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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
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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]
Número total de Autores: 14
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
Número total de Afiliações: 7
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
Linha de fomento: 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
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs