共查询到20条相似文献,搜索用时 15 毫秒
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Yun Li Esther Pohl Redouane Boulouiz Margit Schraders Gudrun Nürnberg Majida Charif Simon von Ameln Ingelore Baessmann Joris A. Veltman Peter Nürnberg Christian Kubisch Abdelhamid Barakat Bernd Wollnik 《American journal of human genetics》2010,86(3):479-137
We performed genome-wide homozygosity mapping in a large consanguineous family from Morocco and mapped the autosomal-recessive nonsyndromic hearing loss (ARNSHL) in this family to the DFNB79 locus on chromosome 9q34. By sequencing of 62 positional candidate genes of the critical region, we identified a causative homozygous 11 bp deletion, c.42_52del, in the TPRN gene in all seven affected individuals. The deletion is located in exon 1 and results in a frameshift and premature protein truncation (p.Gly15AlafsX150). Interestingly, the deleted sequence is part of a repetitive and CG-rich motive predicted to be prone to structural aberrations during crossover formation. We identified another family with progressive ARNSHL linked to this locus, whose affected members were shown to carry a causative 1 bp deletion (c.1347delG) in exon 1 of TPRN. The function of the encoded protein, taperin, is unknown; yet, partial homology to the actin-caping protein phostensin suggests a role in actin dynamics. 相似文献
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Margit Schraders Laura Ruiz-Palmero Ersan Kalay Jaap Oostrik Francisco?J. del?Castillo Orhan Sezgin Andy?J. Beynon Tim?M. Strom Ronald?J.E. Pennings Celia?Zazo Seco Anne?M.M. Oonk Henricus?P.M. Kunst María Domínguez-Ruiz Ana?M. García-Arumi Miguel del?Campo Manuela Villamar Lies?H. Hoefsloot Felipe Moreno Ronald?J.C. Admiraal Ignacio del?Castillo Hannie Kremer 《American journal of human genetics》2012,91(5):883-889
Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow “U” or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis. 相似文献
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Regie?Lyn?P. Santos-Cortez Kwanghyuk Lee Zahid Azeem Patrick?J. Antonellis Lana?M. Pollock Saadullah Khan Irfanullah Paula?B. Andrade-Elizondo Ilene Chiu Mark?D. Adams Sulman Basit Joshua?D. Smith University of Washington Center?for?Mendelian Genomics Deborah?A. Nickerson Brian?M. McDermott Jr. Wasim Ahmad Suzanne?M. Leal 《American journal of human genetics》2013,93(1):132-140
Previously, DFNB89, a locus associated with autosomal-recessive nonsyndromic hearing impairment (ARNSHI), was mapped to chromosomal region 16q21–q23.2 in three unrelated, consanguineous Pakistani families. Through whole-exome sequencing of a hearing-impaired individual from each family, missense mutations were identified at highly conserved residues of lysyl-tRNA synthetase (KARS): the c.1129G>A (p.Asp377Asn) variant was found in one family, and the c.517T>C (p.Tyr173His) variant was found in the other two families. Both variants were predicted to be damaging by multiple bioinformatics tools. The two variants both segregated with the nonsyndromic-hearing-impairment phenotype within the three families, and neither mutation was identified in ethnically matched controls or within variant databases. Individuals homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies but did not show evidence of auditory or limb neuropathy. It has been demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, as well as to Deiters’ cells, the sulcus epithelium, the basilar membrane, and the surface of the spiral limbus. It is hypothesized that KARS variants affect aminoacylation in inner-ear cells by interfering with binding activity to tRNA or p38 and with tetramer formation. The identification of rare KARS variants in ARNSHI-affected families defines a gene that is associated with ARNSHI. 相似文献
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Ziv Gan-Or Naima BouslamNazha Birouk Alexandra LissoubaDaniel B. Chambers Julie VérièpeAlaura Androschuk Sandra B. LaurentDaniel Rochefort Dan SpiegelmanAlexandre Dionne-Laporte Anna SzutoMeijiang Liao Denise A. FiglewiczAhmed Bouhouche Ali BenomarMohamed Yahyaoui Reda OuazzaniGrace Yoon Nicolas DupréOksana Suchowersky Francois V. BolducJ. Alex Parker Patrick A. DionPierre Drapeau Guy A. RouleauBouchra Ouled Amar Bencheikh 《American journal of human genetics》2016,98(6):1271
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Tao Yang Jose G. Gurrola II Sui M. Chiu Peter M. Snyder 《American journal of human genetics》2009,84(5):651-657
