{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:55Z","timestamp":1787028235190,"version":"build-2736575974"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008856","name":"Health Commission of Zhejiang Province","doi-asserted-by":"publisher","award":["2021RC022"],"award-info":[{"award-number":["2021RC022"]}],"id":[{"id":"10.13039\/501100008856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008856","name":"Health Commission of Zhejiang Province","doi-asserted-by":"publisher","award":["20201203B210"],"award-info":[{"award-number":["20201203B210"]}],"id":[{"id":"10.13039\/501100008856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008856","name":"Health Commission of Zhejiang Province","doi-asserted-by":"publisher","award":["ZD20220010"],"award-info":[{"award-number":["ZD20220010"]}],"id":[{"id":"10.13039\/501100008856","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hangzhou Bureau of Science and Technology","award":["2021RC022"],"award-info":[{"award-number":["2021RC022"]}]},{"name":"Hangzhou Bureau of Science and Technology","award":["20201203B210"],"award-info":[{"award-number":["20201203B210"]}]},{"name":"Hangzhou Bureau of Science and Technology","award":["ZD20220010"],"award-info":[{"award-number":["ZD20220010"]}]},{"name":"Hangzhou Municipal Health Commission","award":["2021RC022"],"award-info":[{"award-number":["2021RC022"]}]},{"name":"Hangzhou Municipal Health Commission","award":["20201203B210"],"award-info":[{"award-number":["20201203B210"]}]},{"name":"Hangzhou Municipal Health Commission","award":["ZD20220010"],"award-info":[{"award-number":["ZD20220010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The mitochondrial 1555A&gt;G mutation plays a critical role in aminoglycoside-induced and non-syndromic hearing loss (AINSHL). Previous studies have suggested that mitochondrial secondary variants may modulate the clinical expression of m.1555A&gt;G-induced deafness, but the molecular mechanism has remained largely undetermined. In this study, we investigated the contribution of a deafness-associated tRNAGln 4394C&gt;T mutation to the clinical expression of the m.1555A&gt;G mutation. Interestingly, a three-generation family with both the m.1555A&gt;G and m.4394C&gt;T mutations exhibited a higher penetrance of hearing loss than another family harboring only the m.1555A&gt;G mutation. At the molecular level, the m.4394C&gt;T mutation resides within a very conserved nucleotide of tRNAGln, which forms a new base-pairing (7T-66A) and may affect tRNA structure and function. Using trans-mitochondrial cybrid cells derived from three subjects with both the m.1555A&gt;G and m.4394C&gt;T mutations, three patients with only the m.1555A&gt;G mutation and three control subjects without these primary mutations, we observed that cells with both the m.1555A&gt;G and m.4394C&gt;T mutations exhibited more severely impaired mitochondrial functions than those with only the m.1555A&gt;G mutation. Furthermore, a marked decrease in mitochondrial RNA transcripts and respiratory chain enzymes was observed in cells harboring both the m.1555A&gt;G and m.4394C&gt;T mutations. Thus, our data suggest that the m.4394C&gt;T mutation may play a synergistic role in the m.1555A&gt;G mutation, enhancing mitochondrial dysfunctions and contributing to a high penetrance of hearing loss in families with both mtDNA pathogenic mutations.<\/jats:p>","DOI":"10.3390\/genes13101794","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T20:43:21Z","timestamp":1665261801000},"page":"1794","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mitochondrial tRNAGln 4394C&gt;T Mutation May Contribute to the Clinical Expression of 1555A&gt;G-Induced Deafness"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1246-2563","authenticated-orcid":false,"given":"Yu","family":"Ding","sequence":"first","affiliation":[{"name":"Central Laboratory, Hangzhou First People\u2019s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoshu","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Hangzhou First People\u2019s Hospital, Affiliated to Zhejiang University School of Medicine, Huansha Road No. 261, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinxian","family":"Guo","sequence":"additional","affiliation":[{"name":"Central Laboratory, Hangzhou First People\u2019s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhang","family":"Leng","sequence":"additional","affiliation":[{"name":"Central Laboratory, Hangzhou First People\u2019s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16094","DOI":"10.1038\/nrdp.2016.94","article-title":"Congenital hearing loss","volume":"3","author":"Korver","year":"2017","journal-title":"Nat. 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