Identification of novel genes and functional studies in nonsyndromic deafness
| Full text | |
| Author(s): Show less - |
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]
Total Authors: 14
|
| Affiliation: | [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
Total Affiliations: 7
|
| Document type: | Journal article |
| Source: | SCIENTIFIC REPORTS; v. 8, JUN 7 2018. |
| Web of Science Citations: | 0 |
| 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. (AU) | |
| FAPESP's process: | 98/14254-2 - The Human Genome Research Center |
| Grantee: | Mayana Zatz |
| Support type: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |
| FAPESP's process: | 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center |
| Grantee: | Mayana Zatz |
| Support type: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |