NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss

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da Silva, Rodrigo Salazar ^[1] ; Goes Dantas, Vitor Lima ^[1] ; Alves, Leandro Ucela ^[1] ; Batissoco, Ana Carla ^{[1, 2]} ; Oiticica, Jeanne ^[2] ; Lawrence, Elizabeth A. ^[3] ; Kawafi, Abdelwahab ^[3] ; Yang, Yushi ^{[4, 5, 6]} ; Nicastro, Fernanda Stavale ^[7] ; Novaes, Beatriz Caiuby ^[7] ; Hammond, Chrissy ^[3] ; Kague, Erika ^{[1, 3]} ; Mingroni Netto, Regina Celia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ctr Pesquisas Genoma Humano & Celulas Tronco, Inst Biociencias, Dept Genet & Biol Evolut, BR-05508090 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Lab Otorrinolaringol LIM32, Fac Med, Hosp Clin, BR-01246903 Sao Paulo - Brazil

^[3] Univ Bristol, Sch Pharmacol Physiol & Neurosci, Bristol BS8 1TD, Avon - England

^[4] Univ Bristol, Sch Phys, Bristol BS8 1TL, Avon - England

^[5] Univ Bristol, Ctr Nanosci & Quantum Informat, Bristol BS8 1FD, Avon - England

^[6] Univ Bristol, Bristol Ctr Funct Nanomat, Bristol BS8 1FD, Avon - England

^[7] Pontificia Univ Catolica Sao Paulo, Div Educ & Reabilitacao Disturbios Comunicacao, BR-04022040 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Human Molecular Genetics; v. 29, n. 22, p. 3691-3705, NOV 15 2020.
• Citações Web of Science: 0

Resumo

Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM\_181659, c.2810C> G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3-/- did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3-/-, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3-/- and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment. (AU)

• 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