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      Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness

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          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.

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          Author and article information

          Journal
          9215429
          2408
          Hum Mutat
          Hum. Mutat.
          Human mutation
          1059-7794
          1098-1004
          7 July 2016
          21 August 2016
          October 2016
          01 October 2017
          : 37
          : 10
          : 991-1003
          Affiliations
          [1 ]Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892
          [2 ]Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland 21201
          [3 ]Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
          [4 ]Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54550, Pakistan
          [5 ]Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
          [6 ]Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, University of Health Sciences, Lahore 54550, Pakistan
          Author notes
          [* ]Correspondence to: Thomas B. Friedman, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892. friedman@ 123456nidcd.nih.gov
          [‡]

          These authors contributed equally to this work

          Article
          PMC5021573 PMC5021573 5021573 nihpa799885
          10.1002/humu.23042
          5021573
          27375115
          db549ac6-9820-41b3-acf5-69f34a934237
          History
          Categories
          Article

          DFNB3 ,deafness,myosin 15, MYO15A ,shaker 2,giant exon,micro exon

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