Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness

Human MutationVolume 37, Issue 10 p. 991-1003 Mutation Update Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness Atteeq U. Rehman, Atteeq U. Rehman Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892 These authors contributed equally to this work. Current address: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.Search for more papers by this authorJonathan E. Bird, Jonathan E. Bird Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892 These authors contributed equally to this work.Search for more papers by this authorRabia Faridi, Rabia Faridi Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892 Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 54550 PakistanSearch for more papers by this authorMohsin Shahzad, Mohsin Shahzad Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201Search for more papers by this authorSujay Shah, Sujay Shah Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892Search for more papers by this authorKwanghyuk Lee, Kwanghyuk Lee Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030Search for more papers by this authorShaheen N. Khan, Shaheen N. Khan Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 54550 PakistanSearch for more papers by this authorAyesha Imtiaz, Ayesha Imtiaz Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892Search for more papers by this authorZubair M. Ahmed, Zubair M. Ahmed Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201Search for more papers by this authorSaima Riazuddin, Saima Riazuddin Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201Search for more papers by this authorRegie Lyn P. Santos-Cortez, Regie Lyn P. Santos-Cortez Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030Search for more papers by this authorWasim Ahmad, Wasim Ahmad Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320 PakistanSearch for more papers by this authorSuzanne M. Leal, Suzanne M. Leal Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030Search for more papers by this authorSheikh Riazuddin, Sheikh Riazuddin Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, University of Health Sciences, Lahore, 54550 PakistanSearch for more papers by this authorThomas B. Friedman, Corresponding Author Thomas B. Friedman friedman@nidcd.nih.gov Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892Correspondence to: Thomas B. Friedman, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892. E-mail: friedman@nidcd.nih.govSearch for more papers by this author Atteeq U. Rehman, Atteeq U. Rehman Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892 These authors contributed equally to this work. Current address: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.Search for more papers by this authorJonathan E. Bird, Jonathan E. Bird Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892 These authors contributed equally to this work.Search for more papers by this authorRabia Faridi, Rabia Faridi Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892 Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 54550 PakistanSearch for more papers by this authorMohsin Shahzad, Mohsin Shahzad Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201Search for more papers by this authorSujay Shah, Sujay Shah Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892Search for more papers by this authorKwanghyuk Lee, Kwanghyuk Lee Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030Search for more papers by this authorShaheen N. Khan, Shaheen N. Khan Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 54550 PakistanSearch for more papers by this authorAyesha Imtiaz, Ayesha Imtiaz Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892Search for more papers by this authorZubair M. Ahmed, Zubair M. Ahmed Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201Search for more papers by this authorSaima Riazuddin, Saima Riazuddin Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201Search for more papers by this authorRegie Lyn P. Santos-Cortez, Regie Lyn P. Santos-Cortez Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030Search for more papers by this authorWasim Ahmad, Wasim Ahmad Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320 PakistanSearch for more papers by this authorSuzanne M. Leal, Suzanne M. Leal Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030Search for more papers by this authorSheikh Riazuddin, Sheikh Riazuddin Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, University of Health Sciences, Lahore, 54550 PakistanSearch for more papers by this authorThomas B. Friedman, Corresponding Author Thomas B. Friedman friedman@nidcd.nih.gov Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892Correspondence to: Thomas B. Friedman, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892. E-mail: friedman@nidcd.nih.govSearch for more papers by this author First published: 04 July 2016 https://doi.org/10.1002/humu.23042Citations: 50 Current address: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030. Contract grant sponsors: Intramural Research Program of the NIDCD/NIH (DC000048-19); Higher Education Commission of Pakistan (HEC); NIDCD (grants R01 DC003594, R01 DC011651, R01DC012564, R01DC011803). Communicated by Jürgen Horst Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat ABSTRACT Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal-recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A. Citing Literature Supporting Information Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Filename Description humu23042-sup-0001-SupMat.docx1.2 MB Supp. Figure S1. The six-nucleotide microexon 8 of MYO15A and surrounding splice acceptor and splice donor sites are evolutionary conserved. Nucleotides not identical to human MYO15A sequence are shown in red. Nucleotide sequences and their alignment were retrieved from the “conservation track” of the UCSC Genome Browser (https://genome.ucsc.edu/). Supp. Figure S2. Seventeen pedigrees of families co-segregating deafness and mutations of MYO15A. Fourteen of these mutations are novel while the remaining four mutations p.Gln1229*, p.Gln1510*, p.Ile1633Thr and p.Arg1937Cys have been reported and hence are either recurrent mutational events or founder alleles (see Table 3). In family PKDF132, two affected males (highlighted by dashed-rectangles) are not homozygous for the p.Gln1510* mutation and represent another case of intrafamilial genetic heterogeneity, a phenomenon we documented in consanguineous and non-consanguineous families segregating hereditary deafness [Rehman et al., 2015]. An apparently normal hearing female highlighted by a grey rectangle in family PKDF132 is homozygous for p.Gln1510*. She was unavailable for evaluation of her hearing by an audiologist. humu23042-sup-0002-TableS1.xlsx44.5 KB Supp. Table S1. Mutations of MYO15A Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume37, Issue10October 2016Pages 991-1003 RelatedInformation