Mutations in SLC26A4 cause nonsyndromic hearing loss associated with an enlarged vestibular aqueduct (EVA, also known as DFNB4) and Pendred syndrome (PS), the most common type of autosomal-recessive syndromic deafness. In many patients with an EVA/PS phenotype, mutation screening of SLC26A4 fails to identify two disease-causing allele variants. That a sizable fraction of patients carry only one SLC26A4 mutation suggests that EVA/PS is a complex disease involving other genetic factors. Here, we show that mutations in the inwardly rectifying K+ channel gene KCNJ10 are associated with nonsyndromic hearing loss in carriers of SLC26A4 mutations with an EVA/PS phenotype. In probands from two families, we identified double heterozygosity in affected individuals. These persons carried single mutations in both SLC26A4 and KCNJ10. The identified SLC26A4 mutations have been previously implicated in EVA/PS, and the KCNJ10 mutations reduce K+ conductance activity, which is critical for generating and maintaining the endocochlear potential. In addition, we show that haploinsufficiency of Slc26a4 in the Slc26a4+/− mouse mutant results in reduced protein expression of Kcnj10 in the stria vascularis of the inner ear. Our results link KCNJ10 mutations with EVA/PS and provide further support for the model of EVA/PS as a multigenic complex disease. 相似文献
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Alberta A.H.J. Thiadens Anneke I. den Hollander Susanne Roosing Renate C. Zekveld-Vroon Elfride De Baere Mary J. van Schooneveld Janneke J.C. van Lith-Verhoeven Norka van Moll-Ramirez L. Ingeborgh van den Born Frans P.M. Cremers Caroline C.W. Klaver 《American journal of human genetics》2009,85(2):240-247
Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes. 相似文献
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Bettina Lorenz-Depiereux Dov Tiosano Gabriele Häusler 《American journal of human genetics》2010,86(2):267-272
The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene—in addition to PHEX, FGF23, and DMP1—that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization. 相似文献
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Walid El-Sayed David A. Parry Mushtaq Ahmed Yasmin Rashid Sharifa Al Harasi Chris F. Inglehearn 《American journal of human genetics》2009,85(5):699-705
Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns. One subset, known as hypomaturation AI, is characterised by near-normal volumes of organic enamel matrix but with weak, creamy-brown opaque enamel that fails prematurely after tooth eruption. Mutations in genes critical to enamel matrix formation have been documented, but current understanding of other key events in enamel biomineralization is limited. We investigated autosomal-recessive hypomaturation AI in a consanguineous Pakistani family. A whole-genome SNP autozygosity screen identified a locus on chromosome 15q21.3. Sequencing candidate genes revealed a point mutation in the poorly characterized WDR72 gene. Screening of WDR72 in a panel of nine additional hypomaturation AI families revealed the same mutation in a second, apparently unrelated, Pakistani family and two further nonsense mutations in Omani families. Immunohistochemistry confirmed intracellular localization in maturation-stage ameloblasts. WDR72 function is unknown, but as a putative β propeller is expected to be a scaffold for protein-protein interactions. The nearest homolog, WDR7, is involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Vesicle trafficking is important in maturation-stage ameloblasts with respect to secretion into immature enamel and removal of cleaved enamel matrix proteins via endocytosis. This raises the intriguing possibility that WDR72 is critical to ameloblast vesicle turnover during enamel maturation. 相似文献
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Anna C. Thomas Hywel WilliamsNúria Setó-Salvia Chiara BacchelliDagan Jenkins Mary O’SullivanKonstantinos Mengrelis Miho IshidaLouise Ocaka Estelle ChanudetChela James Francesco LescaiGlenn Anderson Deborah MorroghMina Ryten Andrew J. DuncanYun Jin Pai Jorge M. SaraivaFabiana Ramos Bernadette FarrenDawn Saunders Bertrand VernayPaul Gissen Anna Straatmaan-IwanowskaFrank Baas Nicholas W. WoodJoshua Hersheson Henry HouldenJane Hurst Richard ScottMaria Bitner-Glindzicz Gudrun E. MooreSérgio B. Sousa Philip Stanier 《American journal of human genetics》2015,96(6):1008-1009
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Xuezhong Liu Dongyi Han Jianzhong Li Xiaomei Ouyang Xu Li Zhanguo Jin Maria Bitner-Glindzicz Heng Xu Roland D. Eavey Jonathan G. Seidman Li L. Du Pu Dai Denise Yan 《American journal of human genetics》2010,86(1):65-627
We report a large Chinese family with X-linked postlingual nonsyndromic hearing impairment in which the critical linkage interval spans a genetic distance of 5.41 cM and a physical distance of 15.1 Mb that overlaps the DFN2 locus. Mutation screening of the PRPS1 gene in this family and in the three previously reported DFN2 families identified four different missense mutations in PRPS1. These mutations result in a loss of phosphoribosyl pyrophosphate (PRPP) synthetase 1 activity, as was shown in silico by structural analysis and was shown in vitro by enzymatic activity assays in erythrocytes and fibroblasts from patients. By in situ hybridization, we demonstrate expression of Prps1 in murine vestibular and cochlea hair cells, with continuous expression in hair cells and postnatal expression in the spiral ganglion. Being the second identified gene associated with X-linked nonsyndromic deafness, PRPS1 will be a good candidate gene for genetic testing for X-linked nonsyndromic hearing loss. 相似文献
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Tom Walsh Hashem Shahin Tal Elkan-Miller Anne M. Thornton Amal Abu Rayyan Karen B. Avraham Moien Kanaan 《American journal of human genetics》2010,87(1):90-94
Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82. The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2, a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss. 相似文献
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Dikla Bandah-Rozenfeld Rob W.J. Collin Eyal Banin Karlien L.M. Coene Anna M. Siemiatkowska Lina Zelinger Dirk J. Lefeber Inbar Erdinest Francesca Simonelli Ellen A.W. Blokland Caroline C.W. Klaver Raheel Qamar Sandro Banfi Dror Sharon Anneke I. den Hollander 《American journal of human genetics》2010,87(2):199-208
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP. 相似文献
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Julie M. Schultz Zubair M. Ahmed Saima Riazuddin Ali M. Waryah Matthew F. Starost Stephanie Buckley Madhulika Kabra Muhammad J. Hassan Muhammad Ansar Edward R. Wilcox Wasim Ahmad Suzanne M. Leal Thomas B. Friedman 《American journal of human genetics》2009,85(1):25-137
A gene causing autosomal-recessive, nonsyndromic hearing loss, DFNB39, was previously mapped to an 18 Mb interval on chromosome 7q11.22-q21.12. We mapped an additional 40 consanguineous families segregating nonsyndromic hearing loss to the DFNB39 locus and refined the obligate interval to 1.2 Mb. The coding regions of all genes in this interval were sequenced, and no missense, nonsense, or frameshift mutations were found. We sequenced the noncoding sequences of genes, as well as noncoding genes, and found three mutations clustered in intron 4 and exon 5 in the hepatocyte growth factor gene (HGF). Two intron 4 deletions occur in a highly conserved sequence that is part of the 3′ untranslated region of a previously undescribed short isoform of HGF. The third mutation is a silent substitution, and we demonstrate that it affects splicing in vitro. HGF is involved in a wide variety of signaling pathways in many different tissues, yet these putative regulatory mutations cause a surprisingly specific phenotype, which is nonsydromic hearing loss. Two mouse models of Hgf dysregulation, one in which an Hgf transgene is ubiquitously overexpressed and the other a conditional knockout that deletes Hgf from a limited number of tissues, including the cochlea, result in deafness. Overexpression of HGF is associated with progressive degeneration of outer hair cells in the cochlea, whereas cochlear deletion of Hgf is associated with more general dysplasia. 相似文献
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Gaël Manes Isabelle Meunier Almudena Avila-Fernández Sandro Banfi Guylène Le Meur Xavier Zanlonghi Marta Corton Francesca Simonelli Philippe Brabet Gilles Labesse Isabelle Audo Saddek Mohand-Said Christina Zeitz José-Alain Sahel Michel Weber Hélène Dollfus Claire-Marie Dhaenens Delphine Allorge Elfride De Baere Robert K. Koenekoop Susanne Kohl Frans P.M. Cremers Joe G. Hollyfield Audrey Sénéchal Maxime Hebrard Béatrice Bocquet Carmen Ayuso García Christian P. Hamel 《American journal of human genetics》2013