Distinct expression and function of whirlin isoforms in the inner ear and retina: An insight into pathogenesis of USH2D and DFNB31

Abstract

Usher syndrome (USH) is the most common inherited deaf-blindness with the majority of USH causative genes also involved in nonsyndromic recessive deafness (DFNB). The mechanism underlying this disease variation of USH genes is unclear. Here, we addressed this issue by investigating the DFNB31 gene, whosemutations cause USH2D or DFNB31 depending on their position. We found that the mouse DFNB31 ortholog (Dfnb31) expressed differentmRNAvariants andwhirlin protein isoforms in the cochlea and retina, where these isoforms played different roles spatially and temporally. Full-length (FL-) whirlin in photoreceptors and hair cell stereociliary bases is important for the USH type 2 protein complex, while FL- and C-terminal (C-) whirlins in hair cell stereociliary tips participate in stereociliary elongation. Mutations in thewhirlin N-terminal region disrupted FL-whirlin isoformin the inner ear and retina but not C-whirlin in the inner ear, and led to retinal degeneration aswell asmoderate to severe hearing loss. By contrast, amutation in the whirlin C-terminal region eliminated all normal whirlin isoforms but generated a truncated N-terminal whirlin protein fragment, which was partially functional in the retina and thus prevented retinal degeneration. Mice with this mutation had profound hearing loss. In summary, disruption of distinctwhirlin isoformsby Dfnb31 mutations leads to a variety of phenotype configurations and may explain the mechanism underlying the different disease manifestations of human DFNB31 mutations. Our findings have a potential to improve diagnosis and treatment of USH disease and quality of life in USH patients.