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.
Highlights
Hearing loss affects almost 466 million people worldwide and is estimated to affect more than 900 million people by 2050 [1]
Genetic factors play an important role in the pathogenesis of the disease, with up to 55% of age-related hearing loss attributed to genetics [2]
Our work provides evidence of NCOA3 playing an important role in skeletal system homeostasis and suggests NCOA3 as a potential candidate gene associated with hearing impairment
Summary
Hearing loss affects almost 466 million people worldwide and is estimated to affect more than 900 million people by 2050 [1]. Genetic factors play an important role in the pathogenesis of the disease, with up to 55% of age-related hearing loss attributed to genetics [2]. 70% of hereditary deafness cases are non-syndromic [3], of which 20% are autosomal dominant [2]. Autosomal dominant non-syndromic hearing loss (ADNSHL) is typically progressive with late and variable average age of onset, which depends on the nature of the type of mutation and affected gene. Mapping studies of large families have contributed to the identification of several genes associated with hearing loss [4]. The genetic complexity of the condition is highlighted by the large number of genes identified as associated to monogenic inheritance of non-syndromic hearing loss (∼130), and among these, near 50 were related to ADNSHL [9]. Functional studies are key to validate the genetic findings
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