Authors:
Gabrielle Wheway, Miriam Schmidts, Dorus A. Mans, Katarzyna Szymanska, Thanh-Minh T. Nguyen, Hilary Racher, Ian G. Phelps, Grischa Toedt, Julie Kennedy, Kirsten A. Wunderlich,Nasrin Sorusch, Zakia A. Abdelhamed, Subaashini Natarajan, Warren Herridge, Jeroen van Reeuwijk, Nicola Horn, Karsten Boldt, David A. Parry, Stef J. F. Letteboer, Susanne Roosing, Matthew Adams, Sandra M. Bell, Jacquelyn Bond, Julie Higgins, Ewan E. Morrison, Darren C. Tomlinson, Gisela G. Slaats, Teunis J. P. van Dam, Lijia Huang, Kristin Kessler, Andreas Giessl, Clare V. Logan, Evan A. Boyle, Jay Shendure, Shamsa Anazi, Mohammed Aldahmesh, Selwa Al Hazzaa, Robert A. Hegele, Carole Ober, Patrick Frosk, Aizeddin A. Mhanni, Bernard N. Chodirker, Albert E. Chudley, Ryan Lamont, Francois P. Bernier, Chandree L. Beaulieu, Paul Gordon, Richard T. Pon, Clem Donahue, A. James Barkovich, Louis Wolf, Carmel Toomes, Christian T. Thiel, Kym M. Boycott, Martin McKibbin, Chris F. Inglehearn, UK10K Consortium, University of Washington Center for Mendelian Genomics, Fiona Stewart, Heymut Omran, Martijn A. Huynen, Panagiotis I. Sergouniotis, Fowzan S. Alkuraya, Jillian S. Parboosingh, A. Micheil Innes, Colin E. Willoughby, Rachel H. Giles, Andrew R. Webster, Marius Ueffing, Oliver Blacque, Joseph G. Gleeson, Uwe Wolfrum, Philip L. Beales, Toby Gibson, Dan Doherty, Hannah M. Mitchison, Ronald Roepman, & Colin A. Johnson
Summary:
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.
Source:
Nature Cell Biology; (07/13/15)