Insights into the pathophysiology of DFNA44 hearing loss associated with CCDC50 frameshift variants.
| Autor: | Lachgar-Ruiz M; Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK.; Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER), km 9.100, 28034 Madrid, Spain., Morín M; Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER), km 9.100, 28034 Madrid, Spain., Martelletti E; Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK., Ingham NJ; Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK., Preite L; Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK., Lewis MA; Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK., Serrão de Castro LS; Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER), km 9.100, 28034 Madrid, Spain., Steel KP; Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK., Moreno-Pelayo MÁ; Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS and Biomedical Network Research Centre on Rare Diseases (CIBERER), km 9.100, 28034 Madrid, Spain. |
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| Jazyk: | angličtina |
| Zdroj: | Disease models & mechanisms [Dis Model Mech] 2023 Aug 01; Vol. 16 (8). Date of Electronic Publication: 2023 Aug 17. |
| DOI: | 10.1242/dmm.049757 |
| Abstrakt: | Non-syndromic sensorineural hearing loss (SNHL) is the most common sensory disorder, and it presents a high genetic heterogeneity. 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 months 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. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2023. Published by The Company of Biologists Ltd.) |
| Databáze: | MEDLINE |
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