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

  • Sci Rep. 2018 Jun 7;8(1):8706. doi: 10.1038/s41598-018-26818-2.
Vitor G L Dantas  1 ,  Manmeet H Raval  2 ,  Angela Ballesteros  3 ,  Runjia Cui  3 ,  Laura K Gunther  2 ,  Guilherme L Yamamoto  1 ,  Leandro Ucela Alves  1 ,  André Silva Bueno  1 ,  Karina Lezirovitz  1  4 ,  Sulene Pirana  5  6 ,  Beatriz C A Mendes  7 ,  Christopher M Yengo  8 ,  Bechara Kachar  9 ,  Regina C Mingroni-Netto  10
Affiliations
  • 1. Centro de Pesquisas sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
  • 2. Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA, 17033, USA.
  • 3. Laboratory of Cell Structure and Dynamics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 4. Laboratório de Otorrinolaringologia/LIM32 - Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
  • 5. UNIFAL - Universidade Federal de Alfenas, Alfenas, Brazil.
  • 6. Universidade São Francisco, Braganca Paulista, Brazil.
  • 7. Divisão de Educação e Reabilitação dos Distúrbios da Comunicação da Pontifícia Universidade Católica de São Paulo, São Paulo, Brazil.
  • 8. Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA, 17033, USA. [email protected].
  • 9. Laboratory of Cell Structure and Dynamics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892, USA. [email protected].
  • 10. Centro de Pesquisas sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil. [email protected].
PMID: 29880844 DOI: 10.1038/s41598-018-26818-2
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.