Abstract
Autosomal dominant non‐syndromic hearing loss is genetically heterogeneous with 47 genes identified to date, including POU4F3. In this study, by using a next‐generation sequencing panel targeting 127 deafness genes, we identified a pathogenic frameshift mutation c.704_705del and a missense mutation c.593G>A in two three‐generation Chinese families with late‐onset progressive ADNSHL, respectively. The novel mutations of POU4F3 co‐segregated with the deafness phenotype in these two families. c.704_705del caused a frameshift p.T235fs and c.593G>A caused an amino acid substitution of p.R198H. Both mutations led to an abnormal and incomplete protein structure. POU4F3 with either of the two mutations was transiently transfected into HEI‐OC1 and HEK 293 cell lines and immunofluorescence assay was performed to investigate the subcellular localization of mutated protein. The results indicated that both c.704_705del (p.T235fs) and c.593G>A (p.R198H) could impair the nuclear localization function of POU4F3. The p.R198H POU4F3 protein was detected as a weak band of the correct molecular weight, indicating that the stability of p.R198H POU4F3 differed from that of the wild‐type protein. While, the p.T235fs POU4F3 protein was expressed with a smaller molecular weight, implying this mutation result in a frameshift and premature termination of the POU4F3 protein. In summary, we report two novel mutations of POU4F3 associated with progressive ADNSHL and explored their effects on POU4F3 nuclear localization. These findings expanded the mutation spectrum of POU4F3 and provided new knowledge for the pathogenesis of POU4F3 in hearing loss.
Highlights
Hearing loss is the most frequent sensory impairment in humans, with a morbidity of 1/1000 in newborns.[1]
For autosomal dominant non-syndrome hearing loss (ADNSHL), only 72 loci and 47 corresponding genes have been identified as causative factors
POU4F1 and POU4F2 are mainly expressed in retinal ganglion cells and involved in maintaining visual nervous system.[12]
Summary
Hearing loss is the most frequent sensory impairment in humans, with a morbidity of 1/1000 in newborns.[1]. For autosomal dominant non-syndrome hearing loss (ADNSHL), only 72 loci and 47 corresponding genes have been identified as causative factors (http://hereditaryhearingloss.org/). Because of the high genetic heterogeneity of NSHL, using conventional Sanger sequencing to identify variants causing ARNSHL is extremely time-consuming and expensive. Next-generation sequencing (NGS), characterized by high throughput and low cost, has made it possible to identify most mutations and genes involved in the onset and development of hearing loss. POU4F3-related DFNA15 manifested as late-onset bilateral, progressive hearing loss with down-sloping audiometric configurations.[13,14,15] For example, in a five-generation Dutch family linked with p.L289F on POU4F3, the progression rate for DNFA15 was 0.8-1.4 dB/year.[16]. We investigated the effects of these two mutations on the microscopic structure and subcellular location of POU4F3 in cells
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