CEP76 impairment at the centrosome-cilium interface contributes to a spectrum of ciliopathies
Dysfunction at the centrosome-cilium interface underlies a broad range of ciliopathies. Here, we identify biallelic variants in <i>CEP76</i>, encoding a centrosomal protein, in eight unrelated individuals presenting with neurodevelopmental, ocular, and variable additional multisystem features. Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits, including impaired cilium formation and length, disrupted transition zone architecture, and impaired IFT88-mediated anterograde intraflagellar transport. Zebrafish <i>cep76</i> mutants recapitulate key clinical phenotypes, and in vitro complementation assays confirm pathogenicity for all tested human disease-associated variants. Proteomics analysis identifies CEP76 interactors, including known partners CCP110 and CEP97, and highlights clinically and functionally relevant candidates, including ALMS1 and LUZP1. Together, these findings expand the role of CEP76 beyond centriole duplication to include ciliary assembly and trafficking, establishing it as a ciliopathy gene. This work provides mechanistic insights into <i>CEP76</i>-related disease and broadens our understanding of centrosome-cilium biology.
Authors
- James R. Lupski (ORCID: https://orcid.org/0000-0001-9907-9246)
- Leila Qebibo (ORCID: https://orcid.org/0000-0003-4850-0162)
- Erica E. Davis (ORCID: https://orcid.org/0000-0002-2412-8397)
- Richard A. Lewis (ORCID: https://orcid.org/0000-0002-6644-6385)
- Maha Saad Zaki (ORCID: https://orcid.org/0000-0001-7840-0002)
- Erika Tavares (ORCID: https://orcid.org/0000-0002-5714-1766)
- Béatrice Bocquet (ORCID: https://orcid.org/0000-0002-6369-4818)
- Anne‐Françoise Roux (ORCID: https://orcid.org/0000-0001-5914-2335)
- Isabelle Meunier (ORCID: https://orcid.org/0000-0003-3407-5265)
- Dana Marafi (ORCID: https://orcid.org/0000-0003-2233-3423)
- Farid Ullah (ORCID: https://orcid.org/0000-0001-8108-8347)
- Madeleine Harion (ORCID: https://orcid.org/0000-0003-0488-0044)
- Luke Mansard (ORCID: https://orcid.org/0000-0003-0449-0994)
- Daniel G. Calame (ORCID: https://orcid.org/0000-0001-6860-372X)
- Léna Damaj (ORCID: https://orcid.org/0000-0001-5364-7084)
- Rafał Płoski (ORCID: https://orcid.org/0000-0001-6286-5526)
- Marjolaine Willems (ORCID: https://orcid.org/0000-0002-2959-0935)
- Małgorzata Rydzanicz (ORCID: https://orcid.org/0000-0002-6969-0535)
- Francis Ramond (ORCID: https://orcid.org/0000-0003-4540-8096)
- Thomas Arbogast
- Lydie Bürglen (ORCID: https://orcid.org/0000-0002-1119-6809)
- Tobias Bartolomaeus (ORCID: https://orcid.org/0000-0002-5406-0776)
- Ayşegül Ozantürk
- Rami Abou Jamra (ORCID: https://orcid.org/0000-0002-1542-1399)
- Elise Héon (ORCID: https://orcid.org/0000-0003-4143-9311)
- Stephan Frangakis (ORCID: https://orcid.org/0000-0001-9659-5114)
- Kamal Khan (ORCID: https://orcid.org/0000-0002-7624-0524)
- Mohammad Ayman Al Khateeb
- Jackson P. Ogden
- Katherine Bishara
Institutions
- Northwestern University (US)
- Inserm (FR)
- Baylor College of Medicine (US)
- University of Toronto (CA)
- Université de Montpellier (FR)
- Medical University of Warsaw (PL)
- Hospital for Sick Children (CA)
- Kuwait University (KW)
- Sorbonne Université (FR)
- Hôpital Armand-Trousseau (FR)
- Centre Hospitalier Universitaire de Montpellier (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Lurie Children's Hospital (US)
- Duke Medical Center (US)
- National Research Centre (EG)
- Institute for Neurosciences of Montpellier (FR)
- SickKids Foundation (CA)
- Texas Children's Hospital (US)
- Weill Cornell Medical College in Qatar (QA)
- Centre Hospitalier Universitaire de Saint-Étienne (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Institut catholique de rennes (FR)
- Hamad Medical Corporation (QA)
- Leipzig University (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1126/sciadv.adw3717
- Citations
- 1
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.82