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.

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Hearing loss is one of the most frequent sensorial disorders in humans. When inherited, hearing loss can be autosomal dominant or recessive, X-linked or mitochondrial. Sixty-seven loci have already been mapped and 47 genes were identified as associated with autosomal dominant hearing loss, which is responsible for about 20-30% of hereditary cases. This study aimed to investigate the frequency and the origin of the c.2090T>G p.Leu697Trp mutation in MYO3A gene, identified in the Laboratory of Human Genetics-(LGH) IBUSP as related to nonsyndromic autosomal dominant hearing loss, in Brazilian families with autosomal dominant hearing loss. This study also aimed to identify the genes and corresponding mutations that explain nonsyndromic autosomal dominant hearing loss in two large families also under investigation in LGH-IBUSP. In relation to studies regarding the c.2090T>G p.Leu697Trp mutation in MYO3A gene, the screening of this mutation in a collection of 101 probands from families with autosomal dominant hearing loss revealed the presence of the mutation in four families, in addition to the two families originally ascertained in the laboratory. We concluded that this mutation explained about 3% of autosomal dominant deafness cases investigated, and it plays an important role in causing autosomal dominant hearing loss among Brazilian families, which justifies its investigation in similar pedigrees concerning the phenotype and the mechanism of genetic transmission. Additional analysis, as identity by descent (IBD), performed by the Laboratory team, revealed a kinship coefficient equivalent to second cousins between the affected individuals of the five families, which indicates close relationship between them and a probable common origin for the mutation. The age of the mutation (age of the most recent common ancestor) was estimated near 27,4 generations, which is equivalent to about 675 years (CI: 350-1325). Local ancestry study approaches revealed that the region in which the mutation is located has European Ancestry. Though it is not possible to estimate whether the mutation arose in Europe or in Brazil in an individual of European origin, the identification of the same alteration in an individual with hearing loss in Netherlands, reported in the LOVD database,