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

Abstract

ABSTRACT 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.