{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T20:57:26Z","timestamp":1784235446489,"version":"3.55.0"},"reference-count":68,"publisher":"The Company of Biologists","issue":"11","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DC014553"],"award-info":[{"award-number":["DC014553"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DC017482"],"award-info":[{"award-number":["DC017482"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["18K16869"],"award-info":[{"award-number":["18K16869"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["20K18330"],"award-info":[{"award-number":["20K18330"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["21K09574"],"award-info":[{"award-number":["21K09574"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Oto-Rhino-Laryngological Society of Japan"},{"name":"Hugh Knowles Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>KCNQ4 encodes the homotetrameric voltage-dependent potassium ion channel Kv7.4, and is the causative gene for autosomal dominant nonsyndromic sensorineural hearing loss, DFNA2. Dominant-negative inhibition accounts for the observed dominant inheritance of many DFNA2-associated KCNQ4 variants. In addition, haploinsufficiency has been presumed as the pathological mechanism for truncated Kv7.4 variants lacking the C-terminal tetramerization region, as they are unlikely to exert a dominant-negative inhibitory effect. Such truncated Kv7.4 variants should result in relatively mild hearing loss when heterozygous; however, this is not always the case. In this study, we characterized Kv7.4Q71fs (c.211delC), Kv7.4W242X (c.725G&amp;gt;A) and Kv7.4A349fs (c.1044_1051del8) in heterologous expression systems and found that expression of these truncated Kv7.4 variants induced cell death. We also found similar cell death-inducing cytotoxic effects in truncated Kv7.1 (KCNQ1) variants, suggesting that the generality of our findings could account for the dominant inheritance of many, if not most, truncated Kv7 variants. Moreover, we found that the application of autophagy inducers can ameliorate the cytotoxicity, providing a novel insight for the development of alternative therapeutic strategies for Kv7.4 variants.<\/jats:p>","DOI":"10.1242\/dmm.049015","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T07:50:29Z","timestamp":1633679429000},"source":"Crossref","is-referenced-by-count":10,"title":["Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss"],"prefix":"10.1242","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7492-165X","authenticated-orcid":false,"given":"Takashi","family":"Kojima","sequence":"first","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"},{"name":"Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7335-3622","authenticated-orcid":false,"given":"Koichiro","family":"Wasano","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"},{"name":"Laboratory of Auditory Disorders, Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4264-3023","authenticated-orcid":false,"given":"Satoe","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, 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, IL 60611, USA"},{"name":"The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, IL 60608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"2021112610023193000_DMM049015C1","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.leukres.2007.11.039","article-title":"Irreversible sensorineural hearing loss due to Imatinib","volume":"32","author":"Attili","year":"2008","journal-title":"Leuk. 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