Abstract
Whole-exome sequencing of samples from affected members of two unrelated families with late-onset non-syndromic hearing loss revealed a novel mutation (c.2090 T > G; NM_017433) in MYO3A. The mutation was confirmed in 36 affected individuals, showing autosomal dominant inheritance. The mutation alters a single residue (L697W or p.Leu697Trp) in the motor domain of the stereocilia protein MYO3A, leading to a reduction in ATPase activity, motility, and an increase in actin affinity. MYO3A-L697W showed reduced filopodial actin protrusion initiation in COS7 cells, and a predominant tipward accumulation at filopodia and stereocilia when coexpressed with wild-type MYO3A and espin-1, an actin-regulatory MYO3A cargo. The combined higher actin affinity and duty ratio of the mutant myosin cause increased retention time at stereocilia tips, resulting in the displacement of the wild-type MYO3A protein, which may impact cargo transport, stereocilia length, and mechanotransduction. The dominant negative effect of the altered myosin function explains the dominant inheritance of deafness.
Highlights
Hearing loss is the most frequent sensory disability, affecting almost 360 million people of different ages (World Health Organization, WHO, 2012)
Three different mutations were identified in MYO3A (DFNB30) in this study and all the affected individuals carried at least two of these mutations, some of them being homozygotes and others being compound heterozygotes for the mutations[3]
Several reports have identified additional MYO3A mutations associated with autosomal recessive hearing loss
Summary
Hearing loss is the most frequent sensory disability, affecting almost 360 million people of different ages (World Health Organization, WHO, 2012). It is important to note that, in addition to extensive locus heterogeneity and allelic diversity within the same locus, some genetic mutations lead to a recessive hearing loss while other mutations in the same gene lead to a dominant hearing loss. There is a lack of knowledge about the mechanisms of dominant inheritance and/or late onset hearing loss of genetic origin, any clinical data related to such phenotypes are vital to understand the molecular basis of hearing loss progression. The first report revealed an autosomal recessive mutation in a highly conserved residue of the MYO3A motor domain (p.Ser614Phe) from a consanguineous Kazakh family with a congenital hearing-loss phenotype[18]. The second report characterized an autosomal dominant mutation (p.Gly488Glu) in the MYO3A motor domain associated with progressive hearing loss in a two-generation African American family[16]. Our results allowed us to propose a model for how the mutation leads to a dominant negative impact on the function of MYO3A in inner ear hair cell stereocilia
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