", "breast", "and", "ovarian", "cancer", "is", "assumed,", "the", "proportion", "linked", "is", "1.0", "(95%", "confidence", "interval", ".46-1.0).", "The", "linkage", "of", "familial", "site-specific", "ovarian", "cancer", "to", "BRCA1", " ", "indicates", "the", "possibility", "of", "predictive", "testing", "in", "such", "families;", "however,", "this", "is", "only", "appropriate", "in", "families", "where", "the", "evidence", "for", "linkage", "to", "BRCA1", " ", "is", "conclusive." ]
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Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. In a study of nine families with "site-specific" ovarian cancer (criterion: three or more cases of epithelial ovarian cancer and no cases of breast cancer diagnosed at age < 50 years) we have obtained evidence of linkage to the breast-ovarian cancer susceptibility gene, BRCA1 on 17q12-21. If the risk of cancer in these families is assumed to be restricted to the ovary, the best estimate of the proportion of families linked to BRCA1 is .78 (95% confidence interval .32-1.0). If predisposition to both breast and ovarian cancer is assumed, the proportion linked is 1.0 (95% confidence interval .46-1.0). The linkage of familial site-specific ovarian cancer to BRCA1 indicates the possibility of predictive testing in such families; however, this is only appropriate in families where the evidence for linkage to BRCA1 is conclusive.
9245996
[ "The", "seventh", "form", "of", "autosomal", "recessive", "limb-girdle", "muscular", "dystrophy", "is", "mapped", "to", "17q11-12.", "The", "group", "of", "autosomal", "recessive", "(AR)", "muscular", "dystrophies", "includes,", "among", "others,", "two", "main", "clinical", "entities,", "the", "limb-girdle", "muscular", "dystrophies", "(LGMDs)", "and", "the", "distal", "muscular", "dystrophies.", "The", "former", "are", "characterized", "mainly", "by", "muscle", "wasting", "of", "the", "upper", "and", "lower", "limbs,", "with", "a", "wide", "range", "of", "clinical", "severity.", "This", "clinical", "heterogeneity", "has", "been", "demonstrated", "at", "the", "molecular", "level,", "since", "the", "genes", "for", "six", "AR", "forms", "have", "been", "cloned", "and/or", "have", "been", "mapped", "to", "15q15.1", "(LGMD2A),", " ", "2p12-16", "(LGMD2B),", " ", "13q12", "(LGMD2C),", " ", "17q12-q21.33", "(LGMD2D),4q12", " ", "(LGMD2E),", " ", "and", "5q33-34", "(LGMD2F).", " ", "The", "AR", "distal", "muscular", "dystrophies", "originally", "included", "two", "subgroups,", "Miyoshi", "myopathy,", "characterized", "mainly", "by", "extremely", "elevated", "serum", "creatine", "kinase", "(CK)", "activity", "and", "by", "a", "dystrophic", "muscle", "pattern,", "and", "Nonaka", "myopathy,", "which", "is", "distinct", "from", "the", "others", "because", "of", "the", "normal", "to", "slightly", "elevated", "serum", "CK", "levels", "and", "a", "myopathic", "muscle", "pattern", "with", "rimmed", "vacuoles.", "With", "regard", "to", "our", "unclassified", "AR", "LGMD", "families,", "analysis", "of", "the", "affected", "sibs", "from", "one", "of", "them", "(family", "LG61)", "revealed", "some", "clinical", "and", "laboratory", "findings", "(early", "involvement", "of", "the", "distal", "muscles,", "mildly", "elevated", "serum", "CK", "levels,", "and", "rimmed", "vacuoles", "in", "muscle", "biopsies)", "that", "usually", "are", "not", "observed", "in", "the", "analysis", "of", "patients", "with", "LGMD2A-LGMD2F.", "In", "the", "present", "investigation,", "through", "a", "genomewide", "search", "in", "family", "LG61,", "we", "demonstrated", "linkage", "of", "the", "allele", "causing", "this", "form", "of", "muscular", "dystrophy", "to", "a", "3-cM", "region", "on", "17q11-12.", "We", "suggest", "that", "this", "form,", "which,", "interestingly,", "clinically", "resembles", "AR", "Kugelberg-Welander", "disease,", "should", "be", "classified", "as", "LGMD2G.", " ", "In", "addition,", "our", "results", "indicate", "the", "existence", "of", "still", "another", "locus", "causing", "severe", "LGMD." ]
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The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12. The group of autosomal recessive (AR) muscular dystrophies includes, among others, two main clinical entities, the limb-girdle muscular dystrophies (LGMDs) and the distal muscular dystrophies. The former are characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. This clinical heterogeneity has been demonstrated at the molecular level, since the genes for six AR forms have been cloned and/or have been mapped to 15q15.1 (LGMD2A), 2p12-16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D),4q12 (LGMD2E), and 5q33-34 (LGMD2F). The AR distal muscular dystrophies originally included two subgroups, Miyoshi myopathy, characterized mainly by extremely elevated serum creatine kinase (CK) activity and by a dystrophic muscle pattern, and Nonaka myopathy, which is distinct from the others because of the normal to slightly elevated serum CK levels and a myopathic muscle pattern with rimmed vacuoles. With regard to our unclassified AR LGMD families, analysis of the affected sibs from one of them (family LG61) revealed some clinical and laboratory findings (early involvement of the distal muscles, mildly elevated serum CK levels, and rimmed vacuoles in muscle biopsies) that usually are not observed in the analysis of patients with LGMD2A-LGMD2F. In the present investigation, through a genomewide search in family LG61, we demonstrated linkage of the allele causing this form of muscular dystrophy to a 3-cM region on 17q11-12. We suggest that this form, which, interestingly, clinically resembles AR Kugelberg-Welander disease, should be classified as LGMD2G. In addition, our results indicate the existence of still another locus causing severe LGMD.
10762557
[ "Complement", "factor", "H", " ", "gene", "mutation", "associated", "with", "autosomal", "recessive", "atypical", "hemolytic", "uremic", "syndrome." ]
[ 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.
20598277
[ "Terminal", "osseous", "dysplasia", "is", "caused", "by", "a", "single", "recurrent", "mutation", "in", "the", "FLNA", " ", "gene.", "Terminal", "osseous", "dysplasia", "(TOD)", "is", "an", "X-linked", "dominant", "male-lethal", "disease", "characterized", "by", "skeletal", "dysplasia", "of", "the", "limbs,", "pigmentary", "defects", "of", "the", "skin,", "and", "recurrent", "digital", "fibroma", "with", "onset", "in", "female", "infancy.", "After", "performing", "X-exome", "capture", "and", "sequencing,", "we", "identified", "a", "mutation", "at", "the", "last", "nucleotide", "of", "exon", "31", "of", "the", "FLNA", " ", "gene", "as", "the", "most", "likely", "cause", "of", "the", "disease.", "The", "variant", "c.5217G>A", " ", "was", "found", "in", "six", "unrelated", "cases", "(three", "families", "and", "three", "sporadic", "cases)", "and", "was", "not", "found", "in", "400", "control", "X", "chromosomes,", "pilot", "data", "from", "the", "1000", "Genomes", "Project,", "or", "the", "FLNA", " ", "gene", "variant", "database.", "In", "the", "families,", "the", "variant", "segregated", "with", "the", "disease,", "and", "it", "was", "transmitted", "four", "times", "from", "a", "mildly", "affected", "mother", "to", "a", "more", "seriously", "affected", "daughter.", "We", "show", "that,", "because", "of", "nonrandom", "X", "chromosome", "inactivation,", "the", "mutant", "allele", "was", "not", "expressed", "in", "patient", "fibroblasts.", "RNA", "expression", "of", "the", "mutant", "allele", "was", "detected", "only", "in", "cultured", "fibroma", "cells", "obtained", "from", "15-year-old", "surgically", "removed", "material.", "The", "variant", "activates", "a", "cryptic", "splice", "site,", "removing", "the", "last", "48", "nucleotides", "from", "exon", "31.", "At", "the", "protein", "level,", "this", "results", "in", "a", "loss", "of", "16", "amino", "acids", "(", "p.Val1724_Thr1739del", "),", "predicted", "to", "remove", "a", "sequence", "at", "the", "surface", "of", "filamin", "repeat", "15.", "Our", "data", "show", "that", "TOD", "is", "caused", "by", "this", "single", "recurrent", "mutation", "in", "the", "FLNA", " ", "gene." ]
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Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids ( p.Val1724_Thr1739del ), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene.
1363805
[ "Mutations", "in", "the", "medium", "chain", "acyl-CoA", "dehydrogenase", "(", "MCAD", "medium", "chain", "acyl-CoA", "dehydrogenase", " ", "(MCAD)", "gene.", "Medium", "chain", "acyl-CoA", "dehydrogenase", "(", "MCAD", "Medium", "chain", "acyl-CoA", "dehydrogenase", " ", "(MCAD)", "catalyzes", "the", "first", "reaction", "of", "the", "beta-oxidation", "cycle", "for", "4-10-carbon", "fatty", "acids.", "MCAD", " ", "deficiency", "is", "one", "of", "the", "most", "frequent", "inborn", "metabolic", "disorders", "in", "populations", "of", "northwestern", "European", "origin.", "In", "the", "compilation", "of", "data", "from", "a", "worldwide", "study", "of", "172", "unrelated", "patients", "each", "representing", "an", "independent", "pedigree,", "a", "total", "of", "8", "different", "mutations", "have", "been", "identified.", "Among", "them,", "a", "single", "prevalent", "mutation,", "985A-->G,", "was", "found", "in", "90%", "of", "344", "variant", "alleles.", "985A-->G", " ", "causes", "glutamate", "substitution", "for", "lysine-304", " ", "in", "the", "mature", "MCAD", "subunit,", "which", "causes", "impairment", "of", "tetramer", "assembly", "and", "instability", "of", "the", "protein.", "Three", "of", "7", "rarer", "mutations", "have", "been", "identified", "in", "a", "few", "unrelated", "patients,", "while", "the", "remaining", "4", "have", "each", "been", "found", "in", "only", "a", "single", "pedigree.", "In", "addition", "to", "tabulating", "the", "mutations,", "the", "acyl-CoA", "dehydrogenase", "gene", "family,", "the", "structure", "of", "the", "MCAD", "gene", "and", "the", "evolution", "of", "985A-->G", "MCAD", "acyl-CoA", "dehydrogenase", "985A-->G", ",", "was", "found", "in", "90%", "of", "344", "variant", "alleles.", "985A-->G", "causes", "glutamate", "substitution", "for", "lysine-304", "in", "the", "mature", "MCAD", "subunit,", "which", "causes", "impairment", "of", "tetramer", "assembly", "and", "instability", "of", "the", "protein.", "Three", "of", "7", "rarer", "mutations", "have", "been", "identified", "in", "a", "few", "unrelated", "patients,", "while", "the", "remaining", "4", "have", "each", "been", "found", "in", "only", "a", "single", "pedigree.", "In", "addition", "to", "tabulating", "the", "mutations,", "the", "acyl-CoA", "dehydrogenase", "gene", "family,", "the", "structure", "of", "the", "MCAD", "gene", "and", "the", "evolution", "of", "985A-->G", "mutation", "are", "briefly", "discussed." ]
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Mutations in the medium chain acyl-CoA dehydrogenase ( MCAD medium chain acyl-CoA dehydrogenase (MCAD) gene. Medium chain acyl-CoA dehydrogenase ( MCAD Medium chain acyl-CoA dehydrogenase (MCAD) catalyzes the first reaction of the beta-oxidation cycle for 4-10-carbon fatty acids. MCAD deficiency is one of the most frequent inborn metabolic disorders in populations of northwestern European origin. In the compilation of data from a worldwide study of 172 unrelated patients each representing an independent pedigree, a total of 8 different mutations have been identified. Among them, a single prevalent mutation, 985A-->G, was found in 90% of 344 variant alleles. 985A-->G causes glutamate substitution for lysine-304 in the mature MCAD subunit, which causes impairment of tetramer assembly and instability of the protein. Three of 7 rarer mutations have been identified in a few unrelated patients, while the remaining 4 have each been found in only a single pedigree. In addition to tabulating the mutations, the acyl-CoA dehydrogenase gene family, the structure of the MCAD gene and the evolution of 985A-->G MCAD acyl-CoA dehydrogenase 985A-->G , was found in 90% of 344 variant alleles. 985A-->G causes glutamate substitution for lysine-304 in the mature MCAD subunit, which causes impairment of tetramer assembly and instability of the protein. Three of 7 rarer mutations have been identified in a few unrelated patients, while the remaining 4 have each been found in only a single pedigree. In addition to tabulating the mutations, the acyl-CoA dehydrogenase gene family, the structure of the MCAD gene and the evolution of 985A-->G mutation are briefly discussed.
18752264
[ "Ethnically", "diverse", "causes", "of", "Walker-Warburg", "syndrome", "(WWS):", "FCMD", "mutations", "are", "a", "more", "common", "cause", "of", "WWS", "outside", "of", "the", "Middle", "East.", "Walker-Warburg", "syndrome", "(WWS)", "is", "a", "genetically", "heterogeneous", "autosomal", "recessive", "disease", "characterized", "by", "congenital", "muscular", "dystrophy,", "cobblestone", "lissencephaly,", "and", "ocular", "malformations.", "Mutations", "in", "six", "genes", "involved", "in", "the", "glycosylation", "of", "á-dystroglycan", "(", "POMT1", ",", "POMT2", ",", "POMGNT1", ",", "FCMD", ",", "FKRP", " ", "and", "LARGE", ")", "have", "been", "identified", "in", "WWS", "patients,", "but", "account", "for", "only", "a", "portion", "of", "WWS", "cases.", "To", "better", "understand", "the", "genetics", "of", "WWS", "and", "establish", "the", "frequency", "and", "distribution", "of", "mutations", "across", "WWS", "genes,", "we", "genotyped", "all", "known", "loci", "in", "a", "cohort", "of", "43", "WWS", "patients", "of", "varying", "geographical", "and", "ethnic", "origin.", "Surprisingly,", "we", "reached", "a", "molecular", "diagnosis", "for", "40%", "of", "our", "patients", "and", "found", "mutations", "in", "POMT1", ",", "POMT2", ",", "FCMD", " ", "and", "FKRP", ",", "many", "of", "which", "were", "novel", "alleles,", "but", "no", "mutations", "in", "POMGNT1", " ", "or", "LARGE", ".", "Notably,", "the", "FCMD", " ", "gene", "was", "a", "more", "common", "cause", "of", "WWS", "than", "previously", "expected", "in", "the", "European/American", "subset", "of", "our", "cohort,", "including", "all", "Ashkenazi", "Jewish", "cases,", "who", "carried", "the", "same", "founder", "mutation." ]
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Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East. Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of á-dystroglycan ( POMT1 , POMT2 , POMGNT1 , FCMD , FKRP and LARGE ) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1 , POMT2 , FCMD and FKRP , many of which were novel alleles, but no mutations in POMGNT1 or LARGE . Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.
9012405
[ "A", "mutation", "in", "the", "XPB/ERCC3", " ", "DNA", "repair", "transcription", "gene,", "associated", "with", "trichothiodystrophy.", "Trichothiodystrophy", "(TTD)", "is", "a", "rare,", "autosomal", "recessive", "disorder", "characterized", "by", "sulfur-deficient", "brittle", "hair", "and", "nails,", "mental", "retardation,", "impaired", "sexual", "development,", "and", "ichthyosis.", "Photosensitivity", "has", "been", "reported", "in", "approximately", "50%", "of", "the", "cases,", "but", "no", "skin", "cancer", "is", "associated", "with", "TTD.", "Virtually", "all", "photosensitive", "TTD", "patients", "have", "a", "deficiency", "in", "the", "nucleotide", "excision", "repair", "(NER)", "of", "UV-induced", "DNA", "damage", "that", "is", "indistinguishable", "from", "that", "of", "xeroderma", "pigmentosum", "(XP)", "complementation", "group", "D", "(XP-D)", "patients.", "DNA", "repair", "defects", "in", "XP-D", "are", "associated", "with", "two", "additional,", "quite", "different", "diseases;", "XP,", "a", "sun-sensitive", "and", "cancer-prone", "repair", "disorder,", "and", "Cockayne", "syndrome", "(CS),", "a", "photosensitive", "condition", "characterized", "by", "physical", "and", "mental", "retardation", "and", "wizened", "facial", "appearance.", "One", "photosensitive", "TTD", "case", "constitutes", "a", "new", "repair-deficient", "complementation", "group,", "TTD-A.", "Remarkably,", "both", "TTD-A", "and", "XP-D", "defects", "are", "associated", "with", "subunits", "of", "TFIIH,", "a", "basal", "transcription", "factor", "with", "a", "second", "function", "in", "DNA", "repair.", "Thus,", "mutations", "in", "TFIIH", "components", "may,", "on", "top", "of", "a", "repair", "defect,", "also", "cause", "transcriptional", "insufficiency,", "which", "may", "explain", "part", "of", "the", "non-XP", "clinical", "features", "of", "TTD.", "Besides", "XPD", "and", "TTDA,", "the", "XPB", " ", "gene", "product", "is", "also", "part", "of", "TFIIH.", "To", "date,", "three", "patients", "with", "the", "remarkable", "conjunction", "of", "XP", "and", "CS", "but", "not", "TTD", "have", "been", "assigned", "to", "XP", "complementation", "group", "B", "(XP-B).", "Here", "we", "present", "the", "characterization", "of", "the", "NER", "defect", "in", "two", "mild", "TTD", "patients", "(TTD6VI", "and", "TTD4VI)", "and", "confirm", "the", "assignment", "to", "X-PB.", "The", "causative", "mutation", "was", "found", "to", "be", "a", "single", "base", "substitution", "resulting", "in", "a", "missense", "mutation", "(", "T119P", ")", "in", "a", "region", "of", "the", "XPB", " ", "protein", "completely", "conserved", "in", "yeast,", "Drosophila,", "mouse,", "and", "man.", "These", "findings", "define", "a", "third", "TTD", "complementation", "group,", "extend", "the", "clinical", "heterogeneity", "associated", "with", "XP-B,", "stress", "the", "exclusive", "relationship", "between", "TTD", "and", "mutations", "in", "subunits", "of", "repair/transcription", "factor", "TFIIH", ",", "and", "strongly", "support", "the", "concept", "of", "\"transcription", "syndromes.\"" ]
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A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation ( T119P ) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH , and strongly support the concept of "transcription syndromes."
