An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes

Journal article

Publication Details

Author(s): Wheway G, Schmidts M, Mans DA, Szymanska K, Nguyen TMT, Racher H, Phelps IG, Toedts G, Kennedy J, Wunderlich KA, Sorusch N, Abdelhamed ZA, Natarajan S, Herridge W, Van Reeuwijk J, Horn N, Boldt K, Parry DA, Letteboer SJF, Roosing S, Adams M, Bell SM, Bond J, Higgins J, Morrison EE, Tomlinson DC, Slaats GG, Van Dam TJP, Huang L, Keßler K, Gießl A, Logan CV, Boyle EA, Shendure J, Anazi S, Aldahmesh M, Al Hazzaa S, Hegele RA, Ober C, Frosk P, Mhanni AA, Chodirker BN, Chudley AE, Lamont R, Bernier FP, Beaulieu CL, Gordon P, Pon RT, Donahue C, Barkovich AJ, Wolf L, Toomes C, Thiel C, Boycott KM, Mckibbin M, Inglehearn CF, Stewart F, Omran H, Huynen MA, Sergouniotis PI, Alkuraya FS, Parboosingh JS, Innes AM, Willoughby CE, Giles RH, Webster AR, Ueffing M, Blacque O, Gleeson JG, Wolfrum U, Beales PL, Gibson T, Doherty D, Mitchison HM, Roepman R, Johnson CA
Journal: Nature Cell Biology
Publication year: 2015
Volume: 17
Journal issue: 8
Pages range: 1074-87
ISSN: 1465-7392


Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

FAU Authors / FAU Editors

Gießl, Andreas PD Dr.
Lehrstuhl für Tierphysiologie
Keßler, Kristin
Lehrstuhl für Humangenetik
Thiel, Christian PD Dr.
Medizinische Fakultät

External institutions with authors

Belfast City Hospital / Ospidéal Chathair Bhéal Feirste
Eberhard Karls Universität Tübingen
European Molecular Biology Laboratory (EMBL)
Johannes Gutenberg-Universität Mainz
King Faisal Specialist Hospital & Research Centre
Moorfields Eye Hospital NHS Foundation Trust
Radboud University Nijmegen
Rockefeller University
St James's University Hospital
The University of Liverpool
Universitätsklinikum Münster
University College Dublin (UCD)
University College London (UCL)
University Medical Centre Utrecht (UMC Utrecht)
University of Calgary
University of California San Francisco (UCSF)
University of Chicago
University of Leeds
University of Manitoba
University of Ottawa
University of Washington
Western University

How to cite

Wheway, G., Schmidts, M., Mans, D.A., Szymanska, K., Nguyen, T.-M.T., Racher, H.,... Johnson, C.A. (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nature Cell Biology, 17(8), 1074-87.

Wheway, Gabrielle, et al. "An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes." Nature Cell Biology 17.8 (2015): 1074-87.


Last updated on 2019-21-07 at 08:00