@article{2db8996e104a492da9fab8e17e3b4199,
title = "Insights into the pathophysiology of DFNA44 hearing loss associated with CCDC50 frameshift variants",
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.",
keywords = "CCDC50, Deafness, DFNA44, Mouse mutant, Next-generation sequencing, Progressive hearing loss, Ymer",
author = "Marı{\'a} Lachgar-Ruiz and Matı{\'a}s Morın and Elisa Martelletti and Ingham, {Neil J.} and Lorenzo Preite and Lewis, {Morag A.} and {de Castro}, {Luciana Santos Serra{\~o}} and Steel, {Karen P.} and Moreno-Pelayo, {Miguel {\'A}ngel}",
note = "Funding Information: We thank the Wellcome Sanger Institute and its funders for providing the mutant mouse line Ccdc50tm1a, and the INFRAFRONTIER/EMMA (www.infrafrontier.eu) partner (Harwell) from which the mouse was received. Funding information may be found at www.sanger.ac.uk/mouseportal and the associated primary phenotypic information at www.mousephenotype.org. This work has been funded by the Instituto de Salud Carlos III (ISCIII) through the project PI20/0429 (to M.A.M.-P.) and co-funded by the European Union within the Spanish National Plan for Scientific and Technical Research and Innovation 2014-2016, 2017-2020 and 2021-2024 (PI14/0948, PI17/1659 and IMP/00009 to M.A.M.-P.); the Regional Government of Madrid Comunidad de Madrid (B2017/ BMD3721 to M.A.M.-P.); the Wellcome Trust (WT089622MA to K.P.S.) and the Royal National Institute for Deaf People (S28 to K.P.S). L.S.S.d.C. was supported by a post-doctoral training grant (201399/2012-1) from the Programa Ci{\^e}ncia sem Fronteiras and Conselho Nacional de Desenvolvimento Cientı{\'f}ico e Tecnol{\'o}gico (Brazil). Open Access funding provided by Instituto de Salud Carlos III (PI20-0429) and co-funded by the European Union within the Spanish National Plan for Scientific and Technical Research and Innovation. Deposited in PMC for immediate release. Publisher Copyright: {\textcopyright} 2023. Published by The Company of Biologists Ltd.",
year = "2023",
month = aug,
day = "17",
doi = "10.1242/dmm.049757",
language = "English",
volume = "16",
journal = "Disease models & mechanisms",
issn = "1754-8403",
publisher = "The Company of Biologists",
number = "8",
}
