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Impaired calmodulin binding of myosin‐7A causes autosomal dominant hearing loss ( DFNA11 )
Author(s) -
Bolz Hanno,
Bolz SteffenSebastian,
Schade Götz,
Kothe Christian,
Mohrmann Gerrit,
Hess Markus,
Gal Andreas
Publication year - 2004
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9272
Subject(s) - calmodulin , biology , missense mutation , mutant , myosin , myosin light chain kinase , microbiology and biotechnology , genetics , signal transduction , mutation , hearing loss , wild type , biochemistry , gene , audiology , medicine , enzyme
Both myosin 7A (MYO7A) and calmodulin (CaM) are required for transduction and adaptation processes in inner ear hair cells. We identified a novel heterozygous missense mutation (c.2557C>T; p.R853C) in a family with autosomal dominant non‐syndromic hearing loss that changes an evolutionarily invariant residue of the fifth IQ motif (IQ 5 ), a putative calmodulin (CaM) binding domain, of MYO7A. Functional effects of the p.R853C mutation were investigated in a physiological cellular environment by expressing MYO7A IQ 5 ‐containing peptides in smooth muscle cells of microarteries, in which overexpression of wildtype IQ 5 (with intact calmodulin binding) would be expected to compete with myosin light chain kinase (MLCK) for CaM binding. Indeed, analysis of calmodulin‐dependent vasoconstriction suggests constitutive binding of CaM to the wildtype, but not the p.R853C‐mutated IQ 5 motif at all physiologically relevant Ca 2+ concentrations. Thus our data suggest a disturbed CaM/MYO7A binding of the p.R853C mutant, this amino acid change may result in impaired adaptation to environmental stimuli and progressive deterioration of hearing transduction in heterozygotes. A defect in CaM/MYO7A interaction represents a novel pathomechanism for genetic hearing loss. It provides an attractive molecular target for therapeutic interventions aimed to delay or prevent the onset of hearing loss in families with mutations in myosin IQ domains. © 2004 Wiley‐Liss, Inc.