Nature cell biology · 2015

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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Wheway Gabrielle, Schmidts Miriam, Mans Dorus A, Szymanska Katarzyna, Nguyen Thanh-Minh T, Racher Hilary, Phelps Ian G, Toedt Grischa, Kennedy Julie, Wunderlich Kirsten A, Sorusch Nasrin, Abdelhamed Zakia A, Natarajan Subaashini, Herridge Warren, van Reeuwijk Jeroen, Horn Nicola, Boldt Karsten, Parry David A, Letteboer Stef J F, Roosing Susanne, Adams Matthew, Bell Sandra M, Bond Jacquelyn, Higgins Julie, Morrison Ewan E, Tomlinson Darren C, Slaats Gisela G, van Dam Teunis J P, Huang Lijia, Kessler Kristin, Giessl Andreas, Logan Clare V, Boyle Evan A, Shendure Jay, Anazi Shamsa, Aldahmesh Mohammed, Al Hazzaa Selwa, Hegele Robert A, Ober Carole, Frosk Patrick, Mhanni Aizeddin A, Chodirker Bernard N, Chudley Albert E, Lamont Ryan, Bernier Francois P, Beaulieu Chandree L, Gordon Paul, Pon Richard T, Donahue Clem, Barkovich A James, Wolf Louis, Toomes Carmel, Thiel Christian T, Boycott Kym M, McKibbin Martin, Inglehearn Chris F, UK10K Consortium, University of Washington Center for Mendelian Genomics, Stewart Fiona, Omran Heymut, Huynen Martijn A, Sergouniotis Panagiotis I, Alkuraya Fowzan S, Parboosingh Jillian S, Innes A Micheil, Willoughby Colin E, Giles Rachel H, Webster Andrew R, Ueffing Marius, Blacque Oliver, Gleeson Joseph G, Wolfrum Uwe, Beales Philip L, Gibson Toby, Doherty Dan, Mitchison Hannah M, Roepman Ronald, Johnson Colin A

Аннотация

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.

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

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