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Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome.
- Source :
-
Human mutation [Hum Mutat] 2020 Dec; Vol. 41 (12), pp. 2179-2194. Date of Electronic Publication: 2020 Nov 01. - Publication Year :
- 2020
-
Abstract
- Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss-of-function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense-mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF-variants cause a ciliopathy with features of Joubert syndrome.<br /> (© 2020 The Authors. Human Mutation published by Wiley Periodicals LLC.)
- Subjects :
- Abnormalities, Multiple diagnostic imaging
Abnormalities, Multiple pathology
Adolescent
Animals
Cerebellum diagnostic imaging
Cerebellum pathology
Child
Child, Preschool
Cilia metabolism
Cilia pathology
Ciliopathies diagnostic imaging
Ciliopathies pathology
Eye Abnormalities diagnostic imaging
Eye Abnormalities pathology
Female
Fibroblasts metabolism
Fibroblasts pathology
Homozygote
Humans
Infant
Infant, Newborn
Kidney Diseases, Cystic diagnostic imaging
Kidney Diseases, Cystic pathology
Magnetic Resonance Imaging
Male
Pedigree
Phenotype
Retina diagnostic imaging
Retina pathology
Smoothened Receptor metabolism
Young Adult
Zebrafish genetics
Abnormalities, Multiple genetics
Carrier Proteins genetics
Cerebellum abnormalities
Ciliopathies genetics
Eye Abnormalities genetics
Kidney Diseases, Cystic genetics
Mutation genetics
Nuclear Proteins genetics
Retina abnormalities
Subjects
Details
- Language :
- English
- ISSN :
- 1098-1004
- Volume :
- 41
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Human mutation
- Publication Type :
- Academic Journal
- Accession number :
- 33131181
- Full Text :
- https://doi.org/10.1002/humu.24127