ABSTRACT Usher syndrome type III (USH3) is a genetic disorder characterized by progressive, post‐lingual hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa. USH3 is caused by mutations in CLRN1 , which encodes clarin‐1, a tetraspanin‐like protein. Mutations in CLRN2 , which encodes the related protein clarin‐2, are also implicated in progressive, non‐syndromic hearing loss in both humans and mice. USH3 patients show considerable phenotypic variability, even among individuals with the same mutation. This variability may result from environmental factors or interactions with other inner ear genes, such as CLRN2 . To investigate the functional interplay of these genes, we generated Clrn1 – /− Clrn2 −/− double knockout mice. RNA‐sequencing and functional/physiological analyses revealed that clarin‐1 and clarin‐2 jointly regulate mechanoelectrical transduction, ionic homeostasis, and synaptic organization. Their combined loss leads to more severe hearing phenotype compared to Clrn1 −/− and Clrn2 −/− mice, which reveals a functional compensation between them. CLRN2 variants may exacerbate hearing loss in USH3 patients, supporting inclusion of CLRN2 in genetic screening. By revealing a functional, compensatory interplay between clarin‐1 and clarin‐2, this study reframes CLRN1‐ associated deafness as a network‐dependent disorder and provides a mechanistic basis for genetic stratification and therapeutic directions in USH3 and related sensorineural hearing loss.
Wentling et al. (Thu,) studied this question.