Myo3a Causes Human Dominant Deafness And Interacts With Protocadherin 15-Cd2 Isoform.

Myo3a Causes Human Dominant Deafness And Interacts With Protocadherin 15-Cd2 Isoform.

Hum Mutat. 2016 Feb 3;

Authors: Grati M, Yan D, Raval MH, Walsh T, Ma Q, Chakchouk I, Kannan-Sundhari A, Mittal R, Masmoudi S, Blanton SH, Tekin M, King MC, Yengo CM, Liu XZ

Abstract
Hereditary hearing loss is characterized by both allelic and locus genetic heterogeneity. Both recessive and dominant forms of hearing loss may be caused by different mutations in the same deafness gene. In a family with post-lingual progressive non-syndromic deafness, whole exome sequencing of genomic DNA from five hearing-impaired relatives revealed a single variant, p.Gly488Glu (rs145970949:G>A) in MYO3A, co-segregating with hearing loss as an autosomal dominant trait. This amino acid change, predicted to be pathogenic, alters a highly conserved residue in the motor domain of MYO3A. The mutation severely alters the ATPase activity and motility of the protein in vitro, and the mutant protein fails to accumulate in the filopodia tips in COS7 cells. However, the mutant MYO3A was able to reach the tips of organotypic inner ear culture hair cell stereocilia, raising the possibility of a local effect on positioning of the mechano-electrical transduction (MET) complex at the stereocilia tips. To address this hypothesis, we investigated the interaction of MYO3A with the cytosolic tail of the integral tip-link protein protocadherin 15 (PCDH15), a core component of MET complex. Interestingly, we uncovered a novel interaction between MYO3A and PCDH15 shedding new light on the function of myosin IIIA at stereocilia tips. This article is protected by copyright. All rights reserved.

PMID: 26841241 [PubMed - as supplied by publisher]

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