Avtor/Urednik		Wheway, Gabrielle; Schmidts, Miriam; Mans, Dorus A.; Szymanska, Katarzyna; Nguyen, Thanh-Minh T.; Racher, Hilary; Phelps, Ian G.; Toedt, Grischa; Kennedy, Julie; Sergouniotis, Panagiotis I.
Naslov		An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
Tip		članek
Vol. in št.		Letnik 17, št. 8
Leto izdaje		2015
Obseg		str. 1074-1087
ISSN		1465-7392 - Nature cell biology
Jezik		eng
Abstrakt		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.
Proste vsebinske oznake		genetic disorders ciliopathy defects in primary biogenesis genske motnje ciliopatija napake v primarni biogenezi