AUTHORS
Giulia Ascari, Frank Peelman, Pietro Farinelli, Toon Rosseel, Nina Lambrechts, Kirsten A Wunderlich, Matias Wagner, Konstantinos Nikopoulos, Pernille Martens, Irina Balikova, Lara Derycke, Gabriële Holtappels, Olga Krysko, Thalia Van Laethem, Sarah De Jaegere, Brecht Guillemyn, Riet De Rycke, Jan De Bleecker, David Creytens, Jo Van Dorpe, Jan Gerris, Claus Bachert, Christiane Neuhofer, Sophie Walraedt, Almut Bischoff, Lotte B Pedersen, Thomas Klopstock, Carlo Rivolta, Bart P Leroy, Elfride De Baere, Frauke Coppieters
Hum Mutat. 2020 May;41(5):998-1011. doi: 10.1002/humu.23993. Epub 2020 Feb 12.
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.
PMID:31999394 | PMC:PMC7187288 | DOI:10.1002/humu.23993
