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This study identified a novel\n                    <jats:italic>KCNQ4<\/jats:italic>\n                    variant, c.825G&gt;T (p.Trp275Cys), associated with progressive hereditary hearing loss in a family. In\u00a0vitro experiments and structural predictions revealed that this mutation did not affect KCNQ4 channel localization, subunit assembly, or pore size. However, the mutation induced longitudinal extension of the channel, reduced protein stability, and impaired potassium ion selectivity, thereby disrupting potassium ion homeostasis in the inner ear and ultimately leading to hearing loss. Zebrafish models further validated the critical role of the\n                    <jats:italic>kcnq4<\/jats:italic>\n                    gene in inner ear development. We used morpholino to knock down\n                    <jats:italic>kcnq4<\/jats:italic>\n                    in zebrafish and rescued the phenotype by reintroducing wild\u2010type\n                    <jats:italic>kcnq4<\/jats:italic>\n                    mRNA. This approach revealed significant changes in otolith morphology, a marked reduction in hair cell numbers, and abnormal motor responses. Additionally, we cloned and completed the coding sequence (CDS) of\n                    <jats:italic>kcnq4<\/jats:italic>\n                    mRNA from the AB strain of zebrafish, enriching the available database information. Our findings provide new insights into the molecular mechanisms underlying\n                    <jats:italic>KCNQ4<\/jats:italic>\n                    \u2010related hereditary hearing loss and lay the groundwork for developing precision treatments and early intervention strategies.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500557r","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T10:17:12Z","timestamp":1765361832000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathogenic Mechanism of the\n                    <i>KCNQ4<\/i>\n                    Gene Variant in Hearing Loss and Functional Validation in a Zebrafish Model"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6444-5426","authenticated-orcid":false,"given":"Hui","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou Gansu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou Gansu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0340-6180","authenticated-orcid":false,"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Genetics, International School of Medicine Zhejiang University  Hangzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou Gansu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-6736","authenticated-orcid":false,"given":"Min\u2010Xin","family":"Guan","sequence":"additional","affiliation":[{"name":"Institute of Genetics, International School of Medicine Zhejiang University  Hangzhou Zhejiang China"},{"name":"Center for Mitochondrial Biomedicine, the Fourth Affiliated Hospital Zhejiang University School of Medicine  Yiwu Zhejiang China"},{"name":"Center for Genetic Medicine, International Institute of Medicine Zhejiang University  Yiwu Zhejiang China"},{"name":"Joint Institute of Genetics and Genomic Medicine Between Zhejiang University and University of Toronto  Zhejiang Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4650-5237","authenticated-orcid":false,"given":"Yufen","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou Gansu China"},{"name":"Gansu Provincial Committee of the Chinese People's Political Consultative Conference  Lanzhou Gansu China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"World Health Organization \u201cDeafness and Hearing Loss \u201d(2024) https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/deafness\u2010and\u2010hearing\u2010loss\/."},{"key":"e_1_2_11_3_1","unstructured":"w.Walls H.Azaiez andR. 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