Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome

Daniel Epting, Lokuliyange D.S. Senaratne, Elisabeth Ott, Asbjørn Holmgren, Dulika Sumathipala, Selma M. Larsen, Julia Wallmeier, Diana Bracht, Kari Anne M. Frikstad, Suzanne Crowley, Alma Sikiric, Tuva Barøy, Barbara Käsmann-Kellner, Eva Decker, Christian Decker, Nadine Bachmann, Sebastian Patzke, Ian G. Phelps, Nicholas Katsanis, Rachel GilesMiriam Schmidts, Manuela Zucknick, Soeren S. Lienkamp, Heymut Omran, Erica E. Davis, Dan Doherty, Petter Strømme, Eirik Frengen, Carsten Bergmann*, Doriana Misceo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)2179-2194
Number of pages16
JournalHuman mutation
Issue number12
StatePublished - Dec 2020


  • CBY1
  • Joubert syndrome
  • ciliopathy
  • primary cilia defect
  • whole exome sequencing
  • zebrafish

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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