17668385
[ "Mutations", "in", "the", "BRWD3", " ", "gene", "cause", "X-linked", "mental", "retardation", "associated", "with", "macrocephaly.", "In", "the", "course", "of", "systematic", "screening", "of", "the", "X-chromosome", "coding", "sequences", "in", "250", "families", "with", "nonsyndromic", "X-linked", "mental", "retardation", "(XLMR),", "two", "families", "were", "identified", "with", "truncating", "mutations", "in", "BRWD3,", " ", "a", "gene", "encoding", "a", "bromodomain", "and", "WD-repeat", "domain-containing", "protein.", "In", "both", "families,", "the", "mutation", "segregates", "with", "the", "phenotype", "in", "affected", "males.", "Affected", "males", "have", "macrocephaly", "with", "a", "prominent", "forehead,", "large", "cupped", "ears,", "and", "mild-to-moderate", "intellectual", "disability.", "No", "truncating", "variants", "were", "found", "in", "520", "control", "X", "chromosomes.", "BRWD3", " ", "is", "therefore", "a", "new", "gene", "implicated", "in", "the", "etiology", "of", "XLMR", "associated", "with", "macrocephaly", "and", "may", "cause", "disease", "by", "altering", "intracellular", "signaling", "pathways", "affecting", "cellular", "proliferation." ]
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Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain-containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation.
21882294
[ "SgD-CNV,", "a", "database", "for", "common", "and", "rare", "copy", "number", "variants", "in", "three", "Asian", "populations.", "Copy", "number", "variants", "(CNVs)", "extend", "our", "understanding", "of", "the", "genetic", "diversity", "in", "humans.", "However,", "the", "distribution", "and", "characteristics", "of", "CNVs", "in", "Asian", "populations", "remain", "largely", "unexplored,", "especially", "for", "rare", "CNVs", "that", "have", "emerged", "as", "important", "genetic", "factors", "for", "complex", "traits.", "In", "the", "present", "study,", "we", "performed", "an", "in-depth", "investigation", "of", "common", "and", "rare", "CNVs", "across", "8,148", "individuals", "from", "the", "three", "major", "Asian", "ethnic", "groups:", "Chinese", "(n", "=", "1,945),", "Malays", "(n", "=", "2,399),", "and", "Indians", "(n", "=", "2,217)", "in", "Singapore,", "making", "this", "investigation", "the", "most", "comprehensive", "genome-wide", "survey", "of", "CNVs", "outside", "the", "European-ancestry", "populations", "to", "date.", "We", "detected", "about", "16", "CNVs", "per", "individual", "and", "the", "ratio", "of", "loss", "to", "gain", "events", "is", "∼2:1.", "The", "majority", "of", "the", "CNVs", "are", "of", "low", "frequency", "(<10%),", "and", "40%", "are", "rare", "(<1%).", "In", "each", "population,", "∼20%", "of", "the", "CNVs", "are", "not", "previously", "catalogued", "in", "the", "Database", "of", "Genomic", "Variants", "(DGV).", "Contrary", "to", "findings", "from", "European", "studies,", "the", "common", "CNVs", "(>5%)", "in", "our", "populations", "are", "not", "well", "tagged", "by", "SNPs", "in", "Illumina", "1M", "and", "610K", "arrays,", "and", "most", "disease-associated", "common", "CNVs", "previously", "reported", "in", "Caucasians", "are", "rare", "in", "our", "populations.", "We", "also", "report", "noticeable", "population", "differentiation", "in", "the", "CNV", "landscape", "of", "these", "Asian", "populations,", "with", "the", "greatest", "diversity", "seen", "between", "the", "Indians", "and", "the", "Chinese." ]
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SgD-CNV, a database for common and rare copy number variants in three Asian populations. Copy number variants (CNVs) extend our understanding of the genetic diversity in humans. However, the distribution and characteristics of CNVs in Asian populations remain largely unexplored, especially for rare CNVs that have emerged as important genetic factors for complex traits. In the present study, we performed an in-depth investigation of common and rare CNVs across 8,148 individuals from the three major Asian ethnic groups: Chinese (n = 1,945), Malays (n = 2,399), and Indians (n = 2,217) in Singapore, making this investigation the most comprehensive genome-wide survey of CNVs outside the European-ancestry populations to date. We detected about 16 CNVs per individual and the ratio of loss to gain events is ∼2:1. The majority of the CNVs are of low frequency (<10%), and 40% are rare (<1%). In each population, ∼20% of the CNVs are not previously catalogued in the Database of Genomic Variants (DGV). Contrary to findings from European studies, the common CNVs (>5%) in our populations are not well tagged by SNPs in Illumina 1M and 610K arrays, and most disease-associated common CNVs previously reported in Caucasians are rare in our populations. We also report noticeable population differentiation in the CNV landscape of these Asian populations, with the greatest diversity seen between the Indians and the Chinese.
15386213
[ "Statistical", "tests", "for", "admixture", "mapping", "with", "case-control", "and", "cases-only", "data.", "Admixture", "mapping", "is", "a", "promising", "new", "tool", "for", "discovering", "genes", "that", "contribute", "to", "complex", "traits.", "This", "mapping", "approach", "uses", "samples", "from", "recently", "admixed", "populations", "to", "detect", "susceptibility", "loci", "at", "which", "the", "risk", "alleles", "have", "different", "frequencies", "in", "the", "original", "contributing", "populations.", "Although", "the", "idea", "for", "admixture", "mapping", "has", "been", "around", "for", "more", "than", "a", "decade,", "the", "genomic", "tools", "are", "only", "now", "becoming", "available", "to", "make", "this", "a", "feasible", "and", "attractive", "option", "for", "complex-trait", "mapping.", "In", "this", "article,", "we", "describe", "new", "statistical", "methods", "for", "analyzing", "multipoint", "data", "from", "admixture-mapping", "studies", "to", "detect", "\"ancestry", "association.\"", "The", "new", "test", "statistics", "do", "not", "assume", "a", "particular", "disease", "model;", "instead,", "they", "are", "based", "simply", "on", "the", "extent", "to", "which", "the", "sample's", "ancestry", "proportions", "at", "a", "locus", "deviate", "from", "the", "genome", "average.", "Our", "power", "calculations", "show", "that,", "for", "loci", "at", "which", "the", "underlying", "risk-allele", "frequencies", "are", "substantially", "different", "in", "the", "ancestral", "populations,", "the", "power", "of", "admixture", "mapping", "can", "be", "comparable", "to", "that", "of", "association", "mapping", "but", "with", "a", "far", "smaller", "number", "of", "markers.", "We", "also", "show", "that,", "although", "\"ancestry", "informative", "markers\"", "(AIMs)", "are", "superior", "to", "random", "single-nucleotide", "polymorphisms", "(SNPs),", "random", "SNPs", "can", "perform", "quite", "well", "when", "AIMs", "are", "not", "available.", "Hence,", "researchers", "who", "study", "admixed", "populations", "in", "which", "AIMs", "are", "not", "available", "can", "perform", "admixture", "mapping", "with", "the", "use", "of", "modestly", "higher", "densities", "of", "random", "markers.", "Software", "to", "perform", "the", "gene-mapping", "calculations,", "\"MALDsoft,\"", "is", "freely", "available", "on", "the", "Pritchard", "Lab", "Web", "site." ]
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Statistical tests for admixture mapping with case-control and cases-only data. Admixture mapping is a promising new tool for discovering genes that contribute to complex traits. This mapping approach uses samples from recently admixed populations to detect susceptibility loci at which the risk alleles have different frequencies in the original contributing populations. Although the idea for admixture mapping has been around for more than a decade, the genomic tools are only now becoming available to make this a feasible and attractive option for complex-trait mapping. In this article, we describe new statistical methods for analyzing multipoint data from admixture-mapping studies to detect "ancestry association." The new test statistics do not assume a particular disease model; instead, they are based simply on the extent to which the sample's ancestry proportions at a locus deviate from the genome average. Our power calculations show that, for loci at which the underlying risk-allele frequencies are substantially different in the ancestral populations, the power of admixture mapping can be comparable to that of association mapping but with a far smaller number of markers. We also show that, although "ancestry informative markers" (AIMs) are superior to random single-nucleotide polymorphisms (SNPs), random SNPs can perform quite well when AIMs are not available. Hence, researchers who study admixed populations in which AIMs are not available can perform admixture mapping with the use of modestly higher densities of random markers. Software to perform the gene-mapping calculations, "MALDsoft," is freely available on the Pritchard Lab Web site.
10677322
[ "Estimation", "of", "variance", "components", "of", "quantitative", "traits", "in", "inbred", "populations.", "Use", "of", "variance-component", "estimation", "for", "mapping", "of", "quantitative-trait", "loci", "in", "humans", "is", "a", "subject", "of", "great", "current", "interest.", "When", "only", "trait", "values,", "not", "genotypic", "information,", "are", "considered,", "variance-component", "estimation", "can", "also", "be", "used", "to", "estimate", "heritability", "of", "a", "quantitative", "trait.", "Inbred", "pedigrees", "present", "special", "challenges", "for", "variance-component", "estimation.", "First,", "there", "are", "more", "variance", "components", "to", "be", "estimated", "in", "the", "inbred", "case,", "even", "for", "a", "relatively", "simple", "model", "including", "additive,", "dominance,", "and", "environmental", "effects.", "Second,", "more", "identity", "coefficients", "need", "to", "be", "calculated", "from", "an", "inbred", "pedigree", "in", "order", "to", "perform", "the", "estimation,", "and", "these", "are", "computationally", "more", "difficult", "to", "obtain", "in", "the", "inbred", "than", "in", "the", "outbred", "case.", "As", "a", "result,", "inbreeding", "effects", "have", "generally", "been", "ignored", "in", "practice.", "We", "describe", "here", "the", "calculation", "of", "identity", "coefficients", "and", "estimation", "of", "variance", "components", "of", "quantitative", "traits", "in", "large", "inbred", "pedigrees,", "using", "the", "example", "of", "HDL", " ", "in", "the", "Hutterites.", "We", "use", "a", "multivariate", "normal", "model", "for", "the", "genetic", "effects,", "extending", "the", "central-limit", "theorem", "of", "Lange", "to", "allow", "for", "both", "inbreeding", "and", "dominance", "under", "the", "assumptions", "of", "our", "variance-component", "model.", "We", "use", "simulated", "examples", "to", "give", "an", "indication", "of", "under", "what", "conditions", "one", "has", "the", "power", "to", "detect", "the", "additional", "variance", "components", "and", "to", "examine", "their", "impact", "on", "variance-component", "estimation.", "We", "discuss", "the", "implications", "for", "mapping", "and", "heritability", "estimation", "by", "use", "of", "variance", "components", "in", "inbred", "populations." ]
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Estimation of variance components of quantitative traits in inbred populations. Use of variance-component estimation for mapping of quantitative-trait loci in humans is a subject of great current interest. When only trait values, not genotypic information, are considered, variance-component estimation can also be used to estimate heritability of a quantitative trait. Inbred pedigrees present special challenges for variance-component estimation. First, there are more variance components to be estimated in the inbred case, even for a relatively simple model including additive, dominance, and environmental effects. Second, more identity coefficients need to be calculated from an inbred pedigree in order to perform the estimation, and these are computationally more difficult to obtain in the inbred than in the outbred case. As a result, inbreeding effects have generally been ignored in practice. We describe here the calculation of identity coefficients and estimation of variance components of quantitative traits in large inbred pedigrees, using the example of HDL in the Hutterites. We use a multivariate normal model for the genetic effects, extending the central-limit theorem of Lange to allow for both inbreeding and dominance under the assumptions of our variance-component model. We use simulated examples to give an indication of under what conditions one has the power to detect the additional variance components and to examine their impact on variance-component estimation. We discuss the implications for mapping and heritability estimation by use of variance components in inbred populations.
16909392
[ "Navajo", "neurohepatopathy", "is", "caused", "by", "a", "mutation", "in", "the", "MPV17", " ", "gene.", "Navajo", "neurohepatopathy", "(NNH)", "is", "an", "autosomal", "recessive", "disease", "that", "is", "prevalent", "among", "Navajo", "children", "in", "the", "southwestern", "United", "States.", "The", "major", "clinical", "features", "are", "hepatopathy,", "peripheral", "neuropathy,", "corneal", "anesthesia", "and", "scarring,", "acral", "mutilation,", "cerebral", "leukoencephalopathy,", "failure", "to", "thrive,", "and", "recurrent", "metabolic", "acidosis", "with", "intercurrent", "infections.", "Infantile,", "childhood,", "and", "classic", "forms", "of", "NNH", "have", "been", "described.", "Mitochondrial", "DNA", "(mtDNA)", "depletion", "was", "detected", "in", "the", "livers", "of", "two", "patients,", "suggesting", "a", "primary", "defect", "in", "mtDNA", "maintenance.", "Homozygosity", "mapping", "of", "two", "families", "with", "NNH", "suggested", "linkage", "to", "chromosome", "2p24.", "This", "locus", "includes", "the", "MPV17", " ", "gene,", "which,", "when", "mutated,", "causes", "a", "hepatocerebral", "form", "of", "mtDNA", "depletion.", "Sequencing", "of", "the", "MPV17", "gene", "in", "six", "patients", "with", "NNH", "from", "five", "families", "revealed", "the", "homozygous", "R50Q", "MPV17", " ", "gene", "in", "six", "patients", "with", "NNH", "from", "five", "families", "revealed", "the", "homozygous", "R50Q", "mutation", "described", "elsewhere.", "Identification", "of", "a", "single", "missense", "mutation", "in", "patients", "with", "NNH", "confirms", "that", "the", "disease", "is", "probably", "due", "to", "a", "founder", "effect", "and", "extends", "the", "phenotypic", "spectrum", "associated", "with", "MPV17", " ", "mutations." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0 ]
Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Navajo neurohepatopathy (NNH) is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance. Homozygosity mapping of two families with NNH suggested linkage to chromosome 2p24. This locus includes the MPV17 gene, which, when mutated, causes a hepatocerebral form of mtDNA depletion. Sequencing of the MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q mutation described elsewhere. Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations.
8257990
[ "Base", "substitutions", "in", "the", "human", "dystrophin", "gene:", "detection", "by", "using", "the", "single-strand", "conformation", "polymorphism", "(SSCP)", "technique.", "We", "have", "established", "the", "experimental", "conditions", "to", "screen", "twenty", "regions", "of", "the", "dystrophin", "gene", "using", "the", "method", "of", "single-strand", "conformational", "polymorphism", "(SSCP)", "analysis.", "The", "aim", "of", "this", "study", "was", "to", "identify", "point", "mutations", "in", "patients", "with", "Duchenne", "or", "Becker", "muscular", "dystrophy", "(DMD", "or", "BMD)", "who", "have", "no", "gross", "DNA", "rearrangements", "detectable", "by", "Southern", "blot", "analysis", "or", "multiplex", "exon", "amplification.", "The", "investigation", "of", "thirteen", "patients", "using", "this", "procedure", "resulted", "in", "the", "detection", "of", "seven", "sequence", "polymorphisms", "(four", "identified", "in", "this", "study)", "that", "will", "be", "useful", "allelic", "markers", "in", "familial", "DNA", "analysis.", "Three", "rare", "sequence", "variants", "could", "be", "found", "(two", "of", "them", "being", "novel", "variants)", "but", "we", "were", "unable", "to", "demonstrate", "mutations", "that", "could", "be", "clearly", "sufficient", "to", "be", "responsible", "for", "the", "phenotype.", "This", "analysis", "confirmed", "the", "efficiency", "of", "the", "SSCP", "technique", "for", "the", "detection", "of", "nucleotide", "substitutions.", "Application", "of", "this", "approach", "to", "mutation", "or", "polymorphism", "detection", "to", "other", "exons", "of", "the", "gene", "will", "improve", "carrier", "and", "prenatal", "diagnosis." ]
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Base substitutions in the human dystrophin gene: detection by using the single-strand conformation polymorphism (SSCP) technique. We have established the experimental conditions to screen twenty regions of the dystrophin gene using the method of single-strand conformational polymorphism (SSCP) analysis. The aim of this study was to identify point mutations in patients with Duchenne or Becker muscular dystrophy (DMD or BMD) who have no gross DNA rearrangements detectable by Southern blot analysis or multiplex exon amplification. The investigation of thirteen patients using this procedure resulted in the detection of seven sequence polymorphisms (four identified in this study) that will be useful allelic markers in familial DNA analysis. Three rare sequence variants could be found (two of them being novel variants) but we were unable to demonstrate mutations that could be clearly sufficient to be responsible for the phenotype. This analysis confirmed the efficiency of the SSCP technique for the detection of nucleotide substitutions. Application of this approach to mutation or polymorphism detection to other exons of the gene will improve carrier and prenatal diagnosis.
