Characterization of a novel MYO3A missense mutation associated with a dominant form of late onset hearing loss

Vitor G.L. Dantas, Manmeet H. Raval, Angela Ballesteros, Runjia Cui, Laura K. Gunther, Guilherme L. Yamamoto, Leandro Ucela Alves, André Silva Bueno, Karina Lezirovitz, Sulene Pirana, Beatriz C.A. Mendes, Christopher M. Yengo, Bechara Kachar, Regina C. Mingroni-Netto

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21 Scopus citations


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; NM017433) 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.

Original languageEnglish (US)
Article number8706
JournalScientific reports
Issue number1
StatePublished - Dec 1 2018

All Science Journal Classification (ASJC) codes

  • General


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