Insights into the pathophysiology of DFNA44 hearing loss associated with CCDC50 frameshift variants

• Published in: Disease models & mechanisms Vol. 16; no. 8
• Main Authors: Lachgar-Ruiz, María, Morín, Matías, Martelletti, Elisa, Ingham, Neil J, Preite, Lorenzo, Lewis, Morag A, de Castro, Luciana Santos Serrão, Steel, Karen P, Moreno-Pelayo, Miguel Ángel
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.08.2023; The Company of Biologists
• Subjects: ccdc50; deafness; dfna44; mouse mutant; next-generation sequencing; progressive hearing loss; ymer; Deafness; Progressive hearing loss; Mouse mutant; Ymer; DFNA44; Next generation sequencing; CCDC50
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.049757

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 novel mutation in CCDC50 (c.828_858del, p.(Asp276Glufs*40)) segregating with the hearing impairment in a Spanish family with autosomal dominant DFNA44 SNHL that is predicted to disrupt the 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 old, thus 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-encoded protein Ymer. Therefore, we conclude that the CLENGL sequence is necessary to form the aggregates. Taken together the in vivo and in vitro results obtained in this study suggest that the two Spanish mutations in CCDC50 exert their effect through a dominant-negative or gain of function mechanism rather than by haploinsufficiency.