7717407
[ "Human", "T-cell", "receptor", "V", "beta", "gene", "polymorphism", "and", "multiple", "sclerosis.", "Population-based", "genetic", "associations", "have", "been", "reported", "between", "RFLPs", "detected", "with", "probes", "corresponding", "to", "the", "genes", "encoding", "the", "beta", "chain", "of", "the", "T-cell", "receptor", "for", "antigen", "(TCRB)", "and", "a", "variety", "of", "autoimmune", "disorders.", "In", "the", "case", "of", "multiple", "sclerosis", "(MS),", "these", "studies", "have", "localized", "a", "putative", "disease-associated", "gene", "to", "a", "region", "of", "approximately", "110", "kb", "in", "length,", "located", "within", "the", "TCRB", "Human", "T-cell", "receptor", "V", "beta", " ", "gene", "polymorphism", "and", "multiple", "sclerosis.", "Population-based", "genetic", "associations", "have", "been", "reported", "between", "RFLPs", "detected", "with", "probes", "corresponding", "to", "the", "genes", "encoding", "the", "beta", "chain", "of", "the", "T-cell", "receptor", "for", "antigen", "(TCRB)", "and", "a", "variety", "of", "autoimmune", "disorders.", "In", "the", "case", "of", "multiple", "sclerosis", "(MS),", "these", "studies", "have", "localized", "a", "putative", "disease-associated", "gene", "to", "a", "region", "of", "approximately", "110", "kb", "in", "length,", "located", "within", "the", "TCRB", "locus.", "In", "the", "current", "study,", "all", "14", "known", "TCRBV", "(variable", "region)", "genes", "within", "the", "region", "of", "localization", "were", "mapped", "and", "identified.", "The", "nucleotide", "sequences", "of", "these", "genes", "were", "determined", "in", "a", "panel", "of", "six", "MS", "patients", "and", "six", "healthy", "controls,", "who", "were", "human-leukocyte", "antigen", "and", "TCRB-RFLP", "haplotype", "matched.", "Nine", "of", "the", "14", "TCRBV", "genes", "studied", "showed", "evidence", "of", "polymorphism.", "PCR-based", "assays", "for", "each", "of", "these", "polymorphic", "genes", "were", "developed,", "and", "allele", "and", "genotype", "frequencies", "were", "determined", "in", "a", "panel", "of", "DNA", "samples", "from", "48", "MS", "patients", "and", "60", "control", "individuals.", "No", "significant", "differences", "in", "allele,", "genotype,", "or", "phenotype", "frequencies", "were", "observed", "between", "the", "MS", "patients", "and", "controls", "for", "any", "of", "the", "14", "TCRBV-gene", "polymorphisms", "studied.", "In", "light", "of", "the", "extensive", "linkage", "disequilibrium", "across", "the", "region", "studied,", "the", "saturating", "numbers", "of", "polymorphisms", "examined,", "and", "the", "direct", "sequence", "analysis", "of", "all", "BV", "genes", "in", "the", "region,", "these", "results", "suggest", "that", "it", "is", "unlikely", "that", "germ-line", "polymorphism", "in", "the", "TCRBV", "locus", "makes", "a", "major", "contribution", "to", "MS", "susceptibility.(ABSTRACT", "TRUNCATED", "AT", "250", "WORDS)" ]
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Human T-cell receptor V beta gene polymorphism and multiple sclerosis. Population-based genetic associations have been reported between RFLPs detected with probes corresponding to the genes encoding the beta chain of the T-cell receptor for antigen (TCRB) and a variety of autoimmune disorders. In the case of multiple sclerosis (MS), these studies have localized a putative disease-associated gene to a region of approximately 110 kb in length, located within the TCRB Human T-cell receptor V beta gene polymorphism and multiple sclerosis. Population-based genetic associations have been reported between RFLPs detected with probes corresponding to the genes encoding the beta chain of the T-cell receptor for antigen (TCRB) and a variety of autoimmune disorders. In the case of multiple sclerosis (MS), these studies have localized a putative disease-associated gene to a region of approximately 110 kb in length, located within the TCRB locus. In the current study, all 14 known TCRBV (variable region) genes within the region of localization were mapped and identified. The nucleotide sequences of these genes were determined in a panel of six MS patients and six healthy controls, who were human-leukocyte antigen and TCRB-RFLP haplotype matched. Nine of the 14 TCRBV genes studied showed evidence of polymorphism. PCR-based assays for each of these polymorphic genes were developed, and allele and genotype frequencies were determined in a panel of DNA samples from 48 MS patients and 60 control individuals. No significant differences in allele, genotype, or phenotype frequencies were observed between the MS patients and controls for any of the 14 TCRBV-gene polymorphisms studied. In light of the extensive linkage disequilibrium across the region studied, the saturating numbers of polymorphisms examined, and the direct sequence analysis of all BV genes in the region, these results suggest that it is unlikely that germ-line polymorphism in the TCRBV locus makes a major contribution to MS susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)
15372378
[ "A", "mutation", "in", "the", "vesicle-trafficking", "protein", " ", "VAPB", " ", "causes", "late-onset", "spinal", "muscular", "atrophy", "and", "amyotrophic", "lateral", "sclerosis.", "Motor", "neuron", "diseases", "(MNDs)", "are", "a", "group", "of", "neurodegenerative", "disorders", "with", "involvement", "of", "upper", "and/or", "lower", "motor", "neurons,", "such", "as", "amyotrophic", "lateral", "sclerosis", "(ALS),", "spinal", "muscular", "atrophy", "(SMA),", "progressive", "bulbar", "palsy,", "and", "primary", "lateral", "sclerosis.", "Recently,", "we", "have", "mapped", "a", "new", "locus", "for", "an", "atypical", "form", "of", "ALS/MND", "(atypical", "amyotrophic", "lateral", "sclerosis", "[ALS8])", "at", "20q13.3", "in", "a", "large", "white", "Brazilian", "family.", "Here,", "we", "report", "the", "finding", "of", "a", "novel", "missense", "mutation", "in", "the", "vesicle-associated", "membrane", "protein/synaptobrevin-associated", "membrane", "protein", "B", "(", "VAPB", "vesicle-associated", "membrane", "protein/synaptobrevin-associated", "membrane", "protein", "B", " ", "(VAPB)", "gene", "in", "patients", "from", "this", "family.", "Subsequently,", "the", "same", "mutation", "was", "identified", "in", "patients", "from", "six", "additional", "kindreds", "but", "with", "different", "clinical", "courses,", "such", "as", "ALS8,", "late-onset", "SMA,", "and", "typical", "severe", "ALS", "with", "rapid", "progression.", "Although", "it", "was", "not", "possible", "to", "link", "all", "these", "families,", "haplotype", "analysis", "suggests", "a", "founder", "effect.", "Members", "of", "the", "vesicle-associated", "proteins", "are", "intracellular", "membrane", "proteins", "that", "can", "associate", "with", "microtubules", "and", "that", "have", "been", "shown", "to", "have", "a", "function", "in", "membrane", "transport.", "These", "data", "suggest", "that", "clinically", "variable", "MNDs", "may", "be", "caused", "by", "a", "dysfunction", "in", "intracellular", "membrane", "trafficking." ]
[ 0, 0, 0, 0, 1, 2, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 2, 2, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B ( VAPB vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.
12424708
[ "Structural", "and", "functional", "characterization", "of", "factor", "H", "mutations", "associated", "with", "atypical", "hemolytic", "uremic", "syndrome.", "Genetic", "studies", "have", "demonstrated", "the", "involvement", "of", "the", "complement", "regulator", "factor", "H", "in", "nondiarrheal,", "nonverocytotoxin", "(i.e.,", "atypical)", "cases", "of", "hemolytic", "uremic", "syndrome.", "Different", "factor", "H", "factor", "H", " ", "in", "nondiarrheal,", "nonverocytotoxin", "(i.e.,", "atypical)", "cases", "of", "hemolytic", "uremic", "syndrome.", "Different", "factor", "H", "mutations", "have", "been", "identified", "in", "10%-30%", "of", "patients", "with", "atypical", "hemolytic", "uremic", "syndrome", "(aHUS),", "and", "most", "of", "these", "mutations", "alter", "single", "amino", "acids", "in", "the", "C-terminal", "region", "of", "factor", "H", ".", "Although", "these", "mutations", "are", "considered", "to", "be", "responsible", "for", "the", "disease,", "the", "precise", "role", "that", "factor", "H", " ", "plays", "in", "the", "pathogenesis", "of", "aHUS", "is", "unknown.", "We", "report", "here", "the", "structural", "and", "functional", "characterization", "of", "three", "different", "factor", "H", " ", "proteins", "purified", "from", "the", "plasma", "of", "patients", "with", "aHUS", "who", "carry", "the", "factor", "H", "mutations", "W1183L", ",", "V1197A", ",", "or", "R1210C", "factor", "H", " ", "mutations", "W1183L,", "V1197A,", "or", "R1210C.", "Structural", "anomalies", "in", "factor", "H", " ", "were", "found", "only", "in", "R1210C", "carriers;", "these", "individuals", "show,", "in", "their", "plasma,", "a", "characteristic", "high-molecular-weight", "factor", "H", " ", "protein", "that", "results", "from", "the", "covalent", "interaction", "between", "factor", "H", " ", "and", "human", "serum", "albumin.", "Most", "important,", "all", "three", "aHUS-associated", "factor", "H", " ", "proteins", "have", "a", "normal", "cofactor", "activity", "in", "the", "proteolysis", "of", "fluid-phase", "C3b", "by", "factor", "I", "but", "show", "very", "low", "binding", "to", "surface-bound", "C3b.", "This", "functional", "impairment", "was", "also", "demonstrated", "in", "recombinant", "mutant", "factor", "H", "factor", "H", " ", "mutations", "associated", "with", "atypical", "hemolytic", "uremic", "syndrome.", "Genetic", "studies", "have", "demonstrated", "the", "involvement", "of", "the", "complement", "regulator", "factor", "H", "in", "nondiarrheal,", "nonverocytotoxin", "(i.e.,", "atypical)", "cases", "of", "hemolytic", "uremic", "syndrome.", "Different", "factor", "H", "mutations", "have", "been", "identified", "in", "10%-30%", "of", "patients", "with", "atypical", "hemolytic", "uremic", "syndrome", "(aHUS),", "and", "most", "of", "these", "mutations", "alter", "single", "amino", "acids", "in", "the", "C-terminal", "region", "of", "factor", "H.", "Although", "these", "mutations", "are", "considered", "to", "be", "responsible", "for", "the", "disease,", "the", "precise", "role", "that", "factor", "H", "plays", "in", "the", "pathogenesis", "of", "aHUS", "is", "unknown.", "We", "report", "here", "the", "structural", "and", "functional", "characterization", "of", "three", "different", "factor", "H", "proteins", "purified", "from", "the", "plasma", "of", "patients", "with", "aHUS", "who", "carry", "the", "factor", "H", "mutations", "W1183L,", "V1197A,", "or", "R1210C.", "Structural", "anomalies", "in", "factor", "H", "were", "found", "only", "in", "R1210C", " ", "carriers;", "these", "individuals", "show,", "in", "their", "plasma,", "a", "characteristic", "high-molecular-weight", "factor", "H", "protein", "that", "results", "from", "the", "covalent", "interaction", "between", "factor", "H", "and", "human", "serum", "albumin.", "Most", "important,", "all", "three", "aHUS-associated", "factor", "H", "proteins", "have", "a", "normal", "cofactor", "activity", "in", "the", "proteolysis", "of", "fluid-phase", "C3b", "by", "factor", "I", "but", "show", "very", "low", "binding", "to", "surface-bound", "C3b.", "This", "functional", "impairment", "was", "also", "demonstrated", "in", "recombinant", "mutant", "factor", "H", "proteins", "expressed", "in", "COS7", "cells.", "These", "data", "support", "the", "hypothesis", "that", "patients", "with", "aHUS", "carry", "a", "specific", "dysfunction", "in", "the", "protection", "of", "cellular", "surfaces", "from", "complement", "activation,", "offering", "new", "possibilities", "to", "improve", "diagnosis", "and", "develop", "appropriate", "therapies." ]
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Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H . Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L , V1197A , or R1210C factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H factor H mutations associated with atypical hemolytic uremic syndrome. Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H. Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS7 cells. These data support the hypothesis that patients with aHUS carry a specific dysfunction in the protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate therapies.
7825575
[ "Likelihood", "methods", "for", "locating", "disease", "genes", "in", "nonequilibrium", "populations.", "Until", "recently,", "attempts", "to", "map", "disease", "genes", "on", "the", "basis", "of", "population", "associations", "with", "linked", "markers", "have", "been", "based", "on", "expected", "values", "of", "linkage", "disequilibrium.", "These", "methods", "suffer", "from", "the", "large", "variances", "imposed", "on", "disequilibrium", "measures", "by", "the", "evolutionary", "process,", "but", "a", "more", "serious", "problem", "for", "many", "diseases", "is", "that", "they", "assume", "an", "equilibrium", "population.", "For", "diseases", "that", "arose", "only", "a", "few", "hundred", "generations", "ago,", "it", "is", "more", "appropriate", "to", "concentrate", "on", "the", "initial", "growth", "phase", "of", "the", "disease.", "We", "invoke", "a", "Poisson", "branching", "process", "for", "this", "early", "growth,", "and", "estimate", "the", "likelihood", "for", "the", "recombination", "fraction", "between", "marker", "and", "disease", "loci,", "on", "the", "basis", "of", "simulated", "disease", "populations.", "The", "limits", "of", "the", "resulting", "support", "intervals", "for", "the", "recombination", "fraction", "vary", "inversely", "with", "the", "age", "of", "the", "disease", "in", "generations.", "We", "illustrate", "the", "procedure", "with", "data", "on", "cystic", "fibrosis", "and", "diastrophic", "dysplasia,", "for", "which", "the", "method", "appears", "appropriate,", "and", "for", "Friedreich", "ataxia", "and", "Huntington", "disease,", "for", "which", "it", "does", "not.", "A", "valuable", "aspect", "of", "the", "method", "is", "the", "ability", "in", "some", "cases", "to", "compare", "likelihoods", "of", "the", "three", "orders", "for", "a", "disease", "locus", "and", "two", "linked", "marker", "loci." ]
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Likelihood methods for locating disease genes in nonequilibrium populations. Until recently, attempts to map disease genes on the basis of population associations with linked markers have been based on expected values of linkage disequilibrium. These methods suffer from the large variances imposed on disequilibrium measures by the evolutionary process, but a more serious problem for many diseases is that they assume an equilibrium population. For diseases that arose only a few hundred generations ago, it is more appropriate to concentrate on the initial growth phase of the disease. We invoke a Poisson branching process for this early growth, and estimate the likelihood for the recombination fraction between marker and disease loci, on the basis of simulated disease populations. The limits of the resulting support intervals for the recombination fraction vary inversely with the age of the disease in generations. We illustrate the procedure with data on cystic fibrosis and diastrophic dysplasia, for which the method appears appropriate, and for Friedreich ataxia and Huntington disease, for which it does not. A valuable aspect of the method is the ability in some cases to compare likelihoods of the three orders for a disease locus and two linked marker loci.
16358216
[ "A", "novel", "framework", "for", "sib", "pair", "linkage", "analysis.", "Sib", "pair", "linkage", "analysis", "of", "a", "dichotomous", "trait", "is", "a", "popular", "method", "for", "narrowing", "the", "search", "for", "genes", "that", "influence", "complex", "diseases.", "Although", "the", "pedigree", "structures", "are", "uncomplicated", "and", "the", "underlying", "genetic", "principles", "straightforward,", "a", "surprising", "degree", "of", "complexity", "is", "involved", "in", "implementing", "a", "sib", "pair", "study", "and", "interpreting", "the", "results.", "Ascertainment", "may", "be", "based", "on", "affected,", "discordant,", "or", "unaffected", "sib", "pairs,", "as", "well", "as", "on", "pairs", "defined", "by", "threshold", "values", "for", "quantitative", "traits,", "such", "as", "extreme", "discordant", "sib", "pairs.", "To", "optimize", "power,", "various", "domain", "restrictions", "and", "null", "hypotheses", "have", "been", "proposed", "for", "each", "of", "these", "designs,", "yielding", "a", "wide", "array", "of", "choices", "for", "the", "analyst.", "To", "begin,", "we", "systematically", "classify", "the", "major", "sources", "of", "discretion", "in", "sib", "pair", "linkage", "analysis.", "Then,", "we", "extend", "the", "work", "of", "Kruglyak", "and", "Lander", "(1995),", "to", "bring", "the", "various", "forms", "into", "a", "unified", "framework", "and", "to", "facilitate", "a", "more", "general", "approach", "to", "the", "analysis.", "Finally,", "we", "describe", "a", "new,", "freely", "available", "computer", "program,", "Splat", "(Sib", "Pair", "Linkage", "Analysis", "Testing),", "that", "can", "perform", "any", "sib", "pair", "statistical", "test", "currently", "in", "use,", "as", "well", "as", "any", "user-defined", "test", "yet", "to", "be", "proposed.", "Splat", "uses", "the", "expectation", "maximization", "algorithm", "to", "calculate", "maximum-likelihood", "estimates", "of", "sharing", "(subject", "to", "user-specified", "conditions)", "and", "then", "plots", "LOD", "scores", "versus", "chromosomal", "position.", "It", "includes", "a", "novel", "grid-scanning", "capability", "that", "enables", "simultaneous", "visualization", "of", "multiple", "test", "statistics.", "This", "can", "lead", "to", "further", "insight", "into", "the", "genetic", "basis", "of", "the", "disease", "process", "under", "consideration.", "In", "addition,", "phenotype", "definitions", "can", "be", "modified", "without", "the", "recalculation", "of", "inheritance", "vectors,", "thereby", "providing", "considerable", "flexibility", "for", "exploratory", "analysis.", "The", "application", "of", "Splat", "will", "be", "illustrated", "with", "data", "from", "studies", "on", "the", "genetics", "of", "diabetic", "nephropathy." ]
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A novel framework for sib pair linkage analysis. Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs. To optimize power, various domain restrictions and null hypotheses have been proposed for each of these designs, yielding a wide array of choices for the analyst. To begin, we systematically classify the major sources of discretion in sib pair linkage analysis. Then, we extend the work of Kruglyak and Lander (1995), to bring the various forms into a unified framework and to facilitate a more general approach to the analysis. Finally, we describe a new, freely available computer program, Splat (Sib Pair Linkage Analysis Testing), that can perform any sib pair statistical test currently in use, as well as any user-defined test yet to be proposed. Splat uses the expectation maximization algorithm to calculate maximum-likelihood estimates of sharing (subject to user-specified conditions) and then plots LOD scores versus chromosomal position. It includes a novel grid-scanning capability that enables simultaneous visualization of multiple test statistics. This can lead to further insight into the genetic basis of the disease process under consideration. In addition, phenotype definitions can be modified without the recalculation of inheritance vectors, thereby providing considerable flexibility for exploratory analysis. The application of Splat will be illustrated with data from studies on the genetics of diabetic nephropathy.
