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

Autor(es):Mostrar menos -

Dantas, Vitor G. L. ^[1] ; Raval, Manmeet H. ^[2] ; Ballesteros, Angela ^[3] ; Cui, Runjia ^[3] ; Gunther, Laura K. ^[2] ; Yamamoto, Guilherme L. ^[1] ; Alves, Leandro Ucela ^[1] ; Bueno, Andre Silva ^[1] ; Lezirovitz, Karina ^{[1, 4]} ; Pirana, Sulene ^{[5, 6]} ; Mendes, Beatriz C. A. ^[7] ; Yengo, Christopher M. ^[2] ; Kachar, Bechara ^[3] ; Mingroni-Netto, Regina C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Pesquisas Genoma Humano & Celulas Tronco, Sao Paulo - Brazil

^[2] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 - USA

^[3] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 - USA

^[4] Univ Sao Paulo, Fac Med, Hosp Clin, Lab Otorrinolaringol LIM32, Sao Paulo - Brazil

^[5] Univ Sao Francisco, Braganca Paulista, SP - Brazil

^[6] UNIFAL Univ Fed Alfenas, Alfenas - Brazil

^[7] Pontificia Univ Catolica Sao Paulo, Div Educ & Reabilitacao Disturbios Comunicacao, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 8, JUN 7 2018.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 98/14254-2 - Centro de Estudos do Genoma Humano
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs