Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility.
Adolescent
Alleles
Cell Cycle Proteins
/ chemistry
Cilia
/ metabolism
Cone-Rod Dystrophies
/ diagnosis
DNA Mutational Analysis
Female
Fibroblasts
/ metabolism
Founder Effect
Genotype
Hearing Loss
/ diagnosis
Humans
Infertility, Male
/ diagnosis
Male
Middle Aged
Models, Molecular
Mutation, Missense
Pedigree
Phenotype
Protein Conformation
Structure-Activity Relationship
Syndrome
Exome Sequencing
CEP78
cilia
cone-rod dystrophy with hearing loss (CRDHL)
founder
male infertility
missense
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
01
08
2019
revised:
27
12
2019
accepted:
16
01
2020
pubmed:
31
1
2020
medline:
22
7
2021
entrez:
31
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31999394
doi: 10.1002/humu.23993
pmc: PMC7187288
doi:
Substances chimiques
CEP78 protein, human
0
Cell Cycle Proteins
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
998-1011Informations de copyright
© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.
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