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As part of our clinical genetic studies, we ascertained a previously unreported mutation in CCDC50 [c.828_858del, p.(Asp276Glufs*40)] segregating with hearing impairment in a Spanish family with SNHL associated with the autosomal dominant deafness locus DFNA44, which is predicted to disrupt protein function. To gain insight into the mechanism behind DFNA44 mutations, we analysed two Ccdc50 presumed loss-of-function mouse mutants, which showed normal hearing thresholds up to 6\u2005months of age, indicating that haploinsufficiency is unlikely to be the pathogenic mechanism. We then carried out in vitro studies on a set of artificial mutants and on the p.(Asp276Glufs*40) and p.(Phe292Hisfs*37) human mutations, and determined that only the mutants containing the six-amino-acid sequence CLENGL as part of their aberrant protein tail showed an abnormal distribution consisting of perinuclear aggregates of the CCDC50 protein (also known as Ymer). Therefore, we conclude that the CLENGL sequence is necessary to form these aggregates. Taken together, the in vivo and in vitro results obtained in this study suggest that the two identified mutations in CCDC50 exert their effect through a dominant-negative or gain-of-function mechanism rather than by haploinsufficiency.<\/jats:p>","DOI":"10.1242\/dmm.049757","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T11:57:15Z","timestamp":1683806235000},"source":"Crossref","is-referenced-by-count":3,"title":["Insights into the pathophysiology of DFNA44 hearing loss associated with <i>CCDC50<\/i> frameshift variants"],"prefix":"10.1242","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0285-622X","authenticated-orcid":false,"given":"Mar\u00eda","family":"Lachgar-Ruiz","sequence":"first","affiliation":[{"name":"Wolfson Centre for Age-Related Diseases, King's College London 1 , Guy's Campus, London SE1 1UL , UK"},{"name":"Servicio de Gen\u00e9tica, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER) 2 , km 9.100, 28034 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7985-592X","authenticated-orcid":false,"given":"Mat\u00edas","family":"Mor\u00edn","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER) 2 , km 9.100, 28034 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8038-8866","authenticated-orcid":false,"given":"Elisa","family":"Martelletti","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Age-Related Diseases, King's College London 1 , Guy's Campus, London SE1 1UL , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0916-7347","authenticated-orcid":false,"given":"Neil J.","family":"Ingham","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Age-Related Diseases, King's College London 1 , Guy's Campus, London SE1 1UL , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Preite","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Age-Related Diseases, King's College London 1 , Guy's Campus, London SE1 1UL , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1846-8600","authenticated-orcid":false,"given":"Morag A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Age-Related Diseases, King's College London 1 , Guy's Campus, London SE1 1UL , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luciana Santos","family":"Serr\u00e3o de Castro","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER) 2 , km 9.100, 28034 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-5359","authenticated-orcid":false,"given":"Karen P.","family":"Steel","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Age-Related Diseases, King's College London 1 , Guy's Campus, London SE1 1UL , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3839-5098","authenticated-orcid":false,"given":"Miguel \u00c1ngel","family":"Moreno-Pelayo","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER) 2 , km 9.100, 28034 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"2023081707130948900_DMM049757C1","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.ajhg.2018.08.006","article-title":"Genomic landscape and mutational signatures of deafness-associated genes","volume":"103","author":"Azaiez","year":"2018","journal-title":"Am. 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