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USH3 is caused by mutations in\n                    <jats:italic>CLRN1<\/jats:italic>\n                    , which encodes clarin\u20101, a tetraspanin\u2010like protein. Mutations in\n                    <jats:italic>CLRN2<\/jats:italic>\n                    , which encodes the related protein clarin\u20102, are also implicated in progressive, non\u2010syndromic 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\n                    <jats:italic>CLRN2<\/jats:italic>\n                    . To investigate the functional interplay of these genes, we generated\n                    <jats:italic>Clrn1<\/jats:italic>\n                    <jats:sup>\u2013<\/jats:sup>\n                    <jats:sup>\/\u2212<\/jats:sup>\n                    <jats:italic>Clrn2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    double knockout mice. RNA\u2010sequencing and functional\/physiological analyses revealed that clarin\u20101 and clarin\u20102 jointly regulate mechanoelectrical transduction, ionic homeostasis, and synaptic organization. Their combined loss leads to more severe hearing phenotype compared to\n                    <jats:italic>Clrn1<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    and\n                    <jats:italic>Clrn2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, which reveals a functional compensation between them.\n                    <jats:italic>CLRN2<\/jats:italic>\n                    variants may exacerbate hearing loss in USH3 patients, supporting inclusion of\n                    <jats:italic>CLRN2<\/jats:italic>\n                    in genetic screening. By revealing a functional, compensatory interplay between clarin\u20101 and clarin\u20102, this study reframes\n                    <jats:italic>CLRN1\u2010<\/jats:italic>\n                    associated deafness as a network\u2010dependent disorder and provides a mechanistic basis for genetic stratification and therapeutic directions in USH3 and related sensorineural hearing loss.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521853","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T05:30:13Z","timestamp":1769146213000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Compensatory Interplay Between Clarin\u20101 and Clarin\u20102 Deafness\u2010Associated Proteins Governs Phenotypic Variability in Hearing"],"prefix":"10.1002","volume":"13","author":[{"given":"Maureen","family":"Wentling","sequence":"first","affiliation":[{"name":"Institut Pasteur Institut De L'audition, 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