15459972
[ "Novel", "and", "recurrent", "mutations", "clustered", "in", "the", "von", "Willebrand", "factor", "A", "domain", "of", "MATN3", " ", "in", "multiple", "epiphyseal", "dysplasia.", "Multiple", "epiphyseal", "dysplasia", "(MED)", "is", "a", "common", "skeletal", "dysplasia", "characterized", "by", "joint", "pain", "and", "stiffness,", "delayed", "and", "irregular", "ossification", "of", "epiphyses,", "and", "early-onset", "osteoarthritis.", "Six", "genes", "responsible", "for", "MED", "have", "been", "identified,", "including", "COMP", ",", "COL9A1", ",", "COL9A2", ",", "COL9A3", ",", "DSTDT", " ", "and", "MATN3", ".", "MATN3", " ", "encodes", "matrilin-3", ",", "a", "cartilage-specific", "extracellular", "matrix", "protein.", "To", "date,", "seven", "different", "MATN3", " ", "mutations", "have", "been", "identified;", "all", "are", "located", "within", "the", "beta-sheet", "regions", "of", "the", "von", "Willebrand", "factor", "type", "A", "(vWFA)", "domain,", "which", "is", "encoded", "by", "exon", "2.", "We", "examined", "MATN3", " ", "mutations", "in27", "Japanese", "MED", "patients", "who", "were", "possibly", "autosomal", "dominant", "inheritance", "and", "had", "been", "excluded", "for", "COMP", "mutations.", "Ten", "of", "them", "had", "a", "positive", "family", "history.", "We", "examined", "all", "eight", "exons", "of", "MATN3", " ", "by", "PCR", "and", "direct", "sequencing", "from", "genomic", "DNA.", "We", "have", "identified", "four", "missense", "mutations", "in", "eight", "unrelated", "families;", "two", "are", "novel,", "and", "two", "have", "been", "characterized", "previously.", "Like", "previously", "characterized", "MATN3", " ", "mutations,", "those", "identified", "in", "this", "study", "are", "clustered", "within", "exon", "2,", "specifically", "in", "and", "around", "the", "2nd", "beta-sheet", "region", "of", "the", "vWFA", "domain", "(aa.", "120-127).", "Contrary", "to", "the", "previous", "assumption", "that", "the", "MATN3", " ", "mutation", "in", "MED", "is", "confined", "to", "the", "beta-sheet", "regions,", "one", "novel", "mutation", "(", "p.F105S", ")", "is", "located", "outside", "the", "beta-sheet", "region,", "within", "an", "alpha-helix", "region." ]
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Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by joint pain and stiffness, delayed and irregular ossification of epiphyses, and early-onset osteoarthritis. Six genes responsible for MED have been identified, including COMP , COL9A1 , COL9A2 , COL9A3 , DSTDT and MATN3 . MATN3 encodes matrilin-3 , a cartilage-specific extracellular matrix protein. To date, seven different MATN3 mutations have been identified; all are located within the beta-sheet regions of the von Willebrand factor type A (vWFA) domain, which is encoded by exon 2. We examined MATN3 mutations in27 Japanese MED patients who were possibly autosomal dominant inheritance and had been excluded for COMP mutations. Ten of them had a positive family history. We examined all eight exons of MATN3 by PCR and direct sequencing from genomic DNA. We have identified four missense mutations in eight unrelated families; two are novel, and two have been characterized previously. Like previously characterized MATN3 mutations, those identified in this study are clustered within exon 2, specifically in and around the 2nd beta-sheet region of the vWFA domain (aa. 120-127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the beta-sheet regions, one novel mutation ( p.F105S ) is located outside the beta-sheet region, within an alpha-helix region.
1415265
[ "Molecular", "genetic", "study", "of", "the", "frequency", "of", "monosomy", "22q11", "in", "DiGeorge", "syndrome.", "It", "is", "well", "established", "that", "DiGeorge", "syndrome", "(DGS)", "may", "be", "associated", "with", "monosomy", "of", "22q11-pter.", "More", "recently,", "DNA", "probes", "have", "been", "used", "to", "detect", "hemizygosity", "for", "this", "region", "in", "patients", "with", "no", "visible", "karyotypic", "abnormality.", "However,", "DGS", "has", "also", "been", "described", "in", "cases", "where", "the", "cytogenetic", "abnormality", "does", "not", "involve", "22q11;", "for", "instance,", "four", "cases", "of", "10p-", "have", "been", "reported.", "In", "this", "study", "we", "have", "prospectively", "analyzed", "patients,", "by", "using", "DNA", "markers", "from", "22q11,", "to", "assess", "the", "frequency", "of", "22q11", "rearrangements", "in", "DGS.", "Twenty-one", "of", "22", "cases", "had", "demonstrable", "hemizygosity", "for", "22q11.", "Cytogenetic", "analysis", "had", "identified", "interstitial", "deletion", "in", "6", "of", "16", "cases", "tested;", "in", "6", "other", "cases", "no", "karyotype", "was", "available.", "When", "these", "results", "are", "combined", "with", "those", "from", "our", "previous", "studies,", "33", "of", "35", "DGS", "patients", "had", "chromosome", "22q11", "deletions", "detectable", "by", "DNA", "probes." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. It is well established that DiGeorge syndrome (DGS) may be associated with monosomy of 22q11-pter. More recently, DNA probes have been used to detect hemizygosity for this region in patients with no visible karyotypic abnormality. However, DGS has also been described in cases where the cytogenetic abnormality does not involve 22q11; for instance, four cases of 10p- have been reported. In this study we have prospectively analyzed patients, by using DNA markers from 22q11, to assess the frequency of 22q11 rearrangements in DGS. Twenty-one of 22 cases had demonstrable hemizygosity for 22q11. Cytogenetic analysis had identified interstitial deletion in 6 of 16 cases tested; in 6 other cases no karyotype was available. When these results are combined with those from our previous studies, 33 of 35 DGS patients had chromosome 22q11 deletions detectable by DNA probes.
11102997
[ "A", "de", "novo", "adrenoleukodystrophy", "gene", "(", "ABCD1", "adrenoleukodystrophy", " ", "gene", "(ABCD1)", "mutation", "S636I", " ", "without", "detectable", "ABCD1", " ", "protein", "and", "a", "R104C", " ", "mutation", "with", "normal", "amounts", "of", "protein", "from", "an", "Austrian", "patient", "collective." ]
[ 0, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 3, 0, 0, 0, 1, 0, 0, 0, 0, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
A de novo adrenoleukodystrophy gene ( ABCD1 adrenoleukodystrophy gene (ABCD1) mutation S636I without detectable ABCD1 protein and a R104C mutation with normal amounts of protein from an Austrian patient collective.
9838272
[ "The", "sib", "transmission/disequilibrium", "test", "is", "a", "Mantel-Haenszel", "test." ]
[ 0, 0, 0, 0, 0, 0, 0, 0 ]
The sib transmission/disequilibrium test is a Mantel-Haenszel test.
7866409
[ "Mutation", "at", "the", "catalytic", "site", "(", "M519V", ")", "in", "glycogen", "storage", "disease", "type", "II", "(Pompe", "disease)." ]
[ 0, 0, 0, 0, 0, 0, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Mutation at the catalytic site ( M519V ) in glycogen storage disease type II (Pompe disease).
12673802
[ "Oculopharyngeal", "muscular", "dystrophy", "(OPMD)", "due", "to", "a", "small", "duplication", "in", "the", "PABPN1", " ", "gene.", "Oculopharyngeal", "muscular", "dystrophy", "(OPMD)", "is", "a", "late", "onset", "autosomal", "dominant", "muscle", "disorder.", "The", "OPMD-locus", "has", "been", "mapped", "to", "chromosome", "14q11.2-q13.", "The", "polyadenylate", "binding", "protein", "nuclear", "1", "(PABPN1;", "PABP2", "PABPN1", "polyadenylate", "binding", "protein", "nuclear", "1", " ", "(PABPN1;", "PABP2)", "gene", "has", "been", "identified", "as", "the", "mutated", "gene.", "The", "mutation", "consists", "of", "a", "short", "meiotically", "stable", "trinucleotide", "repeat", "in", "the", "first", "exon", "of", "PABPN1", " ", "gene.", "We", "have", "investigated", "Dutch", "OPMD", "patients", "from", "four", "unrelated", "families", "and", "identified", "a", "new", "mutation", "in", "two", "of", "the", "four", "families.", "Instead", "of", "a", "repeat", "expansion", "we", "found", "a", "duplication", "in", "the", "first", "exon", "of", "the", "PABPN1", " ", "gene", "(", "c.27_28ins12", ",", "p.11_12insAAAA", ").", "The", "identification", "of", "this", "new", "mutation", "supports", "the", "theory", "of", "unequal", "crossing-over", "as", "molecular", "mechanism", "causing", "the", "mutation", "in", "the", "PABPN1", " ", "gene", "responsible", "for", "OPMD,", "and", "not", "the", "slippage", "model." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 2, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 3, 0, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene. Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. The OPMD-locus has been mapped to chromosome 14q11.2-q13. The polyadenylate binding protein nuclear 1 (PABPN1; PABP2 PABPN1 polyadenylate binding protein nuclear 1 (PABPN1; PABP2) gene has been identified as the mutated gene. The mutation consists of a short meiotically stable trinucleotide repeat in the first exon of PABPN1 gene. We have investigated Dutch OPMD patients from four unrelated families and identified a new mutation in two of the four families. Instead of a repeat expansion we found a duplication in the first exon of the PABPN1 gene ( c.27_28ins12 , p.11_12insAAAA ). The identification of this new mutation supports the theory of unequal crossing-over as molecular mechanism causing the mutation in the PABPN1 gene responsible for OPMD, and not the slippage model.
20506298
[ "Dissecting", "the", "pathogenic", "mechanisms", "of", "mutations", "in", "the", "pore", "region", "of", "the", "human", "cone", "photoreceptor", "cyclic", "nucleotide-gated", "channel.", "The", "CNGA3", " ", "gene", "encodes", "the", "A3", "subunit", "of", "the", "cone", "photoreceptor", "cyclic", "nucleotide-gated", "(CNG)", "channel,", "an", "essential", "component", "of", "the", "phototransduction", "cascade.", "Certain", "mutations", "in", "CNGA3", "cause", "autosomal", "recessive", "achromatopsia,", "a", "retinal", "disorder", "characterized", "by", "severely", "reduced", "visual", "acuity,", "lack", "of", "color", "discrimination,", "photophobia,", "and", "nystagmus.", "We", "identified", "three", "novel", "mutations", "in", "the", "pore-forming", "region", "of", "CNGA3", " ", "(", "L363P", ",", "G367V", ",", "and", "E376K", ")", "in", "patients", "diagnosed", "with", "achromatopsia.", "We", "assessed", "the", "expression", "and", "function", "of", "channels", "with", "these", "three", "new", "and", "two", "previously", "described", "mutations", "(", "S341P", " ", "and", "P372S", ")", "in", "a", "heterologous", "HEK293", "cell", "expression", "system", "using", "Western", "blot,", "subcellular", "localization", "on", "the", "basis", "of", "immunocytochemistry,", "calcium", "imaging,", "and", "patch", "clamp", "recordings.", "In", "this", "first", "comparative", "functional", "analysis", "of", "disease-associated", "mutations", "in", "the", "pore", "of", "a", "CNG", "channel,", "we", "found", "impaired", "surface", "expression", "of", "S341P", ",", "L363P", ",", "and", "P372S", " ", "mutants", "and", "reduced", "macroscopic", "currents", "for", "channels", "with", "the", "mutations", "S341P", ",", "G367V", ",", "and", "E376K", ".", "Calcium", "imaging", "and", "patch", "clamp", "experiments", "after", "incubation", "at", "37", "degrees", "C", "revealed", "nonfunctional", "homo-", "and", "heteromeric", "channels", "in", "all", "five", "mutants,", "but", "incubation", "at", "27", "degrees", "C", "combined", "with", "coexpression", "of", "the", "B3", "subunit", "restored", "residual", "function", "of", "channels", "with", "the", "mutations", "S341P", ",", "G367V", ",", "and", "E376K", "." ]
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Dissecting the pathogenic mechanisms of mutations in the pore region of the human cone photoreceptor cyclic nucleotide-gated channel. The CNGA3 gene encodes the A3 subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel, an essential component of the phototransduction cascade. Certain mutations in CNGA3 cause autosomal recessive achromatopsia, a retinal disorder characterized by severely reduced visual acuity, lack of color discrimination, photophobia, and nystagmus. We identified three novel mutations in the pore-forming region of CNGA3 ( L363P , G367V , and E376K ) in patients diagnosed with achromatopsia. We assessed the expression and function of channels with these three new and two previously described mutations ( S341P and P372S ) in a heterologous HEK293 cell expression system using Western blot, subcellular localization on the basis of immunocytochemistry, calcium imaging, and patch clamp recordings. In this first comparative functional analysis of disease-associated mutations in the pore of a CNG channel, we found impaired surface expression of S341P , L363P , and P372S mutants and reduced macroscopic currents for channels with the mutations S341P , G367V , and E376K . Calcium imaging and patch clamp experiments after incubation at 37 degrees C revealed nonfunctional homo- and heteromeric channels in all five mutants, but incubation at 27 degrees C combined with coexpression of the B3 subunit restored residual function of channels with the mutations S341P , G367V , and E376K .
15759212
[ "Identifying", "candidate", "Hirschsprung", "disease-associated", "RET", "variants.", "Patients", "with", "sporadic", "Hirschsprung", "disease", "(HSCR)", "show", "increased", "allele", "sharing", "at", "markers", "in", "the", "5'", "region", "of", "the", "RET", " ", "locus,", "indicating", "the", "presence", "of", "a", "common", "ancestral", "RET", " ", "mutation.", "In", "a", "previous", "study,", "we", "found", "a", "haplotype", "of", "six", "SNPs", "that", "was", "transmitted", "to", "55.6%", "of", "our", "patients,", "whereas", "it", "was", "present", "in", "only", "16.2%", "of", "the", "controls", "we", "used.", "Among", "the", "patients", "with", "that", "haplotype,", "90.8%", "had", "it", "on", "both", "chromosomes,", "which", "led", "to", "a", "much", "higher", "risk", "of", "developing", "HSCR", "than", "when", "the", "haplotype", "occurred", "heterozygously.", "To", "more", "precisely", "define", "the", "HSCR-associated", "region", "and", "to", "identify", "candidate", "disease-associated", "variant(s),", "we", "sequenced", "the", "shared", "common", "haplotype", "region", "from", "10", "kb", "upstream", "of", "the", "RET", "RET", " ", "variants.", "Patients", "with", "sporadic", "Hirschsprung", "disease", "(HSCR)", "show", "increased", "allele", "sharing", "at", "markers", "in", "the", "5'", "region", "of", "the", "RET", "locus,", "indicating", "the", "presence", "of", "a", "common", "ancestral", "RET", "mutation.", "In", "a", "previous", "study,", "we", "found", "a", "haplotype", "of", "six", "SNPs", "that", "was", "transmitted", "to", "55.6%", "of", "our", "patients,", "whereas", "it", "was", "present", "in", "only", "16.2%", "of", "the", "controls", "we", "used.", "Among", "the", "patients", "with", "that", "haplotype,", "90.8%", "had", "it", "on", "both", "chromosomes,", "which", "led", "to", "a", "much", "higher", "risk", "of", "developing", "HSCR", "than", "when", "the", "haplotype", "occurred", "heterozygously.", "To", "more", "precisely", "define", "the", "HSCR-associated", "region", "and", "to", "identify", "candidate", "disease-associated", "variant(s),", "we", "sequenced", "the", "shared", "common", "haplotype", "region", "from", "10", "kb", "upstream", "of", "the", "RET", "gene", "through", "intron", "1", "and", "exon", "2", "(in", "total,", "33", "kb)", "in", "a", "patient", "homozygous", "for", "the", "common", "risk", "haplotype", "and", "in", "a", "control", "individual", "homozygous", "for", "the", "most", "common", "nonrisk", "haplotype.", "A", "comparison", "of", "these", "sequences", "revealed", "86", "sequence", "differences.", "Of", "these", "86", "variations,", "8", "proved", "to", "be", "in", "regions", "highly", "conserved", "among", "different", "vertebrates", "and", "within", "putative", "transcription", "factor", "binding", "sites.", "We", "therefore", "considered", "these", "as", "candidate", "disease-associated", "variants.", "Subsequent", "genotyping", "of", "these", "eight", "variants", "revealed", "a", "strong", "disease", "association", "for", "six", "of", "the", "eight", "markers.", "These", "six", "markers", "also", "showed", "the", "largest", "distortions", "in", "allele", "transmission.", "Interspecies", "comparison", "showed", "that", "only", "one", "of", "the", "six", "variations", "was", "located", "in", "a", "region", "also", "conserved", "in", "a", "nonmammalian", "species,", "making", "it", "the", "most", "likely", "candidate", "HSCR-associated", "variant." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Identifying candidate Hirschsprung disease-associated RET variants. Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5' region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET RET variants. Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5' region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET gene through intron 1 and exon 2 (in total, 33 kb) in a patient homozygous for the common risk haplotype and in a control individual homozygous for the most common nonrisk haplotype. A comparison of these sequences revealed 86 sequence differences. Of these 86 variations, 8 proved to be in regions highly conserved among different vertebrates and within putative transcription factor binding sites. We therefore considered these as candidate disease-associated variants. Subsequent genotyping of these eight variants revealed a strong disease association for six of the eight markers. These six markers also showed the largest distortions in allele transmission. Interspecies comparison showed that only one of the six variations was located in a region also conserved in a nonmammalian species, making it the most likely candidate HSCR-associated variant.
