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However, the molecular mechanism through which\n                    <jats:italic>GAS2<\/jats:italic>\n                    variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in\n                    <jats:italic>GAS2<\/jats:italic>\n                    (c.616\u20132\u00a0A\u2009&gt;\u2009G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS\/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of\n                    <jats:italic>GAS2<\/jats:italic>\n                    promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of\n                    <jats:italic>GAS2<\/jats:italic>\n                    variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent\n                    <jats:italic>GAS2<\/jats:italic>\n                    -associated progressive hearing loss.\n                  <\/jats:p>","DOI":"10.1186\/s40246-024-00628-2","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T04:01:47Z","timestamp":1719892907000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family"],"prefix":"10.1186","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1745-081X","authenticated-orcid":false,"given":"Luping","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danya","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"628_CR1","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1182\/blood-2011-11-393983","volume":"120","author":"T Asai","year":"2012","unstructured":"Asai T, Liu Y, Di Giandomenico S, Bae N, Ndiaye-Lobry D, Deblasio A, Menendez S, Antipin Y, Reva B, Wevrick R, Nimer SD. 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