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Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility

Ascari, Giulia and Peelman, Frank and Farinelli, Pietro and Rosseel, Toon and Lambrechts, Nina and Wunderlich, Kirsten A. and Wagner, Matias and Nikopoulos, Konstantinos and Martens, Pernille and Balikova, Irina and Derycke, Lara and Holtappels, Gabriële and Krysko, Olga and Van Laethem, Thalia and De Jaegere, Sarah and Guillemyn, Brecht and De Rycke, Riet and De Bleecker, Jan and Creytens, David and Van Dorpe, Jo and Gerris, Jan and Bachert, Claus and Neuhofer, Christiane and Walraedt, Sophie and Bischoff, Almut and Pedersen, Lotte B. and Klopstock, Thomas and Rivolta, Carlo and Leroy, Bart P. and De Baere, Elfride and Coppieters, Frauke. (2020) Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility. Human mutation, 41 (5). pp. 998-1011.

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Abstract

Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB) > Research Group Rivolta IOB
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley Periodicals, Inc.
ISSN:1098-1004
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:23 Dec 2020 14:22
Deposited On:23 Dec 2020 14:22

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