19576569
[ "Diverse", "evolutionary", "histories", "for", "beta-adrenoreceptor", "genes", "in", "humans.", "In", "humans,", "three", "genes--", "ADRB1", ",", "ADRB2", " ", "and", "ADRB3", "--encode", "beta-adrenoreceptors", "(ADRB);", "these", "molecules", "mediate", "the", "action", "of", "catecholamines", "in", "multiple", "tissues", "and", "play", "pivotal", "roles", "in", "cardiovascular,", "respiratory,", "metabolic,", "and", "immunological", "functions.", "Genetic", "variants", "in", "ADRB", "genes", "have", "been", "associated", "with", "widespread", "diseases", "and", "conditions,", "but", "inconsistent", "results", "have", "often", "been", "obtained.", "Here,", "we", "addressed", "the", "recent", "evolutionary", "history", "of", "ADRB", "genes", "in", "human", "populations.", "Although", "ADRB1", " ", "is", "neutrally", "evolving,", "most", "tests", "rejected", "neutral", "evolution", "for", "ADRB2", " ", "in", "European,", "African,", "and", "Asian", "population", "samples.", "Analysis", "of", "inferred", "haplotypes", "for", "ADRB2", " ", "revealed", "three", "major", "clades", "with", "a", "coalescence", "time", "of", "1-1.5", "million", "years,", "suggesting", "that", "the", "gene", "is", "either", "subjected", "to", "balancing", "selection", "or", "undergoing", "a", "selective", "sweep.", "Haplotype", "analysis", "also", "revealed", "ethnicity-specific", "differences.", "Additionally,", "we", "observed", "significant", "deviations", "from", "Hardy-Weinberg", "equilibrium", "(HWE)", "for", "ADRB2", " ", "genotypes", "in", "distinct", "European", "cohorts;", "HWE", "deviation", "depends", "on", "sex", "(only", "females", "are", "in", "disequilibrium),", "and", "genotypes", "displaying", "maximum", "and", "minimum", "relative", "fitness", "differ", "across", "population", "samples,", "suggesting", "a", "complex", "situation", "possibly", "involving", "epistasis", "or", "maternal", "selection.", "Overall,", "our", "data", "indicate", "that", "future", "association", "studies", "involving", "ADRB2", " ", "will", "benefit", "from", "taking", "into", "account", "ethnicity-specific", "haplotype", "distributions", "and", "sex-based", "effects.", "With", "respect", "to", "ADRB3", ",", "our", "data", "indicate", "that", "the", "gene", "has", "been", "subjected", "to", "a", "selective", "sweep", "in", "African", "populations,", "the", "Trp64", "variant", "possibly", "representing", "the", "selection", "target.", "Given", "the", "previous", "association", "of", "the", "ancestral", "ADRB3", " ", "Arg64", "allele", "with", "obesity", "and", "type", "2", "diabetes,", "dietary", "adaptations", "might", "represent", "the", "underlying", "selective", "force." ]
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Diverse evolutionary histories for beta-adrenoreceptor genes in humans. In humans, three genes-- ADRB1 , ADRB2 and ADRB3 --encode beta-adrenoreceptors (ADRB); these molecules mediate the action of catecholamines in multiple tissues and play pivotal roles in cardiovascular, respiratory, metabolic, and immunological functions. Genetic variants in ADRB genes have been associated with widespread diseases and conditions, but inconsistent results have often been obtained. Here, we addressed the recent evolutionary history of ADRB genes in human populations. Although ADRB1 is neutrally evolving, most tests rejected neutral evolution for ADRB2 in European, African, and Asian population samples. Analysis of inferred haplotypes for ADRB2 revealed three major clades with a coalescence time of 1-1.5 million years, suggesting that the gene is either subjected to balancing selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. Additionally, we observed significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depends on sex (only females are in disequilibrium), and genotypes displaying maximum and minimum relative fitness differ across population samples, suggesting a complex situation possibly involving epistasis or maternal selection. Overall, our data indicate that future association studies involving ADRB2 will benefit from taking into account ethnicity-specific haplotype distributions and sex-based effects. With respect to ADRB3 , our data indicate that the gene has been subjected to a selective sweep in African populations, the Trp64 variant possibly representing the selection target. Given the previous association of the ancestral ADRB3 Arg64 allele with obesity and type 2 diabetes, dietary adaptations might represent the underlying selective force.
12442283
[ "Novel", "mutations", "in", "the", "MYOC", "/GLC1A", "gene", "in", "a", "large", "group", "of", "glaucoma", "patients.", "Mutations", "at", "the", "myocilin", "(", "MYOC", "myocilin", " ", "(MYOC)", "gene", "within", "the", "GLC1A", "locus", "have", "been", "revealed", "in", "2-4%", "of", "patients", "suffering", "primary", "open", "angle", "glaucoma", "(POAG)", "worldwide.", "In", "our", "ongoing", "glaucoma", "study", "six", "hundred", "eighty", "two", "persons", "have", "been", "screened", "for", "MYOC", " ", "mutations.", "The", "first", "group", "consisted", "of", "453", "patients", "from", "a", "long-term", "clinical", "study", "diagnosed", "either", "with", "juvenile", "OAG", "(JOAG),", "POAG,", "ocular", "hypertension", "(OHT)", "or", "normal", "tension", "glaucoma", "(NTG)", "plus", "22", "cases", "of", "secondary", "glaucoma.", "This", "group,", "and", "additional", "83", "healthy", "controls,", "is", "part", "of", "a", "long", "term", "study", "with", "repeated", "clinical", "examinations", "at", "the", "University", "of", "Erlangen-Nurnberg.", "An", "additional", "sample", "of", "124", "glaucoma", "patients", "or", "at", "risk", "persons", "referred", "from", "other", "sources", "were", "included", "in", "the", "mutation", "screening.", "Five", "novel", "mutations,", "namely", "Gly434Ser", ",", "Asn450Asp", ",", "Val251Ala", ",", "Ile345Met", " ", "and", "Ser393Asn", ",", "could", "be", "identified", "as", "cause", "of", "preperimetric", "POAG,", "JOAG,", "normal", "tension", "POAG", "and", "POAG.", "Myocilin", " ", "mutations", "were", "identified", "similar", "with", "previous", "reports", "with", "other", "ethnic", "populations", "at", "the", "rate", "of", "11/341", "(3.2%)", "probands." ]
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Novel mutations in the MYOC /GLC1A gene in a large group of glaucoma patients. Mutations at the myocilin ( MYOC myocilin (MYOC) gene within the GLC1A locus have been revealed in 2-4% of patients suffering primary open angle glaucoma (POAG) worldwide. In our ongoing glaucoma study six hundred eighty two persons have been screened for MYOC mutations. The first group consisted of 453 patients from a long-term clinical study diagnosed either with juvenile OAG (JOAG), POAG, ocular hypertension (OHT) or normal tension glaucoma (NTG) plus 22 cases of secondary glaucoma. This group, and additional 83 healthy controls, is part of a long term study with repeated clinical examinations at the University of Erlangen-Nurnberg. An additional sample of 124 glaucoma patients or at risk persons referred from other sources were included in the mutation screening. Five novel mutations, namely Gly434Ser , Asn450Asp , Val251Ala , Ile345Met and Ser393Asn , could be identified as cause of preperimetric POAG, JOAG, normal tension POAG and POAG. Myocilin mutations were identified similar with previous reports with other ethnic populations at the rate of 11/341 (3.2%) probands.
9399915
[ "Centromere", "DNA", "dynamics:", "latent", "centromeres", "and", "neocentromere", "formation." ]
[ 0, 0, 0, 0, 0, 0, 0, 0 ]
Centromere DNA dynamics: latent centromeres and neocentromere formation.
8503442
[ "The", "haplotype-relative-risk", "(HRR)", "method", "for", "analysis", "of", "association", "in", "nuclear", "families.", "One", "major", "problem", "in", "studying", "an", "association", "between", "a", "marker", "locus", "and", "a", "disease", "is", "the", "selection", "of", "an", "appropriate", "group", "of", "controls.", "However,", "this", "problem", "of", "population", "stratification", "can", "be", "circumvented", "in", "a", "quite", "elegant", "manner", "by", "family-based", "methods.", "The", "haplotype-relative-risk", "(HRR)", "method,", "which", "samples", "nuclear", "families", "with", "a", "single", "affected", "child", "and", "uses", "the", "parental", "haplotypes", "not", "transmitted", "to", "that", "child", "as", "a", "control", "individual,", "represents", "such", "a", "method", "for", "estimating", "the", "relative", "risk", "of", "a", "marker", "phenotype.", "In", "the", "special", "case", "of", "a", "recessive", "disease,", "it", "was", "already", "known", "that", "the", "equivalence", "of", "the", "HRR", "method", "with", "the", "classical", "relative", "risk", "(RR)", "obtained", "from", "independent", "samples", "holds", "only", "if", "the", "probability", "theta", "of", "a", "recombination", "between", "marker", "and", "disease", "locus", "is", "zero.", "We", "extend", "this", "result", "to", "an", "arbitrary", "mode", "of", "inheritance.", "Furthermore,", "we", "compare", "the", "distribution", "of", "the", "estimators", "for", "HRR", "and", "RR", "and", "show", "that,", "in", "the", "case", "of", "a", "positive", "linkage", "disequilibrium", "between", "a", "marker", "and", "disease", "allele,", "the", "distribution", "of", "the", "estimator", "for", "HRR", "is", "(stochastically)", "smaller", "than", "that", "for", "RR,", "irrespective", "of", "the", "recombination", "fraction.", "The", "practical", "implication", "of", "this", "result", "is", "that,", "for", "the", "HRR", "method,", "there", "is", "no", "tendency", "to", "give", "unduly", "high", "risk", "estimators,", "even", "for", "theta", ">", "0.", "Finally,", "we", "give", "an", "expression", "for", "the", "standard", "error", "of", "the", "estimator", "for", "HRR", "by", "taking", "into", "account", "the", "nonindependence", "of", "transmitted", "and", "nontransmitted", "parental", "marker", "alleles", "in", "the", "case", "of", "theta", ">", "0." ]
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The haplotype-relative-risk (HRR) method for analysis of association in nuclear families. One major problem in studying an association between a marker locus and a disease is the selection of an appropriate group of controls. However, this problem of population stratification can be circumvented in a quite elegant manner by family-based methods. The haplotype-relative-risk (HRR) method, which samples nuclear families with a single affected child and uses the parental haplotypes not transmitted to that child as a control individual, represents such a method for estimating the relative risk of a marker phenotype. In the special case of a recessive disease, it was already known that the equivalence of the HRR method with the classical relative risk (RR) obtained from independent samples holds only if the probability theta of a recombination between marker and disease locus is zero. We extend this result to an arbitrary mode of inheritance. Furthermore, we compare the distribution of the estimators for HRR and RR and show that, in the case of a positive linkage disequilibrium between a marker and disease allele, the distribution of the estimator for HRR is (stochastically) smaller than that for RR, irrespective of the recombination fraction. The practical implication of this result is that, for the HRR method, there is no tendency to give unduly high risk estimators, even for theta > 0. Finally, we give an expression for the standard error of the estimator for HRR by taking into account the nonindependence of transmitted and nontransmitted parental marker alleles in the case of theta > 0.
17503332
[ "Type", "2", "diabetes", "TCF7L2", " ", "risk", "genotypes", "alter", "birth", "weight:", "a", "study", "of", "24,053", "individuals.", "The", "role", "of", "genes", "in", "normal", "birth-weight", "variation", "is", "poorly", "understood,", "and", "it", "has", "been", "suggested", "that", "the", "genetic", "component", "of", "fetal", "growth", "is", "small.", "Type", "2", "diabetes", "genes", "may", "influence", "birth", "weight", "through", "maternal", "genotype,", "by", "increasing", "maternal", "glycemia", "in", "pregnancy,", "or", "through", "fetal", "genotype,", "by", "altering", "fetal", "insulin", "secretion.", "We", "aimed", "to", "assess", "the", "role", "of", "the", "recently", "described", "type", "2", "diabetes", "gene", "TCF7L2", " ", "in", "birth", "weight.", "We", "genotyped", "the", "polymorphism", "rs7903146", "in", "15,709", "individuals", "whose", "birth", "weight", "was", "available", "from", "six", "studies", "and", "in", "8,344", "mothers", "from", "three", "studies.", "Each", "fetal", "copy", "of", "the", "predisposing", "allele", "was", "associated", "with", "an", "18-g", "(95%", "confidence", "interval", "[CI]", "7-29", "g)", "increase", "in", "birth", "weight", "(P=.001)", "and", "each", "maternal", "copy", "with", "a", "30-g", "(95%", "CI", "15-45", "g)", "increase", "in", "offspring", "birth", "weight", "(P=2.8x10-5).", "Stratification", "by", "fetal", "genotype", "suggested", "that", "the", "association", "was", "driven", "by", "maternal", "genotype", "(31-g", "[95%", "CI", "9-48", "g]", "increase", "per", "allele;", "corrected", "P=.003).", "Analysis", "of", "diabetes-related", "traits", "in", "10,314", "nondiabetic", "individuals", "suggested", "the", "most", "likely", "mechanism", "is", "that", "the", "risk", "allele", "reduces", "maternal", "insulin", "secretion", "(disposition", "index", "reduced", "by", "~0.15", "standard", "deviation;", "P=1x10-4),", "which", "results", "in", "increased", "maternal", "glycemia", "in", "pregnancy", "and", "hence", "increased", "offspring", "birth", "weight.", "We", "combined", "information", "with", "the", "other", "common", "variant", "known", "to", "alter", "fetal", "growth,", "the", "-30G-->A", " ", "polymorphism", "of", "glucokinase", "(rs1799884).", "The", "4%", "of", "offspring", "born", "to", "mothers", "carrying", "three", "or", "four", "risk", "alleles", "were", "119", "g", "(95%", "CI", "62-172", "g)", "heavier", "than", "were", "the", "32%", "born", "to", "mothers", "with", "none", "(for", "overall", "trend,", "P=2x10-7),", "comparable", "to", "the", "impact", "of", "maternal", "smoking", "during", "pregnancy.", "In", "conclusion,", "we", "have", "identified", "the", "first", "type", "2", "diabetes-susceptibility", "allele", "to", "be", "reproducibly", "associated", "with", "birth", "weight.", "Common", "gene", "variants", "can", "substantially", "influence", "normal", "birth-weight", "variation." ]
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Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.
9718347
[ "Molecular", "analysis", "of", "9p", "deletions", "associated", "with", "XY", "sex", "reversal:", "refining", "the", "localization", "of", "a", "sex-determining", "gene", "to", "the", "tip", "of", "the", "chromosome." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Molecular analysis of 9p deletions associated with XY sex reversal: refining the localization of a sex-determining gene to the tip of the chromosome.
7981715
[ "Complex", "arylsulfatase", "A", "alleles", "causing", "metachromatic", "leukodystrophy.", "Metachromatic", "leukodystrophy", "is", "a", "lysosomal", "storage", "disorder", "caused", "by", "the", "deficiency", "of", "arylsulfatase", "A.", "Sequencing", "of", "the", "arylsulfatase", "A", "genes", "of", "a", "patient", "affected", "with", "late", "infantile", "metachromatic", "leukodystrophy", "revealed", "that", "the", "patient", "is", "a", "compound", "heterozygote", "of", "two", "alleles", "carrying", "two", "deleterious", "mutation", "each.", "One", "allele", "bears", "a", "splice", "donor", "site", "mutation", "together", "with", "two", "polymorphisms", "and", "an", "additional", "missense", "mutation", "(", "Gly122", ">", "Ser", ").", "The", "splice", "donor", "site", "mutation", "and", "the", "Gly122", ">", "Ser", " ", "substitution", "have", "been", "described", "recently", "but", "on", "different", "alleles.", "The", "other", "allele", "carries", "two", "missense", "mutations", "causing", "a", "Gly154", ">", "Asp", " ", "and", "a", "Pro167", ">", "Arg", " ", "substitution.", "When", "arylsulfatase", "A", "cDNAs", "carrying", "these", "mutations", "separately", "or", "in", "combination", "were", "transfected", "into", "baby", "hamster", "kidney", "cells", "expression", "of", "arylsulfatase", "A", "activity", "could", "not", "be", "detected.", "Linkage", "of", "mutations", "was", "verified", "by", "sequencing", "of", "the", "parental", "DNAs.", "Biosynthesis", "studies", "performed", "with", "the", "patients'", "fibroblasts", "show", "that", "the", "enzyme", "carrying", "both", "mutations", "is", "synthesized", "in", "almost", "normal", "amounts", "but", "is", "rapidly", "degraded", "in", "an", "early", "biosynthetic", "compartment.", "The", "occurence", "of", "two", "disease", "causing", "mutations", "on", "the", "same", "allele", "is", "a", "novel", "phenomenon", "in", "metachromatic", "leukodystrophy", "and", "as", "far", "as", "lysosomal", "storage", "diseases", "are", "concerned", "have", "so", "far", "only", "been", "described", "in", "Fabry", "disease", "and", "in", "the", "complex", "glucocerebrosidase", "alleles", "associated", "with", "Gaucher", "disease." ]
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Complex arylsulfatase A alleles causing metachromatic leukodystrophy. Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of a patient affected with late infantile metachromatic leukodystrophy revealed that the patient is a compound heterozygote of two alleles carrying two deleterious mutation each. One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation ( Gly122 > Ser ). The splice donor site mutation and the Gly122 > Ser substitution have been described recently but on different alleles. The other allele carries two missense mutations causing a Gly154 > Asp and a Pro167 > Arg substitution. When arylsulfatase A cDNAs carrying these mutations separately or in combination were transfected into baby hamster kidney cells expression of arylsulfatase A activity could not be detected. Linkage of mutations was verified by sequencing of the parental DNAs. Biosynthesis studies performed with the patients' fibroblasts show that the enzyme carrying both mutations is synthesized in almost normal amounts but is rapidly degraded in an early biosynthetic compartment. The occurence of two disease causing mutations on the same allele is a novel phenomenon in metachromatic leukodystrophy and as far as lysosomal storage diseases are concerned have so far only been described in Fabry disease and in the complex glucocerebrosidase alleles associated with Gaucher disease.
