title: Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness.
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.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Atteeq U
authors.initials: AU
authors.lastname: Rehman
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Bird
authors.affiliation: 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, Pakistan.
authors.forename: Rabia
authors.initials: R
authors.lastname: Faridi
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Shahzad
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Sujay
authors.initials: S
authors.lastname: Shah
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 54550, Pakistan.
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Imtiaz
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201.
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.affiliation: Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, 21201.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, University of Health Sciences, Lahore, 54550, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892. friedman@nidcd.nih.gov.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D003638:Deafness / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D009154:Mutation; D009218:Myosins / Q000235:genetics* / Q000378:metabolism*; D059547:Stereocilia / Q000378:metabolism / Q000473:pathology
chemical_list: C485245:MYO15A protein, human; D009218:Myosins
keywords: DFNB3; MYO15A; deafness; giant exon; micro exon; myosin 15; shaker 2