Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11).
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 (IQ5), 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 IQ5-containing peptides in smooth muscle cells of microarteries, in which overexpression of wildtype IQ5 (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 IQ5 motif at all physiologically relevant Ca2+ 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.
Bolz
Hanno
H
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Butenfeld 42, Hamburg, Germany. hanno.bolz@uk-koeln.de
Bolz
Steffen-Sebastian
SS
Schade
Götz
G
Kothe
Christian
C
Mohrmann
Gerrit
G
Hess
Markus
M
Gal
Andreas
A
D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D001667:Binding, Competitive; D002147:Calmodulin / Q000378:metabolism*; D006224:Cricetinae; D018900:Dinucleotide Repeats; D004398:Dyneins; D005260:Female; D005799:Genes, Dominant; D034381:Hearing Loss / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009129:Muscle Tonus; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D020125:Mutation, Missense; D000081412:Myosin VIIa; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014661:Vasoconstriction / Q000235:genetics / Q000502:physiology
D002147:Calmodulin; C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D011993:Recombinant Fusion Proteins; D009219:Myosin-Light-Chain Kinase; D009218:Myosins; D004398:Dyneins