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Wheway, G.* ; Schmidts, M.* ; Mans, D.A.* ; Szymanska, K.* ; Nguyen, T.T.* ; Racher, H.* ; Phelps, I.G.* ; Toedt, G.* ; Kennedy, J.* ; Wunderlich, K.A.* ; Sorusch, N.* ; Abdelhamed, Z.A.* ; Natarajan, S.* ; Herridge, W.* ; van Reeuwijk, J.* ; Horn, N.* ; Boldt, K.* ; Parry, D.A.* ; Letteboer, S.J.* ; Roosing, S.* ; Adams, M.* ; Bell, S.M.* ; Bond, J.* ; Higgins, J.* ; Morrison, E.E.* ; Tomlinson, D.C.* ; Slaats, G.G.* ; van Dam, T.J.* ; Huang, L.* ; Kessler, K.* ; Giessl, A.* ; Logan, C.V.* ; Boyle, E.A.* ; Shendure, J.* ; Anazi, S.* ; Aldahmesh, M.* ; Al Hazzaa, S.* ; Hegele, R.A.* ; Ober, C.* ; Frosk, P.* ; Mhanni, A.A.* ; Chodirker, B.N.* ; Chudley, A.E.* ; Lamont, R.* ; Bernier, F.P.* ; Beaulieu, C.L.* ; Gordon, P.M.* ; Pon, R.T.* ; Donahue, C.* ; Barkovich, A.J.* ; Wolf, L.* ; Toomes, C.* ; Thiel, C.T.* ; Boycott, K.M.* ; McKibbin, M.* ; Inglehearn, C.F.* ; Stewart, F.* ; Omran, H.* ; Huynen, M.A.* ; Sergouniotis, P.I.* ; Alkuraya, F.S.* ; Parboosingh, J.S.* ; Innes, A.M.* ; Willoughby, C.E.* ; Giles, R.H.* ; Webster, A.R.* ; Ueffing, M. ; Blacque, O.E.* ; Gleeson, J.G.* ; Wolfrum, U.* ; Beales, P.L.* ; Gibson, T.J.* ; Doherty, D.* ; Mitchison, H.M.* ; Roepman, R.* ; Johnson, C.A.*

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

Nat. Cell Biol. 17, 1074-1087 (2015)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Joubert-syndrome; Photoreceptor Cells; Primary Cilia; Centriole Biogenesis; Master Regulator; C-elegans; Protein; Mutations; Transport; Rpgrip1
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Journal Nature Cell Biology
Quellenangaben Volume: 17, Issue: 8, Pages: 1074-1087 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) CF Metabolomics & Proteomics (CF-MPC)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-505700-001
PubMed ID 26167768
DOI 10.1038/ncb3201
WOS ID WOS:000358847700014
Scopus ID 84938681395
Erfassungsdatum 2015-07-16
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