Premium
Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome
Author(s) -
Epting Daniel,
Senaratne Lokuliyange D. S.,
Ott Elisabeth,
Holmgren Asbjørn,
Sumathipala Dulika,
Larsen Selma M.,
Wallmeier Julia,
Bracht Diana,
Frikstad KariAnne M.,
Crowley Suzanne,
Sikiric Alma,
Barøy Tuva,
KäsmannKellner Barbara,
Decker Eva,
Decker Christian,
Bachmann Nadine,
Patzke Sebastian,
Phelps Ian G.,
Katsanis Nicholas,
Giles Rachel,
Schmidts Miriam,
Zucknick Manuela,
Lienkamp Soeren S.,
Omran Heymut,
Davis Erica E.,
Doherty Dan,
Strømme Petter,
Frengen Eirik,
Bergmann Carsten,
Misceo Doriana
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24127
Subject(s) - ciliopathy , joubert syndrome , ciliopathies , biology , cilium , polydactyly , zebrafish , ciliogenesis , microbiology and biotechnology , genetics , exencephaly , phenotype , gene , pregnancy , gestation , teratology
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.