title: Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing.
abstract: Human MYO15A is located on chromosome 17p11.2, has 66 exons and encodes unconventional myosin XVA. Recessive mutations of MYO15A are associated with profound, nonsyndromic hearing loss DFNB3 in humans, and deafness and circling behavior in shaker 2 mice. In the inner ear, this motor protein is necessary for the development of hair cell stereocilia, which are actin-filled projections on the apical surface and the site of mechanotransduction of sound. The longest isoform of myosin XVA has 3,530 amino acid residues. Two isoform classes of MYO15A are distinguished by the presence or absence of 1,203 residues preceding the motor domain encoded by alternatively-spliced exon 2. It is not known whether this large N-terminal extension of myosin XVA is functionally necessary for hearing. We ascertained approximately 600 consanguineous families segregating hereditary hearing loss as a recessive trait and found evidence of linkage of markers at the DFNB3 locus to hearing loss in 38 of these families ascertained in Pakistan (n=30), India (n=6), and Turkey (n=2). In this study, we describe 16 novel recessive mutations of MYO15A associated with severe to profound hearing loss segregating in 20 of these DFNB3-linked families. Importantly, two homozygous mutant alleles-c.3313G>T (p.E1105X) and c.3334delG (p.G1112fsX1124) of MYO15A-located in exon 2 are associated with severe to profound hearing loss segregating in two families. These data demonstrate that isoform 1, containing the large N-terminal extension, is also necessary for normal hearing.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville 20850, Maryland, USA.
authors.forename: Nevra
authors.initials: N
authors.lastname: Nal
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Engin
authors.initials: E
authors.lastname: Erkal
authors.forename: Ozgül M
authors.initials: OM
authors.lastname: Alper
authors.forename: Güven
authors.initials: G
authors.lastname: Lüleci
authors.forename: Oktay
authors.initials: O
authors.lastname: Dinç
authors.forename: Ali Muhammad
authors.initials: AM
authors.lastname: Waryah
authors.forename: Quratul
authors.initials: Q
authors.lastname: Ain
authors.forename: Saba
authors.initials: S
authors.lastname: Tasneem
authors.forename: Tayyab
authors.initials: T
authors.lastname: Husnain
authors.forename: Parna
authors.initials: P
authors.lastname: Chattaraj
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Erich
authors.initials: E
authors.lastname: Boger
authors.forename: Manju
authors.initials: M
authors.lastname: Ghosh
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morell
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
mesh_terms: D017398:Alternative Splicing; D002886:Chromosomes, Human, Pair 17; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics*; D005091:Exons; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006309:Hearing; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009218:Myosins / Q000235:genetics* / Q000502:physiology*; D010375:Pedigree; D020033:Protein Isoforms
chemical_list: C485245:MYO15A protein, human; D020033:Protein Isoforms; D009218:Myosins