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

TitleMutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness.
Publication TypeJournal Article
Year of Publication2016
AuthorsRehman, AU, Bird, JE, Faridi, R, Shahzad, M, Shah, S, Lee, K, Khan, SN, Imtiaz, A, Ahmed, ZM, Riazuddin, S, Santos-Cortez, RLyn P, Ahmad, W, Leal, SM, Riazuddin, S, Friedman, TB
JournalHum Mutat
Volume37
Issue10
Pagination991-1003
Date Published2016 10
ISSN1098-1004
KeywordsAlternative Splicing, Animals, Deafness, Disease Models, Animal, Ear, Inner, Exons, Gene Expression Regulation, Developmental, Humans, Mice, Mutation, Myosins, Stereocilia
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.

DOI10.1002/humu.23042
Alternate JournalHum. Mutat.
PubMed ID27375115
PubMed Central IDPMC5021573
Grant ListR01 DC011651 / DC / NIDCD NIH HHS / United States
R01 DC012564 / DC / NIDCD NIH HHS / United States
R01 DC011748 / DC / NIDCD NIH HHS / United States
R01 DC003594 / DC / NIDCD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
Z01 DC000048-10 / / Intramural NIH HHS / United States
Z01 DC000048 / DC / NIDCD NIH HHS / United States
R01 DC011803 / DC / NIDCD NIH HHS / United States