Journal
NATURE CELL BIOLOGY
Volume 17, Issue 8, Pages 1074-U483Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3201
Keywords
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Categories
Funding
- European Community's Seventh Framework Programme [241955]
- Sir Jules Thorn Award for Biomedical Research [JTA/09]
- Medical Research Council [MR/K011154/1]
- Action Medical Research Clinical Training Fellowship [RTF-1411]
- Radboud University Excellence fellowship
- Radboud UMC Hypatia Tenure Track fellowship
- Deutsche Forschungsgemeinschaft (DFG) [SFB 1140, TH 896/3-3]
- Netherlands Organization for Scientific Research [NWO Vici-865.12.005]
- Foundation Fighting Blindness [C-CMM-0811-0546-RAD02]
- Dutch Kidney Foundation [CP11.18]
- IZKF (Interdisciplinary Centre for Clinical Research of the Universitat of Erlangen-Nurnberg) grant [F4]
- FAUN foundation, Nuernberg
- Rosetree's Trust [A210, A465]
- Great Ormond Street Hospital Children's Charity
- Milena Carvajal Pro-Kartagener Foundation
- Action Medical Research [GN2101]
- Canadian Institutes of Health Research (CIHR)
- Alberta Children's Hospital Research Institute (ACHRI)
- Alberta Children's Hospital Foundation
- RP Fighting Blindness
- Moorfields Eye Hospital Special Trustees
- National Institute for Health Research (NIHR
- Moorfields Eye Hospital and Institute of Ophthalmology, London, UK)
- Foundation Fighting Blindness (US)
- NINDS [R01NS064077]
- University of Washington Intellectual and Developmental Disabilities Research Center Genetics Core [P30HD002274]
- NCI [R21CA160080]
- Wellcome Trust [ME041596, WT091310]
- NHGRI [U54HG006493]
- BBSRC [BB/M020991/1] Funding Source: UKRI
- MRC [G0801843, G0700073, MR/M000532/1, MR/K011154/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M020991/1] Funding Source: researchfish
- Medical Research Council [G0801843, MR/M000532/1, G0700073] Funding Source: researchfish
- National Institute for Health Research [ACF-2013-06-009] Funding Source: researchfish
- Rosetrees Trust [M279-F1] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish
- Newlife [12-13/11] Funding Source: researchfish
- Action Medical Research [1794, 2101] Funding Source: researchfish
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD083091, P30HD002274] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R21CA160080] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL085197] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG006493, UM1HG006493] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS048453, R01NS064077] Funding Source: NIH RePORTER
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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.
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