18726931
[ "FOXL2", " ", "mutations", "and", "genomic", "rearrangements", "in", "BPES.", "The", "FOXL2", " ", "gene", "is", "one", "of", "10", "forkhead", "genes,", "the", "mutations", "of", "which", "lead", "to", "human", "developmental", "disorders,", "often", "with", "ocular", "manifestations.", "Mutations", "in", "FOXL2", "are", "known", "to", "cause", "blepharophimosis", "syndrome", "(BPES),", "an", "autosomal", "dominant", "eyelid", "malformation", "associated", "(type", "I)", "or", "not", "(type", "II)", "with", "ovarian", "dysfunction,", "leading", "to", "premature", "ovarian", "failure", "(POF).", "In", "addition,", "a", "few", "mutations", "have", "been", "described", "in", "patients", "with", "isolated", "POF.", "Here,", "we", "review", "all", "currently", "described", "FOXL2", " ", "sequence", "variations", "and", "genomic", "rearrangements", "in", "BPES", "and", "POF.", "Using", "a", "combined", "mutation", "detection", "approach,", "it", "is", "possible", "to", "identify", "the", "underlying", "genetic", "defect", "in", "a", "major", "proportion", "(88%)", "of", "typical", "BPES", "patients.", "Of", "all", "genetic", "defects", "found", "in", "our", "BPES", "cohort,", "intragenic", "mutations", "represent", "81%.", "They", "include", "missense", "changes,", "frameshift", "and", "nonsense", "mutations,", "in-frame", "deletions,", "and", "duplications,", "that", "are", "distributed", "along", "the", "single-exon", "gene.", "Genomic", "rearrangements", "comprising", "both", "deletions", "encompassing", "FOXL2", " ", "and", "deletions", "located", "outside", "its", "transcription", "unit,", "represent", "12%", "and", "5%", "of", "all", "genetic", "defects", "in", "our", "BPES", "cohort,", "respectively.", "One", "of", "the", "challenges", "of", "genetic", "testing", "in", "BPES", "is", "the", "establishment", "of", "genotype-phenotype", "correlations,", "mainly", "with", "respect", "to", "the", "ovarian", "phenotype.", "Genetic", "testing", "should", "be", "performed", "in", "the", "context", "of", "genetic", "counseling,", "however,", "and", "should", "be", "systematically", "complemented", "by", "a", "multidisciplinary", "clinical", "follow-up.", "Another", "challenge", "for", "health", "care", "professionals", "involved", "in", "BPES", "is", "the", "treatment", "of", "the", "eyelid", "phenotype", "and", "the", "prevention", "or", "treatment", "of", "POF." ]
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FOXL2 mutations and genomic rearrangements in BPES. The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (POF). In addition, a few mutations have been described in patients with isolated POF. Here, we review all currently described FOXL2 sequence variations and genomic rearrangements in BPES and POF. Using a combined mutation detection approach, it is possible to identify the underlying genetic defect in a major proportion (88%) of typical BPES patients. Of all genetic defects found in our BPES cohort, intragenic mutations represent 81%. They include missense changes, frameshift and nonsense mutations, in-frame deletions, and duplications, that are distributed along the single-exon gene. Genomic rearrangements comprising both deletions encompassing FOXL2 and deletions located outside its transcription unit, represent 12% and 5% of all genetic defects in our BPES cohort, respectively. One of the challenges of genetic testing in BPES is the establishment of genotype-phenotype correlations, mainly with respect to the ovarian phenotype. Genetic testing should be performed in the context of genetic counseling, however, and should be systematically complemented by a multidisciplinary clinical follow-up. Another challenge for health care professionals involved in BPES is the treatment of the eyelid phenotype and the prevention or treatment of POF.
7825576
[ "Autosomal", "dominant", "familial", "spastic", "paraplegia:", "reduction", "of", "the", "FSP1", " ", "candidate", "region", "on", "chromosome", "14q", "to", "7", "cM", "and", "locus", "heterogeneity.", "Three", "large", "pedigrees", "of", "German", "descent", "with", "autosomal", "dominant", "\"pure\"", "familial", "spastic", "paraplegia", "(FSP)", "were", "characterized", "clinically", "and", "genetically.", "Haplotype", "and", "linkage", "analyses,", "with", "microsatellites", "covering", "the", "FSP", "region", "on", "chromosome", "14q", "(locus", "FSP1", "),", "were", "performed.", "In", "pedigree", "W,", "we", "found", "a", "haplotype", "that", "cosegregates", "with", "the", "disease", "and", "observed", "three", "crossing-over", "events,", "reducing", "the", "FSP1", " ", "candidate", "region", "to", "7", "cM;", "in", "addition,", "the", "observation", "of", "apparent", "anticipation", "in", "this", "family", "suggests", "a", "trinucleotide", "repeat", "expansion", "as", "the", "mutation.", "In", "pedigrees", "D", "and", "S,", "the", "gene", "locus", "could", "be", "excluded", "from", "the", "whole", "FSP1", " ", "region,", "confirming", "the", "locus", "heterogeneity", "of", "autosomal", "dominant", "FSP." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Autosomal dominant familial spastic paraplegia: reduction of the FSP1 candidate region on chromosome 14q to 7 cM and locus heterogeneity. Three large pedigrees of German descent with autosomal dominant "pure" familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1 ), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigrees D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP.
11793474
[ "Integrating", "mutation", "data", "and", "structural", "analysis", "of", "the", "TP53", " ", "tumor-suppressor", "protein.", "TP53", " ", "encodes", "p53", ",", "which", "is", "a", "nuclear", "phosphoprotein", "with", "cancer-inhibiting", "properties.", "In", "response", "to", "DNA", "damage,", "p53", " ", "is", "activated", "and", "mediates", "a", "set", "of", "antiproliferative", "responses", "including", "cell-cycle", "arrest", "and", "apoptosis.", "Mutations", "in", "the", "TP53", " ", "gene", "are", "associated", "with", "more", "than", "50%", "of", "human", "cancers,", "and", "90%", "of", "these", "affect", "p53-DNA", "interactions,", "resulting", "in", "a", "partial", "or", "complete", "loss", "of", "transactivation", "functions.", "These", "mutations", "affect", "the", "structural", "integrity", "and/or", "p53", "-DNA", "interactions,", "leading", "to", "the", "partial", "or", "complete", "loss", "of", "the", "protein's", "function.", "We", "report", "here", "the", "results", "of", "a", "systematic", "automated", "analysis", "of", "the", "effects", "of", "p53", " ", "mutations", "on", "the", "structure", "of", "the", "core", "domain", "of", "the", "protein.", "We", "found", "that", "304", "of", "the", "882", "(34.4%)", "distinct", "mutations", "reported", "in", "the", "core", "domain", "can", "be", "explained", "in", "structural", "terms", "by", "their", "predicted", "effects", "on", "protein", "folding", "or", "on", "protein-DNA", "contacts.", "The", "proportion", "of", "\"explained\"", "mutations", "increased", "to", "55.6%", "when", "substitutions", "of", "evolutionary", "conserved", "amino", "acids", "were", "included.", "The", "automated", "method", "of", "structural", "analysis", "developed", "here", "may", "be", "applied", "to", "other", "frequently", "mutated", "gene", "mutations", "such", "as", "dystrophin,", "BRCA1", ",", "and", "G6PD", "dystrophin", ",", "BRCA1,", "and", "G6PD." ]
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Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein. TP53 encodes p53 , which is a nuclear phosphoprotein with cancer-inhibiting properties. In response to DNA damage, p53 is activated and mediates a set of antiproliferative responses including cell-cycle arrest and apoptosis. Mutations in the TP53 gene are associated with more than 50% of human cancers, and 90% of these affect p53-DNA interactions, resulting in a partial or complete loss of transactivation functions. These mutations affect the structural integrity and/or p53 -DNA interactions, leading to the partial or complete loss of the protein's function. We report here the results of a systematic automated analysis of the effects of p53 mutations on the structure of the core domain of the protein. We found that 304 of the 882 (34.4%) distinct mutations reported in the core domain can be explained in structural terms by their predicted effects on protein folding or on protein-DNA contacts. The proportion of "explained" mutations increased to 55.6% when substitutions of evolutionary conserved amino acids were included. The automated method of structural analysis developed here may be applied to other frequently mutated gene mutations such as dystrophin, BRCA1 , and G6PD dystrophin , BRCA1, and G6PD.
16642441
[ "Association", "of", "polymorphisms", "in", "the", "Angiotensin-converting", "enzyme", " ", "gene", "with", "Alzheimer", "disease", "in", "an", "Israeli", "Arab", "community.", "Several", "lines", "of", "evidence", "support", "for", "a", "role", "of", "angiotensin", "converting", "enzyme", " ", "(", "ACE", ")", "in", "Alzheimer", "disease", "(AD).", "Most", "genetic", "studies", "have", "focused", "on", "an", "Alu", "insertion/deletion", "(I/D)", "polymorphism", "in", "the", "ACE", " ", "gene", "(", "DCP1", ")", "and", "have", "yielded", "conflicting", "results.", "We", "evaluated", "the", "association", "between", "15", "single-nucleotide", "polymorphisms", "(SNPs)", "in", "DCP1", ",", "including", "the", "I/D", "variant,", "and", "AD", "in", "a", "sample", "of", "92", "patients", "with", "AD", "and", "166", "nondemented", "controls", "from", "an", "inbred", "Israeli", "Arab", "community.", "Although", "there", "was", "no", "evidence", "for", "association", "between", "AD", "and", "I/D,", "we", "observed", "significant", "association", "with", "SNPs", "rs4343", "(P", "=", ".00001)", "and", "rs4351", "(P", "=", ".01).", "Haplotype", "analysis", "revealed", "remarkably", "significant", "evidence", "of", "association", "with", "the", "SNP", "combination", "rs4343", "and", "rs4351", "(global", "P", "=", "7.5", "x", "10(-7)).", "Individuals", "possessing", "the", "haplotype", "\"GA\"", "(frequency", "0.21", "in", "cases", "and", "0.01", "in", "controls)", "derived", "from", "these", "SNPs", "had", "a", "45-fold", "increased", "risk", "of", "developing", "AD", "(95%", "CI", "6.0-343.2)", "compared", "with", "those", "possessing", "any", "of", "the", "other", "three", "haplotypes.", "Longer", "range", "haplotypes", "including", "I/D", "were", "even", "more", "significant", "(lowest", "global", "P", "=", "1.1", "x", "10(-12)),", "but", "the", "only", "consistently", "associated", "alleles", "were", "in", "rs4343", "and", "rs4351.", "These", "results", "suggest", "that", "a", "variant", "in", "close", "proximity", "to", "rs4343", "and", "rs4351", "modulates", "susceptibility", "to", "AD", "in", "this", "community." ]
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Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community. Several lines of evidence support for a role of angiotensin converting enzyme ( ACE ) in Alzheimer disease (AD). Most genetic studies have focused on an Alu insertion/deletion (I/D) polymorphism in the ACE gene ( DCP1 ) and have yielded conflicting results. We evaluated the association between 15 single-nucleotide polymorphisms (SNPs) in DCP1 , including the I/D variant, and AD in a sample of 92 patients with AD and 166 nondemented controls from an inbred Israeli Arab community. Although there was no evidence for association between AD and I/D, we observed significant association with SNPs rs4343 (P = .00001) and rs4351 (P = .01). Haplotype analysis revealed remarkably significant evidence of association with the SNP combination rs4343 and rs4351 (global P = 7.5 x 10(-7)). Individuals possessing the haplotype "GA" (frequency 0.21 in cases and 0.01 in controls) derived from these SNPs had a 45-fold increased risk of developing AD (95% CI 6.0-343.2) compared with those possessing any of the other three haplotypes. Longer range haplotypes including I/D were even more significant (lowest global P = 1.1 x 10(-12)), but the only consistently associated alleles were in rs4343 and rs4351. These results suggest that a variant in close proximity to rs4343 and rs4351 modulates susceptibility to AD in this community.
1550114
[ "Early", "British", "discoveries", "in", "human", "genetics:", "contributions", "of", "R.A.", "Fisher", "and", "J.B.S.", "Haldane", "to", "the", "development", "of", "blood", "groups." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Early British discoveries in human genetics: contributions of R.A. Fisher and J.B.S. Haldane to the development of blood groups.
21665002
[ "A", "congenital", "muscular", "dystrophy", "with", "mitochondrial", "structural", "abnormalities", "caused", "by", "defective", "de", "novo", "phosphatidylcholine", "biosynthesis.", "Congenital", "muscular", "dystrophy", "is", "a", "heterogeneous", "group", "of", "inherited", "muscle", "diseases", "characterized", "clinically", "by", "muscle", "weakness", "and", "hypotonia", "in", "early", "infancy.", "A", "number", "of", "genes", "harboring", "causative", "mutations", "have", "been", "identified,", "but", "several", "cases", "of", "congenital", "muscular", "dystrophy", "remain", "molecularly", "unresolved.", "We", "examined", "15", "individuals", "with", "a", "congenital", "muscular", "dystrophy", "characterized", "by", "early-onset", "muscle", "wasting,", "mental", "retardation,", "and", "peculiar", "enlarged", "mitochondria", "that", "are", "prevalent", "toward", "the", "periphery", "of", "the", "fibers", "but", "are", "sparse", "in", "the", "center", "on", "muscle", "biopsy,", "and", "we", "have", "identified", "homozygous", "or", "compound", "heterozygous", "mutations", "in", "the", "gene", "encoding", "choline", "kinase", "beta", " ", "(", "CHKB", ").", "This", "is", "the", "first", "enzymatic", "step", "in", "a", "biosynthetic", "pathway", "for", "phosphatidylcholine,", "the", "most", "abundant", "phospholipid", "in", "eukaryotes.", "In", "muscle", "of", "three", "affected", "individuals", "with", "nonsense", "mutations,", "choline", "kinase", "activities", "were", "undetectable,", "and", "phosphatidylcholine", "levels", "were", "decreased.", "We", "identified", "the", "human", "disease", "caused", "by", "disruption", "of", "a", "phospholipid", "de", "novo", "biosynthetic", "pathway,", "demonstrating", "the", "pivotal", "role", "of", "phosphatidylcholine", "in", "muscle", "and", "brain." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta ( CHKB ). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.
8981969
[ "Prevalence", "and", "parental", "origin", "of", "de", "novo", "RET", " ", "mutations", "in", "multiple", "endocrine", "neoplasia", "type", "2A", "and", "familial", "medullary", "thyroid", "carcinoma.", "Le", "Groupe", "d'Etude", "des", "Tumeurs", "a", "Calcitonine." ]
[ 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine.
