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
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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