NCOA3identified as a new candidate to explain autosomal dominant progressive hearing loss

Abstract

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.

Non-Syndromic Autosomal Dominant Hearing Loss: The First Italian Family Carrying a Mutation in the NCOA3 Gene

“…Finally, the last two variants (c.2909G>C in the NCOA3 gene and c.9722T>A in the P KHD1L1 gene) were located in genes encoding for proteins described as being involved in normal hearing function [ 7 , 12 ]. The variant located in PKHD1L1 co-segregated with HL only in half of the patients, while the one within the NCOA3 gene was in all the affected members of the family ( Figure 3 A), except for patient III:8 ( Table 2 ).…”

“…The Nuclear Receptor Coactivator 3 ( NCOA3 ) gene comprises 23 exons and encodes a protein of 1420 amino acids involved in the regulation of gene transcription [ 7 ]. Previous studies suggested a link between NCOA3 variants and different pathologies, such as hypertriglyceridemia, obesity and dyslipidemia [ 18 ], or an association with the progression of post-traumatic osteoarthritis, bone mass, abnormal cartilage behavior and notch signaling pathway [ 7 , 19 ].…”

“…The Nuclear Receptor Coactivator 3 ( NCOA3 ) gene comprises 23 exons and encodes a protein of 1420 amino acids involved in the regulation of gene transcription [ 7 ]. Previous studies suggested a link between NCOA3 variants and different pathologies, such as hypertriglyceridemia, obesity and dyslipidemia [ 18 ], or an association with the progression of post-traumatic osteoarthritis, bone mass, abnormal cartilage behavior and notch signaling pathway [ 7 , 19 ]. Recently, da Silva et al described a clear correlation between the NCOA3 gene and HL, showing the involvement of the protein in the development and physiology of the mouse auditory system and describing a family affected by ADNSHL carrying a missense variant in this gene [ 7 ].…”

“…Previous studies suggested a link between NCOA3 variants and different pathologies, such as hypertriglyceridemia, obesity and dyslipidemia [ 18 ], or an association with the progression of post-traumatic osteoarthritis, bone mass, abnormal cartilage behavior and notch signaling pathway [ 7 , 19 ]. Recently, da Silva et al described a clear correlation between the NCOA3 gene and HL, showing the involvement of the protein in the development and physiology of the mouse auditory system and describing a family affected by ADNSHL carrying a missense variant in this gene [ 7 ]. In the present work, we reported the second family worldwide with a mutation within the NCOA3 gene and a HL phenotype.…”

“…Here, we describe an Italian family affected by ADNSHL carrying a likely pathogenic variant in NCOA3 , a gene recently described as a novel candidate for autosomal dominant progressive hearing loss in a Brazilian family [ 7 ].…”