11023809
[ "Major", "genes", "regulating", "total", "serum", "immunoglobulin", "E", "levels", "in", "families", "with", "asthma.", "Immunoglobulin", "E", "(", "IgE", "Immunoglobulin", "E", " ", "(IgE)", "has", "a", "major", "role", "in", "the", "pathogenesis", "of", "allergic", "disorders", "and", "asthma.", "Previous", "data", "from", "92", "families,", "each", "identified", "through", "a", "proband", "with", "asthma,", "showed", "evidence", "for", "two", "major", "genes", "regulating", "total", "serum", "IgE", " ", "levels.", "One", "of", "these", "genes", "mapped", "to", "5q31-33.", "In", "the", "current", "study,", "the", "segregation", "analysis", "was", "extended", "by", "the", "addition", "of", "108", "probands", "and", "their", "families,", "ascertained", "in", "the", "same", "manner.", "A", "mixed", "recessive", "model", "(i.e.,", "major", "recessive", "gene", "and", "residual", "genetic", "effect)", "was", "the", "best-fitting", "and", "most-parsimonious", "one-locus", "model", "of", "the", "segregation", "analysis.", "A", "mixed", "two-major-gene", "model", "(i.e.,", "two", "major", "genes", "and", "residual", "genetic", "effect)", "fit", "the", "data", "significantly", "better", "than", "did", "the", "mixed", "recessive", "one-major-gene", "model.", "The", "second", "gene", "modified", "the", "effect", "of", "the", "first", "recessive", "gene.", "Individuals", "with", "the", "genotype", "aaBB", "(homozygous", "high-risk", "allele", "at", "the", "first", "gene", "and", "homozygous", "low-risk", "allele", "at", "the", "second", "locus)", "had", "normal", "IgE", " ", "levels", "(mean", "23", "IU/ml),", "and", "only", "individuals", "with", "genotypes", "aaBb", "and", "aabb", "had", "high", "IgE", " ", "levels", "(mean", "282", "IU/ml).", "A", "genomewide", "screening", "was", "performed", "using", "variance-component", "analysis.", "Significant", "evidence", "for", "linkage", "was", "found", "for", "a", "novel", "locus", "at", "7q,", "with", "a", "multipoint", "LOD", "score", "of", "3.", "36", "(P=.00004).", "A", "LOD", "score", "of", "3.65", "(P=.00002)", "was", "obtained", "after", "genotyping", "additional", "markers", "in", "this", "region.", "Evidence", "for", "linkage", "was", "also", "found", "for", "two", "previously", "reported", "regions,", "5q", "and", "12q,", "with", "LOD", "scores", "of", "2.73", "(P=.0002)", "and", "2.46", "(P=.0004),", "respectively.", "These", "results", "suggest", "that", "several", "major", "genes,", "plus", "residual", "genetic", "effects,", "regulate", "total", "serum", "IgE", " ", "levels." ]
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Major genes regulating total serum immunoglobulin E levels in families with asthma. Immunoglobulin E ( IgE Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic disorders and asthma. Previous data from 92 families, each identified through a proband with asthma, showed evidence for two major genes regulating total serum IgE levels. One of these genes mapped to 5q31-33. In the current study, the segregation analysis was extended by the addition of 108 probands and their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitting and most-parsimonious one-locus model of the segregation analysis. A mixed two-major-gene model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-gene model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the first gene and homozygous low-risk allele at the second locus) had normal IgE levels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb had high IgE levels (mean 282 IU/ml). A genomewide screening was performed using variance-component analysis. Significant evidence for linkage was found for a novel locus at 7q, with a multipoint LOD score of 3. 36 (P=.00004). A LOD score of 3.65 (P=.00002) was obtained after genotyping additional markers in this region. Evidence for linkage was also found for two previously reported regions, 5q and 12q, with LOD scores of 2.73 (P=.0002) and 2.46 (P=.0004), respectively. These results suggest that several major genes, plus residual genetic effects, regulate total serum IgE levels.
10486328
[ "Assignment", "of", "the", "locus", "for", "hydrolethalus", "syndrome", "to", "a", "highly", "restricted", "region", "on", "11q23-25.", "Hydrolethalus", "syndrome", "is", "a", "recessively", "inherited", "lethal", "malformation", "syndrome", "characterized", "by", "hydrocephaly", "with", "absent", "midline", "structures", "of", "the", "brain,", "micrognathia,", "polydactyly,", "and", "several", "other", "abnormalities,", "mostly", "in", "the", "midline", "structures.", "Hydrolethalus", "syndrome", "was", "described", "in", "1981", "in", "Finland,", "where", "the", "incidence", "is", "1:20,000.", "Only", "a", "few", "cases", "have", "been", "reported", "elsewhere,", "and", "the", "pathogenesis", "has", "remained", "unknown.", "Here", "we", "report", "the", "assignment", "of", "the", "hydrolethalus", "syndrome", "locus", "to", "chromosome", "11q23-25", "in", "Finnish", "families.", "The", "initial", "genome", "scan", "was", "performed", "using", "DNA", "samples", "from", "only", "15", "affected", "individuals.", "In", "the", "next", "step,", "the", "hydrolethalus", "syndrome", "locus", "was", "assigned", "to", "an", "8.5-cM", "interval", "between", "markers", "D11S4144", "and", "D11S1351", "by", "linkage", "analysis", "in", "eight", "families.", "Finally,", "the", "critical", "locus", "could", "be", "restricted", "by", "linkage", "disequilibrium", "and", "haplotype", "analyses", "to", "a", "0.5-1-cM", "region", "between", "markers", "D11S933", "and", "D11S934.", "Genealogical", "studies", "performed", "in", "40", "families", "affected", "by", "hydrolethalus", "revealed", "no", "regional", "clustering,", "suggesting", "a", "relatively", "early", "introduction", "of", "the", "disease", "mutation", "into", "the", "Finnish", "population", "and", "the", "spreading", "of", "the", "mutation", "with", "the", "inhabitation", "of", "the", "late-settlement", "area." ]
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Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25. Hydrolethalus syndrome is a recessively inherited lethal malformation syndrome characterized by hydrocephaly with absent midline structures of the brain, micrognathia, polydactyly, and several other abnormalities, mostly in the midline structures. Hydrolethalus syndrome was described in 1981 in Finland, where the incidence is 1:20,000. Only a few cases have been reported elsewhere, and the pathogenesis has remained unknown. Here we report the assignment of the hydrolethalus syndrome locus to chromosome 11q23-25 in Finnish families. The initial genome scan was performed using DNA samples from only 15 affected individuals. In the next step, the hydrolethalus syndrome locus was assigned to an 8.5-cM interval between markers D11S4144 and D11S1351 by linkage analysis in eight families. Finally, the critical locus could be restricted by linkage disequilibrium and haplotype analyses to a 0.5-1-cM region between markers D11S933 and D11S934. Genealogical studies performed in 40 families affected by hydrolethalus revealed no regional clustering, suggesting a relatively early introduction of the disease mutation into the Finnish population and the spreading of the mutation with the inhabitation of the late-settlement area.
20817137
[ "Exome", "sequencing", "identifies", "WDR35", " ", "variants", "involved", "in", "Sensenbrenner", "syndrome.", "Sensenbrenner", "syndrome/cranioectodermal", "dysplasia", "(CED)", "is", "an", "autosomal-recessive", "disease", "that", "is", "characterized", "by", "craniosynostosis", "and", "ectodermal", "and", "skeletal", "abnormalities.", "We", "sequenced", "the", "exomes", "of", "two", "unrelated", "CED", "patients", "and", "identified", "compound", "heterozygous", "mutations", "in", "WDR35", " ", "as", "the", "cause", "of", "the", "disease", "in", "each", "of", "the", "two", "patients", "independently,", "showing", "that", "it", "is", "possible", "to", "find", "the", "causative", "gene", "by", "sequencing", "the", "exome", "of", "a", "single", "sporadic", "patient.", "With", "RT-PCR,", "we", "demonstrate", "that", "a", "splice-site", "mutation", "in", "exon", "2", "of", "WDR35", " ", "alters", "splicing", "of", "RNA", "on", "the", "affected", "allele,", "introducing", "a", "premature", "stop", "codon.", "WDR35", " ", "is", "homologous", "to", "TULP4", " ", "(from", "the", "Tubby", "superfamily)", "and", "has", "previously", "been", "characterized", "as", "an", "intraflagellar", "transport", "component,", "confirming", "that", "Sensenbrenner", "syndrome", "is", "a", "ciliary", "disorder." ]
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Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities. We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently, showing that it is possible to find the causative gene by sequencing the exome of a single sporadic patient. With RT-PCR, we demonstrate that a splice-site mutation in exon 2 of WDR35 alters splicing of RNA on the affected allele, introducing a premature stop codon. WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder.
12474144
[ "Support", "for", "association", "of", "schizophrenia", "with", "genetic", "variation", "in", "the", "6p22.3", "gene,", "dysbindin,", "in", "sib-pair", "families", "with", "linkage", "and", "in", "an", "additional", "sample", "of", "triad", "families.", "Genetic", "variants", "in", "a", "gene", "on", "6p22.3,", "dysbindin", "dysbindin", ",", "in", "sib-pair", "families", "with", "linkage", "and", "in", "an", "additional", "sample", "of", "triad", "families.", "Genetic", "variants", "in", "a", "gene", "on", "6p22.3,", "dysbindin,", "have", "been", "shown", "recently", "to", "be", "associated", "with", "schizophrenia", "(Straub", "et", "al.", "2002a).", "There", "is", "no", "doubt", "that", "replication", "in", "other", "independent", "samples", "would", "enhance", "the", "significance", "of", "this", "finding", "considerably.", "Since", "the", "gene", "is", "located", "in", "the", "center", "of", "the", "linkage", "peak", "on", "chromosome", "6p", "that", "we", "reported", "earlier,", "we", "decided", "to", "test", "six", "of", "the", "most", "positive", "DNA", "polymorphisms", "in", "a", "sib-pair", "sample", "and", "in", "an", "independently", "ascertained", "sample", "of", "triads", "comprising", "203", "families,", "including", "the", "families", "for", "which", "we", "detected", "linkage", "on", "chromosome", "6p.", "Evidence", "for", "association", "was", "observed", "in", "the", "two", "samples", "separately", "as", "well", "as", "in", "the", "combined", "sample", "(P=.00068", "for", "SNP", "rs760761).", "Multilocus", "haplotype", "analysis", "increased", "the", "significance", "further", "to", ".00002", "for", "a", "two-locus", "haplotype", "and", "to", ".00001", "for", "a", "three-locus", "haplotype.", "Estimation", "of", "frequencies", "for", "six-locus", "haplotypes", "revealed", "one", "common", "haplotype", "with", "a", "frequency", "of", "73.4%", "in", "transmitted,", "and", "only", "57.6%", "in", "nontransmitted,", "parental", "haplotypes.", "All", "other", "six-locus", "haplotypes", "occurring", "at", "a", "frequency", "of", ">1%", "were", "less", "often", "transmitted", "than", "nontransmitted.", "Our", "results", "represent", "a", "first", "successful", "replication", "of", "linkage", "disequilibrium", "in", "psychiatric", "genetics", "detected", "in", "a", "region", "with", "previous", "evidence", "of", "linkage", "and", "will", "encourage", "the", "search", "for", "causes", "of", "schizophrenia", "by", "the", "genetic", "approach." ]
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Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Genetic variants in a gene on 6p22.3, dysbindin dysbindin , in sib-pair families with linkage and in an additional sample of triad families. Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be associated with schizophrenia (Straub et al. 2002a). There is no doubt that replication in other independent samples would enhance the significance of this finding considerably. Since the gene is located in the center of the linkage peak on chromosome 6p that we reported earlier, we decided to test six of the most positive DNA polymorphisms in a sib-pair sample and in an independently ascertained sample of triads comprising 203 families, including the families for which we detected linkage on chromosome 6p. Evidence for association was observed in the two samples separately as well as in the combined sample (P=.00068 for SNP rs760761). Multilocus haplotype analysis increased the significance further to .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype. Estimation of frequencies for six-locus haplotypes revealed one common haplotype with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted, parental haplotypes. All other six-locus haplotypes occurring at a frequency of >1% were less often transmitted than nontransmitted. Our results represent a first successful replication of linkage disequilibrium in psychiatric genetics detected in a region with previous evidence of linkage and will encourage the search for causes of schizophrenia by the genetic approach.
9973288
[ "Hyperparathyroidism-jaw", "tumor", "syndrome:", "the", "HRPT2", " ", "locus", "is", "within", "a", "0.7-cM", "region", "on", "chromosome", "1q.", "Hyperparathyroidism-jaw", "tumor", "syndrome", "(HPT-JT)", "is", "an", "autosomal", "dominant", "disease", "characterized", "by", "the", "development", "of", "multiple", "parathyroid", "adenomas", "and", "multiple", "fibro-osseous", "tumors", "of", "the", "maxilla", "and", "mandible.", "Some", "families", "have", "had", "affected", "members", "with", "involvement", "of", "the", "kidneys,", "variously", "reported", "as", "Wilms", "tumors,", "nephroblastomas,", "and", "hamartomas.", "The", "HPT-JT", "gene", "(HRPT2)", " ", "maps", "to", "chromosome", "1q25-q31.", "We", "describe", "further", "investigation", "of", "two", "HPT-JT", "families", "(K3304", "and", "K3349)", "identified", "through", "the", "literature.", "These", "two", "expanded", "families", "and", "two", "previously", "reported", "families", "were", "investigated", "jointly", "for", "linkage", "with", "21", "new,", "closely", "linked", "markers.", "Multipoint", "linkage", "analysis", "resulted", "in", "a", "maximum", "LOD", "score", "of", "7.83", "(at", "recombination", "fraction", "0)", "for", "markers", "D1S2848-D1S191.", "Recombination", "events", "in", "these", "families", "reduced", "the", "HRPT2", " ", "region", "to", "approximately", "14.7", "cM.", "In", "addition,", "two", "of", "these", "four", "study", "families", "(i.e.,", "K3304", "and", "K11687)", "share", "a", "2.2-cM", "length", "of", "their", "(expanded)", "affected", "haplotype,", "indicating", "a", "possible", "common", "origin.", "Combining", "the", "linkage", "data", "and", "shared-haplotype", "data,", "we", "propose", "a", "0.7-cM", "candidate", "region", "for", "HRPT2." ]
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Hyperparathyroidism-jaw tumor syndrome: the HRPT2 locus is within a 0.7-cM region on chromosome 1q. Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease characterized by the development of multiple parathyroid adenomas and multiple fibro-osseous tumors of the maxilla and mandible. Some families have had affected members with involvement of the kidneys, variously reported as Wilms tumors, nephroblastomas, and hamartomas. The HPT-JT gene (HRPT2) maps to chromosome 1q25-q31. We describe further investigation of two HPT-JT families (K3304 and K3349) identified through the literature. These two expanded families and two previously reported families were investigated jointly for linkage with 21 new, closely linked markers. Multipoint linkage analysis resulted in a maximum LOD score of 7.83 (at recombination fraction 0) for markers D1S2848-D1S191. Recombination events in these families reduced the HRPT2 region to approximately 14.7 cM. In addition, two of these four study families (i.e., K3304 and K11687) share a 2.2-cM length of their (expanded) affected haplotype, indicating a possible common origin. Combining the linkage data and shared-haplotype data, we propose a 0.7-cM candidate region for HRPT2.
9915936
[ "1998", "ASHG", "presidential", "address.", "Making", "genomic", "medicine", "a", "reality." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
1998 ASHG presidential address. Making genomic medicine a reality.
11058905
[ "Six", "novel", "MEN1", " ", "gene", "mutations", "in", "sporadic", "parathyroid", "tumors.", "We", "report", "nine", "mutations", "of", "the", "multiple", "endocrine", "neoplasia", "type", "1", " ", "(", "MEN1", ")", "gene", "in", "sporadic", "parathyroid", "adenomas.", "Six", "of", "them", "have", "not", "previously", "been", "described:", "E60X", ",", "P32R", ",", "261delA", ",", "934+2T-->G", ",", "S443P", ",", "and", "1593insC", ".", "The", "tissue", "samples", "were", "initially", "submitted", "to", "LOH", "analysis", "at", "11q13", "followed", "by", "SSCP", "screening", "of", "LOH-positive", "samples.", "Mutations", "were", "identified", "by", "direct", "sequencing", "and", "subcloning.", "Three", "(", "E60X", ",", "P32R", ",", "and", "261delA", ")", "were", "in", "exon", "2,", "one", "(934+2bp)", "in", "the", "splice", "junction", "of", "exon", "5,", "one", "(", "S443P", ")", "in", "exon", "9,", "and", "one", "(", "1593insC", ")", "in", "exon", "10.", "The", "3", "mutations", "in", "exon", "2", "were", "associated", "with", "loss", "and/or", "creation", "of", "a", "restriction", "site.", "The", "corresponding", "germline", "sequence", "of", "the", "MEN1", " ", "gene", "was", "normal.", "Most", "mutations", "would", "likely", "result", "in", "a", "nonfunctional", "menin", "protein,", "and", "therefore", "in", "the", "loss", "of", "a", "tumor", "suppressor", "protein." ]
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Six novel MEN1 gene mutations in sporadic parathyroid tumors. We report nine mutations of the multiple endocrine neoplasia type 1 ( MEN1 ) gene in sporadic parathyroid adenomas. Six of them have not previously been described: E60X , P32R , 261delA , 934+2T-->G , S443P , and 1593insC . The tissue samples were initially submitted to LOH analysis at 11q13 followed by SSCP screening of LOH-positive samples. Mutations were identified by direct sequencing and subcloning. Three ( E60X , P32R , and 261delA ) were in exon 2, one (934+2bp) in the splice junction of exon 5, one ( S443P ) in exon 9, and one ( 1593insC ) in exon 10. The 3 mutations in exon 2 were associated with loss and/or creation of a restriction site. The corresponding germline sequence of the MEN1 gene was normal. Most mutations would likely result in a nonfunctional menin protein, and therefore in the loss of a tumor suppressor protein.
