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

Wheway G, Schmidts M, Mans DA, Szymanska K, Nguyen TMT, Racher H, Phelps IG, Toedts G, Kennedy J, Wunderlich KA, Sorusch N, Abdelhamed ZA, Natarajan S, Herridge W, Van Reeuwijk J, Horn N, Boldt K, Parry DA, Letteboer SJF, Roosing S, Adams M, Bell SM, Bond J, Higgins J, Morrison EE, Tomlinson DC, Slaats GG, Van Dam TJP, Huang L, Keßler K, Gießl A, Logan CV, Boyle EA, Shendure J, Anazi S, Aldahmesh M, Al Hazzaa S, Hegele RA, Ober C, Frosk P, Mhanni AA, Chodirker BN, Chudley AE, Lamont R, Bernier FP, Beaulieu CL, Gordon P, Pon RT, Donahue C, Barkovich AJ, Wolf L, Toomes C, Thiel C, Boycott KM, Mckibbin M, Inglehearn CF, Stewart F, Omran H, Huynen MA, Sergouniotis PI, Alkuraya FS, Parboosingh JS, Innes AM, Willoughby CE, Giles RH, Webster AR, Ueffing M, Blacque O, Gleeson JG, Wolfrum U, Beales PL, Gibson T, Doherty D, Mitchison HM, Roepman R, Johnson CA (2015)


Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 17

Pages Range: 1074-87

Journal Issue: 8

DOI: 10.1038/ncb3201

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.

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APA:

Wheway, G., Schmidts, M., Mans, D.A., Szymanska, K., Nguyen, T.-M.T., Racher, H.,... Johnson, C.A. (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nature Cell Biology, 17(8), 1074-87. https://dx.doi.org/10.1038/ncb3201

MLA:

Wheway, Gabrielle, et al. "An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes." Nature Cell Biology 17.8 (2015): 1074-87.

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