Mutant alleles on gene GJB2 were observed in 40% (31/77) of the subjects in the sample. Pathogenic variants were detected in only 12% (9/77) of the individuals. More studies are required to elucidate the genetic causes of hearing loss in miscegenated populations.
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.
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