8100466
[ "Detection", "of", "polymorphisms", "using", "thermal", "cycling", "with", "a", "single", "oligonucleotide", "on", "a", "DNA", "sequencing", "gel.", "A", "method", "is", "described", "for", "the", "detection", "of", "restriction", "fragment", "length", "polymorphisms", "(RFLPs)", "in", "single", "copy", "genes", "in", "mammalian", "cells", "using", "one", "5'-labelled", "oligonucleotide.", "This", "linear", "amplification", "(LA)", "method", "employs", "a", "single", "oligonucleotide", "as", "primer,", "which", "is", "extended", "by", "Taq", "DNA", "polymerase", "up", "to", "a", "restriction", "enzyme", "cleavage", "site.", "The", "products", "are", "arithmetically", "amplified", "by", "thermal", "cycling.", "The", "size", "of", "the", "products", "are", "determined", "by", "the", "sequence", "of", "the", "oligonucleotide", "and", "the", "position", "of", "the", "restriction", "enzyme", "cleavage", "site.", "Hence,", "an", "RFLP", "can", "be", "observed", "by", "measuring", "the", "size", "of", "the", "products.", "Polymorphisms", "which", "differ", "in", "size", "by", "a", "small", "number", "of", "base", "pairs,", "as", "are", "found", "in", "(CA)n", "repeats,", "are", "especially", "suitable", "for", "analysis", "by", "the", "LA", "procedure", "since", "the", "products", "are", "run", "on", "DNA", "sequencing", "gels.", "A", "number", "of", "genes", "were", "examined", "by", "the", "procedure", "and", "all", "produced", "a", "satisfactory", "signal", "including", "GC-rich", "template.", "It", "is", "proposed", "that", "the", "LA", "method", "would", "be", "suitable", "for", "large-scale", "genetic", "linkage", "analysis.", "The", "LA", "procedure", "has", "many", "advantages", "including", "the", "ability", "to", "multiplex", "signals", "under", "the", "same", "conditions,", "and", "lower", "cost", "since", "only", "one", "primer", "is", "needed." ]
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Detection of polymorphisms using thermal cycling with a single oligonucleotide on a DNA sequencing gel. A method is described for the detection of restriction fragment length polymorphisms (RFLPs) in single copy genes in mammalian cells using one 5'-labelled oligonucleotide. This linear amplification (LA) method employs a single oligonucleotide as primer, which is extended by Taq DNA polymerase up to a restriction enzyme cleavage site. The products are arithmetically amplified by thermal cycling. The size of the products are determined by the sequence of the oligonucleotide and the position of the restriction enzyme cleavage site. Hence, an RFLP can be observed by measuring the size of the products. Polymorphisms which differ in size by a small number of base pairs, as are found in (CA)n repeats, are especially suitable for analysis by the LA procedure since the products are run on DNA sequencing gels. A number of genes were examined by the procedure and all produced a satisfactory signal including GC-rich template. It is proposed that the LA method would be suitable for large-scale genetic linkage analysis. The LA procedure has many advantages including the ability to multiplex signals under the same conditions, and lower cost since only one primer is needed.
19804848
[ "Familial", "hemophagocytic", "lymphohistiocytosis", "type", "5", "(FHL-5)", "is", "caused", "by", "mutations", "in", "Munc18-2", " ", "and", "impaired", "binding", "to", "syntaxin", "11.", "Rapid", "intracellular", "transport", "and", "secretion", "of", "cytotoxic", "granules", "through", "the", "immunological", "synapse", "requires", "a", "balanced", "interaction", "of", "several", "proteins.", "Disturbance", "of", "this", "highly", "regulated", "process", "underlies", "familial", "hemophagocytic", "lymphohistiocytosis", "(FHL),", "a", "genetically", "heterogeneous", "autosomal-recessive", "disorder", "characterized", "by", "a", "severe", "hyperinflammatory", "phenotype.", "Here,", "we", "have", "assigned", "FHL-5", "to", "a", "1", "Mb", "region", "on", "chromosome", "19p", "by", "using", "high-resolution", "SNP", "genotyping", "in", "eight", "unrelated", "FHL", "patients", "from", "consanguineous", "families.", "Subsequently,", "we", "found", "nine", "different", "mutations,", "either", "truncating", "or", "missense,", "in", "STXBP2", " ", "in", "twelve", "patients", "from", "Turkey,", "Saudi", "Arabia,", "and", "Central", "Europe.", "STXBP2", " ", "encodes", "syntaxin", "binding", "protein", "2", " ", "(", "Munc18-2", "),", "involved", "in", "the", "regulation", "of", "vesicle", "transport", "to", "the", "plasma", "membrane.", "We", "have", "identified", "syntaxin", "11", ",", "a", "SNARE", "protein", "mutated", "in", "FHL-4,", "as", "an", "interaction", "partner", "of", "STXBP2", ".", "This", "interaction", "is", "eliminated", "by", "the", "missense", "mutations", "found", "in", "our", "FHL-5", "patients,", "which", "leads", "to", "a", "decreased", "stability", "of", "both", "proteins,", "as", "shown", "in", "patient", "lymphocytes.", "Activity", "of", "natural", "killer", "and", "cytotoxic", "T", "cells", "was", "markedly", "reduced", "or", "absent,", "as", "determined", "by", "CD107", "degranulation.", "Our", "findings", "thus", "identify", "a", "key", "role", "for", "STXBP2", "FHL-5", " ", "to", "a", "1", "Mb", "region", "on", "chromosome", "19p", "by", "using", "high-resolution", "SNP", "genotyping", "in", "eight", "unrelated", "FHL", "patients", "from", "consanguineous", "families.", "Subsequently,", "we", "found", "nine", "different", "mutations,", "either", "truncating", "or", "missense,", "in", "STXBP2", "in", "twelve", "patients", "from", "Turkey,", "Saudi", "Arabia,", "and", "Central", "Europe.", "STXBP2", "encodes", "syntaxin", "binding", "protein", "2", "(Munc18-2),", "involved", "in", "the", "regulation", "of", "vesicle", "transport", "to", "the", "plasma", "membrane.", "We", "have", "identified", "syntaxin", "11,", "a", "SNARE", "protein", "mutated", "in", "FHL-4,", "as", "an", "interaction", "partner", "of", "STXBP2.", "This", "interaction", "is", "eliminated", "by", "the", "missense", "mutations", "found", "in", "our", "FHL-5", "FHL-4", "syntaxin", "11", ".", "Rapid", "intracellular", "transport", "and", "secretion", "of", "cytotoxic", "granules", "through", "the", "immunological", "synapse", "requires", "a", "balanced", "interaction", "of", "several", "proteins.", "Disturbance", "of", "this", "highly", "regulated", "process", "underlies", "familial", "hemophagocytic", "lymphohistiocytosis", "(FHL),", "a", "genetically", "heterogeneous", "autosomal-recessive", "disorder", "characterized", "by", "a", "severe", "hyperinflammatory", "phenotype.", "Here,", "we", "have", "assigned", "FHL-5", "to", "a", "1", "Mb", "region", "on", "chromosome", "19p", "by", "using", "high-resolution", "SNP", "genotyping", "in", "eight", "unrelated", "FHL", "patients", "from", "consanguineous", "families.", "Subsequently,", "we", "found", "nine", "different", "mutations,", "either", "truncating", "or", "missense,", "in", "STXBP2", "in", "twelve", "patients", "from", "Turkey,", "Saudi", "Arabia,", "and", "Central", "Europe.", "STXBP2", "encodes", "syntaxin", "binding", "protein", "2", "(Munc18-2),", "involved", "in", "the", "regulation", "of", "vesicle", "transport", "to", "the", "plasma", "membrane.", "We", "have", "identified", "syntaxin", "11,", "a", "SNARE", "protein", "mutated", "in", "FHL-4,", "as", "an", "interaction", "partner", "of", "STXBP2.", "This", "interaction", "is", "eliminated", "by", "the", "missense", "mutations", "found", "in", "our", "FHL-5", "patients,", "which", "leads", "to", "a", "decreased", "stability", "of", "both", "proteins,", "as", "shown", "in", "patient", "lymphocytes.", "Activity", "of", "natural", "killer", "and", "cytotoxic", "T", "cells", "was", "markedly", "reduced", "or", "absent,", "as", "determined", "by", "CD107", "degranulation.", "Our", "findings", "thus", "identify", "a", "key", "role", "for", "STXBP2", "in", "lytic", "granule", "exocytosis." ]
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Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 ( Munc18-2 ), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11 , a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2 . This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 FHL-4 syntaxin 11 . Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.
21412943
[ "Novel", "C2orf71", " ", "mutations", "account", "for", "∼1%", "of", "cases", "in", "a", "large", "French", "arRP", "cohort.", "Autosomal-recessive", "retinitis", "pigmentosa", "(arRP)", "is", "a", "genetically", "heterogeneous", "group", "of", "disorders", "to", "which", "a", "novel", "gene,", "C2orf71", ",", "was", "recently", "associated.", "The", "purpose", "of", "our", "study", "was", "to", "establish", "the", "prevalence", "and", "nature", "of", "C2orf71", " ", "mutations", "in", "a", "clinically", "well-characterized", "cohort", "of", "345", "sporadic", "and", "arRP", "French", "cases.", "Direct", "sequencing", "of", "C2orf71", " ", "was", "performed", "in", "209", "subjects", "for", "whom", "mutations", "had", "previously", "been", "excluded", "by", "microarray", "technology", "and", "direct", "sequencing", "of", "EYS", ".", "Putative", "pathogenicity", "of", "the", "identified", "variants", "was", "evaluated", "through", "co-segregation", "analysis,", "screening", "of", "more", "than", "188", "control", "chromosomes", "and", "prediction", "programs.", "We", "identified", "two", "patients", "compound", "heterozygous", "for", "mutations", "predicted", "to", "lead", "to", "a", "premature", "stop", "codon,", "3", "of", "which", "are", "novel.", "In", "addition,", "3", "patients", "carried", "a", "single", "variant", "of", "likely", "pathogenicity.", "Furthermore", "a", "large", "number", "of", "novel", "putative", "non-disease", "causing", "variants", "were", "identified,", "highlighting", "the", "extremely", "polymorphic", "nature", "of", "C2orf71", ".", "To", "our", "knowledge,", "our", "study", "provides", "the", "first", "large", "scale", "screening", "of", "C2orf71", " ", "in", "a", "French", "arRP", "cohort", "through", "direct", "sequencing", "and", "suggests", "that", "it", "would", "account", "for", "approximately", "1%", "of", "arRP", "cases." ]
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Novel C2orf71 mutations account for ∼1% of cases in a large French arRP cohort. Autosomal-recessive retinitis pigmentosa (arRP) is a genetically heterogeneous group of disorders to which a novel gene, C2orf71 , was recently associated. The purpose of our study was to establish the prevalence and nature of C2orf71 mutations in a clinically well-characterized cohort of 345 sporadic and arRP French cases. Direct sequencing of C2orf71 was performed in 209 subjects for whom mutations had previously been excluded by microarray technology and direct sequencing of EYS . Putative pathogenicity of the identified variants was evaluated through co-segregation analysis, screening of more than 188 control chromosomes and prediction programs. We identified two patients compound heterozygous for mutations predicted to lead to a premature stop codon, 3 of which are novel. In addition, 3 patients carried a single variant of likely pathogenicity. Furthermore a large number of novel putative non-disease causing variants were identified, highlighting the extremely polymorphic nature of C2orf71 . To our knowledge, our study provides the first large scale screening of C2orf71 in a French arRP cohort through direct sequencing and suggests that it would account for approximately 1% of arRP cases.
17186465
[ "Exact", "tests", "of", "Hardy-Weinberg", "equilibrium", "and", "homogeneity", "of", "disequilibrium", "across", "strata.", "Detecting", "departures", "from", "Hardy-Weinberg", "equilibrium", "(HWE)", "of", "marker-genotype", "frequencies", "is", "a", "crucial", "first", "step", "in", "almost", "all", "human", "genetic", "analyses.", "When", "a", "sample", "is", "stratified", "by", "multiple", "ethnic", "groups,", "it", "is", "important", "to", "allow", "the", "marker-allele", "frequencies", "to", "differ", "over", "the", "strata.", "In", "this", "situation,", "it", "is", "common", "to", "test", "for", "HWE", "by", "using", "an", "exact", "test", "within", "each", "stratum", "and", "then", "using", "the", "minimum", "P", "value", "as", "a", "global", "test.", "This", "approach", "does", "not", "account", "for", "multiple", "testing,", "and,", "because", "it", "does", "not", "combine", "information", "over", "strata,", "it", "does", "not", "have", "optimal", "power.", "Several", "approximate", "methods", "to", "combine", "information", "over", "strata", "have", "been", "proposed,", "but", "most", "of", "them", "sum", "over", "strata", "a", "measure", "of", "departure", "from", "HWE;", "if", "the", "departures", "are", "in", "different", "directions,", "then", "summing", "can", "diminish", "the", "overall", "evidence", "of", "departure", "from", "HWE.", "An", "exact", "stratified", "test", "is", "more", "appealing", "because", "it", "uses", "the", "probability", "of", "genotype", "configurations", "across", "the", "strata", "as", "evidence", "for", "global", "departures", "from", "HWE.", "We", "developed", "an", "exact", "stratified", "test", "for", "HWE", "for", "diallelic", "markers,", "such", "as", "single-nucleotide", "polymorphisms", "(SNPs),", "and", "an", "exact", "test", "for", "homogeneity", "of", "Hardy-Weinberg", "disequilibrium.", "By", "applying", "our", "methods", "to", "data", "from", "Perlegen", "and", "HapMap--a", "combined", "total", "of", "more", "than", "five", "million", "SNP", "genotypes,", "with", "three", "to", "four", "strata", "and", "strata", "sizes", "ranging", "from", "23", "to", "60", "subjects--we", "illustrate", "that", "the", "exact", "stratified", "test", "provides", "more-robust", "and", "more-powerful", "results", "than", "those", "obtained", "by", "either", "the", "minimum", "of", "exact", "test", "P", "values", "over", "strata", "or", "approximate", "stratified", "tests", "that", "sum", "measures", "of", "departure", "from", "HWE.", "Hence,", "our", "new", "methods", "should", "be", "useful", "for", "samples", "composed", "of", "multiple", "ethnic", "groups." ]
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Exact tests of Hardy-Weinberg equilibrium and homogeneity of disequilibrium across strata. Detecting departures from Hardy-Weinberg equilibrium (HWE) of marker-genotype frequencies is a crucial first step in almost all human genetic analyses. When a sample is stratified by multiple ethnic groups, it is important to allow the marker-allele frequencies to differ over the strata. In this situation, it is common to test for HWE by using an exact test within each stratum and then using the minimum P value as a global test. This approach does not account for multiple testing, and, because it does not combine information over strata, it does not have optimal power. Several approximate methods to combine information over strata have been proposed, but most of them sum over strata a measure of departure from HWE; if the departures are in different directions, then summing can diminish the overall evidence of departure from HWE. An exact stratified test is more appealing because it uses the probability of genotype configurations across the strata as evidence for global departures from HWE. We developed an exact stratified test for HWE for diallelic markers, such as single-nucleotide polymorphisms (SNPs), and an exact test for homogeneity of Hardy-Weinberg disequilibrium. By applying our methods to data from Perlegen and HapMap--a combined total of more than five million SNP genotypes, with three to four strata and strata sizes ranging from 23 to 60 subjects--we illustrate that the exact stratified test provides more-robust and more-powerful results than those obtained by either the minimum of exact test P values over strata or approximate stratified tests that sum measures of departure from HWE. Hence, our new methods should be useful for samples composed of multiple ethnic groups.
8651297
[ "Mutations", "and", "phenotype", "in", "isolated", "glycerol", "kinase", "deficiency.", "We", "demonstrate", "that", "isolated", "glycerol", "kinase", " ", "(", "GK", ")", "deficiency", "in", "three", "families", "results", "from", "mutation", "of", "the", "Xp21", "GK", " ", "gene.", "GK", " ", "mutations", "were", "detected", "in", "four", "patients", "with", "widely", "differing", "phenotypes.", "Patient", "1", "had", "a", "splice-site", "mutation", "causing", "premature", "termination.", "His", "general", "health", "was", "good", "despite", "absent", "GK", " ", "activity,", "indicating", "that", "isolated", "GK", " ", "deficiency", "can", "be", "silent.", "Patient", "2", "had", "GK", " ", "deficiency", "and", "a", "severe", "phenotype", "involving", "psychomotor", "retardation", "and", "growth", "delay,", "bone", "dysplasia,", "and", "seizures,", "similar", "to", "the", "severe", "phenotype", "of", "one", "of", "the", "first", "described", "cases", "of", "GK", "deficiency.", "His", "younger", "brother,", "patient", "3,", "also", "had", "GK", " ", "deficiency,", "but", "so", "far", "his", "development", "has", "been", "normal.", "GK", " ", "exon", "17", "was", "deleted", "in", "both", "brothers,", "implicating", "additional", "factors", "in", "causation", "of", "the", "severe", "phenotype", "of", "patient", "2.", "Patient", "4", "had", "both", "GK", "deficiency", "with", "mental", "retardation", "and", "a", "GK", "missense", "mutation", "(", "D440V", "GK", "GK", " ", "deficiency", "with", "mental", "retardation", "and", "a", "GK", "missense", "mutation", "(D440V).", "Possible", "explanations", "for", "the", "phenotypic", "variation", "of", "these", "four", "patients", "include", "ascertainment", "bias;", "metabolic", "or", "environmental", "stress", "as", "a", "precipitating", "factor", "in", "revealing", "GK-related", "changes,", "as", "has", "previously", "been", "described", "in", "juvenile", "GK", " ", "deficiency;", "and", "interactions", "with", "functional", "polymorphisms", "in", "other", "genes", "that", "alter", "the", "effect", "of", "GK", " ", "deficiency", "on", "normal", "development." ]
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Mutations and phenotype in isolated glycerol kinase deficiency. We demonstrate that isolated glycerol kinase ( GK ) deficiency in three families results from mutation of the Xp21 GK gene. GK mutations were detected in four patients with widely differing phenotypes. Patient 1 had a splice-site mutation causing premature termination. His general health was good despite absent GK activity, indicating that isolated GK deficiency can be silent. Patient 2 had GK deficiency and a severe phenotype involving psychomotor retardation and growth delay, bone dysplasia, and seizures, similar to the severe phenotype of one of the first described cases of GK deficiency. His younger brother, patient 3, also had GK deficiency, but so far his development has been normal. GK exon 17 was deleted in both brothers, implicating additional factors in causation of the severe phenotype of patient 2. Patient 4 had both GK deficiency with mental retardation and a GK missense mutation ( D440V GK GK deficiency with mental retardation and a GK missense mutation (D440V). Possible explanations for the phenotypic variation of these four patients include ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as has previously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK deficiency on normal development.
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