Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility
Autor: | Jan De Bleecker, David Creytens, Matias Wagner, Sophie Walraedt, Christiane Neuhofer, Kirsten A. Wunderlich, Almut Turid Bischoff, Irina Balikova, Gabriele Holtappels, Bart P. Leroy, Pietro Farinelli, Thalia Van Laethem, Konstantinos Nikopoulos, Thomas Klopstock, Frank Peelman, Claus Bachert, Lara Derycke, Nina Lambrechts, Sarah De Jaegere, Jan Gerris, Riet De Rycke, Lotte B. Pedersen, Frauke Coppieters, Carlo Rivolta, Giulia Ascari, Elfride De Baere, Toon Rosseel, Pernille Martens, Brecht Guillemyn, Jo Van Dorpe, Olga Krysko |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Male
Models Molecular genetics [Hearing Loss] Protein Conformation Usher syndrome DNA Mutational Analysis Cell Cycle Proteins Compound heterozygosity male infertility Male infertility Medicine and Health Sciences Missense mutation Genetics(clinical) diagnosis [Hearing Loss] founder Genetics (clinical) Research Articles Genetics Genetics & Heredity 0303 health sciences 030305 genetics & heredity diagnosis [Cone-Rod Dystrophies] Syndrome Middle Aged diagnosis [Infertility Male] Founder Effect ddc Pedigree Phenotype metabolism [Cilia] genetics [Cone-Rod Dystrophies] genetics [Infertility Male] Female Life Sciences & Biomedicine metabolism [Fibroblasts] Research Article missense GENES Adolescent Genotype PROTEINS Mutation Missense ultrastructure [Cilia] Biology SPAG17 cone-rod dystrophy with hearing loss (CRDHL) 03 medical and health sciences Structure-Activity Relationship Exome Sequencing medicine CEP78 Humans genetics [Cell Cycle Proteins] Cilia ddc:610 Allele Hearing Loss Infertility Male Alleles 030304 developmental biology Science & Technology COMPLEX MUTATIONS Haplotype cilia Dystrophy Biology and Life Sciences Fibroblasts medicine.disease CENTROSOMES cone‐rod dystrophy with hearing loss (CRDHL) MODEL chemistry [Cell Cycle Proteins] Cone-Rod Dystrophies Founder effect |
Zdroj: | Human mutation 41(5), 998-1011 (2020). doi:10.1002/humu.23993 Human Mutation HUMAN MUTATION 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 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, vol. 41, no. 5, pp. 998-1011 . https://doi.org/10.1002/humu.23993 |
ISSN: | 1059-7794 1098-1004 |
Popis: | 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. ispartof: Human Mutation vol:41 issue:5 pages:998-1011 ispartof: location:United States status: published |
Databáze: | OpenAIRE |
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