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Hum Mutat. 2020 Jan 30. doi: 10.1002/humu.23993. [Epub ahead of print]

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

Author information

1
Department of Biomolecular Medicine, Center for Medical Genetics Ghent, Ghent University Hospital, Ghent University, Ghent, Belgium.
2
Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology (VIB), Ghent University, Ghent, Belgium.
3
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
4
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
5
Department of Physiological Genomics, BMC, Ludwig-Maximilians-Universität München, Planegg, Germany.
6
Institute of Human Genetics, Faculty of Medicine, Technical University of Munich, Munich, Germany.
7
Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
8
Institut für Neurogenomik, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
9
Oncogenomics laboratory, Department of Hematology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
10
Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
11
Department of Ophthalmology, University Hospital Leuven, Leuven, Belgium.
12
Upper Airways Research Laboratory, Department Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium.
13
Department of Biomedical Molecular Biology and Expertise Centre for Transmission Electron Microscopy, Ghent University, Ghent, Belgium.
14
VIB Center for Inflammation Research and BioImaging Core, VIB, Ghent, Belgium.
15
Department of Neurology, Ghent University Hospital, Ghent, Belgium.
16
Department of Pathology, Ghent University Hospital, Ghent, Belgium.
17
Department of Human Structure and Repair, Ghent University Hospital, Ghent, Belgium.
18
Institute of Human Genetics, University Medical Center Göttingen (UMG), Göttingen, Germany.
19
Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany.
20
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
21
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
22
Clinical Research Center, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
23
Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.
24
Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
25
Division of Ophthalmology and Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

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.

KEYWORDS:

CEP78; cilia; cone-rod dystrophy with hearing loss (CRDHL); founder; male infertility; missense

PMID:
31999394
DOI:
10.1002/humu.23993

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