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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)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Joubert-syndrome; Photoreceptor Cells; Primary Cilia; Centriole Biogenesis; Master Regulator; C-elegans; Protein; Mutations; Transport; Rpgrip1

ISSN (print) / ISBN 1465-7392

e-ISSN 1476-4679

Journal Nature Cell Biology

Quellenangaben Volume: 17, Issue: 8, Pages: 1074-1087

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Metabolomics & Proteomics (CF-MPC)