{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:47:29Z","timestamp":1791978449516,"version":"4.4.0"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,3,3]],"date-time":"2024-03-03T00:00:00Z","timestamp":1709424000000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,3]]},"abstract":"\n Abstract<\/jats:title>\n \n DFNB61 is a recessively inherited nonsyndromic hearing loss caused by mutations in\n SLC26A5<\/jats:italic>\n , the gene that encodes the voltage\u2010driven motor protein, prestin. Prestin is abundantly expressed in the auditory outer hair cells that mediate cochlear amplification. Two DFNB61\u2010associated\n SLC26A5<\/jats:italic>\n variants, p.W70X and p.R130S, were identified in patients who are compound heterozygous for these nonsense and missense changes (\n \n SLC26A5\n W70X\/R130S<\/jats:sup>\n <\/jats:italic>\n ). Our recent study showed that mice homozygous for p.R130S (\n \n Slc26a5\n R130S\/R130S<\/jats:sup>\n <\/jats:italic>\n ) suffer from hearing loss that is ascribed to significantly reduced motor kinetics of prestin. Given that W70X\u2010prestin is nonfunctional, compound heterozygous\n \n Slc26a5\n R130S\/\u2212<\/jats:sup>\n <\/jats:italic>\n mice were used as a model for human\n \n SLC26A5\n W70X\/R130S<\/jats:sup>\n <\/jats:italic>\n . By examining the pathophysiological consequences of p.R130S prestin when it is the sole allele for prestin protein production, we determined that this missense change results in progressive outer hair cell loss in addition to its effects on prestin's motor action. Thus, this study defines the pathogenic roles of p.R130S prestin and identifies a limited time window for potential clinical intervention.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n The voltage\u2010driven motor protein, prestin, is encoded by\n SLC26A5<\/jats:italic>\n and expressed abundantly in cochlear outer hair cells (OHCs).\n <\/jats:p>\n <\/jats:list-item>\n \n \n The importance of prestin for normal hearing was demonstrated in mice lacking prestin; however, none of the specific\n SLC26A5<\/jats:italic>\n variants identified to date in human patients has been experimentally demonstrated to be pathogenic.\n <\/jats:p>\n <\/jats:list-item>\n \n \n In this study we used both cell lines and a mouse model to define the pathogenic role of compound heterozygous p.W70X (c.209G>A) and p.R130S (c.390A>C)\n SLC26A5<\/jats:italic>\n variants identified in patients with moderate to profound hearing loss.\n <\/jats:p>\n <\/jats:list-item>\n \n \n As in patients, mice carrying one copy of p.R130S\n Slc26a5\u00a0s<\/jats:italic>\n howed OHC dysfunction and progressive degeneration, which results in congenital progressive hearing loss.\n <\/jats:p>\n <\/jats:list-item>\n \n \n This is the first functional study reporting pathogenic\n SLC26A5<\/jats:italic>\n variants and pointing to the presence of a therapeutic time window for potential clinical interventions targeting the affected OHCs before they are lost.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp285599","type":"journal-article","created":{"date-parts":[[2024,3,3]],"date-time":"2024-03-03T12:53:40Z","timestamp":1709470420000},"page":"1199-1210","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The pathogenic roles of the p.R130S prestin variant in DFNB61\u00a0hearing loss"],"prefix":"10.1113","volume":"602","author":[{"given":"Satoe","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, Feinberg School of Medicine Northwestern University Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Communication Sciences and Disorders Northwestern University Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Ann","family":"Cheatham","sequence":"additional","affiliation":[{"name":"Department of Communication Sciences and Disorders Northwestern University Evanston Illinois USA"},{"name":"The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4440-2277","authenticated-orcid":false,"given":"Kazuaki","family":"Homma","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, Feinberg School of Medicine Northwestern University Chicago Illinois USA"},{"name":"The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University Evanston Illinois 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