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Nat Cell Biol. 2015 Aug;17(8):1074-87. doi: 10.1038/ncb3201. Epub 2015 Jul 13.

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

Author information

  • 1Section of Ophthalmology and Neuroscience, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
  • 21] Genetics and Genomic Medicine and Birth Defects Research Centre, Institute of Child Health, University College London, London WC1N 1EH, UK [2] Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands [3] Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands [4] Pediatric Genetics Section, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg 79112, Germany.
  • 31] Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands [2] Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
  • 4Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, T3B 6A8 Alberta, Canada.
  • 5Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA.
  • 6Structural and Computational Biology, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
  • 7School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland.
  • 8Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, 55122 Mainz, Germany.
  • 9Division of Experimental Ophthalmology and Medical Proteome Center, Center of Ophthalmology, University of Tübingen, 72074 Tübingen, Germany.
  • 10Section of Genetics, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, LS9 7TF, UK.
  • 11Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, Box 268, New York, New York 10065, USA.
  • 12BioScreening Technology Group, Biomedical Health Research Centre, St James's University Hospital, Leeds LS9 7TF, UK.
  • 13Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, 3584 CX, The Netherlands.
  • 14Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
  • 15Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, K1H 8L1 Ontario, Canada.
  • 16Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 17Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 18Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
  • 19Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 201] Department of Ophthalmology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia [2] Department of Ophthalmology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
  • 21Robarts Research Institute, University of Western Ontario, London, N6G 2V4 Ontario, Canada.
  • 22Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
  • 23Department of Pediatrics and Child Health &Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 3P5 Manitoba, Canada.
  • 24Department of Pediatrics, University of California San Francisco, San Francisco, California 92093, USA.
  • 25Department of Radiology, University of California San Francisco, San Francisco, California 92093, USA.
  • 26Department of Pathology, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
  • 27Department of Ophthalmology, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds LS9 7TF, UK.
  • 28Department of Medical Genetics, Belfast City Hospital and Queens University, Belfast BT12 6BA, UK.
  • 29Department of Pediatrics and Adolescent Medicine, University Hospital Muenster, 48149 Muenster, Germany.
  • 301] Moorfields Eye Hospital NHS Foundation Trust and NIHR Ophthalmology Biomedical Research Centre, London EC1V 2PD, UK [2] UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
  • 311] Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia [2] Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
  • 32Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, Faculty of Health &Life Sciences, University of Liverpool, Liverpool L69 3BX, UK.
  • 331] Division of Experimental Ophthalmology and Medical Proteome Center, Center of Ophthalmology, University of Tübingen, 72074 Tübingen, Germany [2] Research Unit of Protein Science, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, 85764 Neuherberg, Germany.
  • 34Genetics and Genomic Medicine and Birth Defects Research Centre, Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 351] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA [2] Divisions of Developmental Medicine and Genetic Medicine, Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105, USA.

Abstract

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.

PMID:
26167768
PMCID:
PMC4536769
DOI:
10.1038/ncb3201
[PubMed - indexed for MEDLINE]
Free PMC Article

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