PuSH - Publication Server of Helmholtz Zentrum München: Functional characterization of the first missense variant in <em>CEP78</em>, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility.

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Ascari, G.* ; Peelman, F.* ; Farinelli, P.* ; Rosseel, T.* ; Lambrechts, N.* ; Wunderlich, K.A.* ; Wagner, M. ; Nikopoulos, K.* ; Martens, P.* ; Balikova, I.* ; Derycke, L.* ; Holtappels, G.* ; Krysko, O.* ; Van Laethem, T.* ; De Jaegere, S.* ; Guillemyn, B.* ; De Rycke, R.* ; de Bleecker, J.* ; Creytens, D.* ; Van Dorpe, J.* ; Gerris, J.* ; Bachert, C.* ; Neuhofer, C.* ; Walraedt, S.* ; Bischoff, A.* ; Pedersen, L.B.* ; Klopstock, T.* ; Rivolta, C.* ; Leroy, B.P.* ; de Baere, E.* ; Coppieters, F.*

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

Hum. Mutat. 41, 998-1011 (2020)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cep78 ; Cilia ; Cone-rod Dystrophy With Hearing Loss (crdhl) ; Founder ; Male Infertility ; Missense

ISSN (print) / ISBN 1059-7794

e-ISSN 1098-1004

Journal Human Mutation

Quellenangaben Volume: 41, Issue: 5, Pages: 998-1011

Publisher Wiley

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)