6533b82afe1ef96bd128b75c
RESEARCH PRODUCT
An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
Richard T. PonRyan E. LamontUwe WolfrumRobert A. HegeleDan DohertyFiona StewartMartin MckibbinJay ShendureGrischa ToedtColin E. WilloughbyJillian S. ParboosinghClem DonahueKirsten A. WunderlichLijia HuangMarius UeffingMarius UeffingHannah M. MitchisonNasrin SoruschTeunis J. P. Van DamZakia AbdelhamedKym M. BoycottFrancois P. BernierMohammed A. AldahmeshSubaashini NatarajanBernard N. ChodirkerCarole OberJulie HigginsMatthew AdamsDarren C. TomlinsonHilary E. RacherThanh Minh T. NguyenIan G. PhelpsAndreas GießlKatarzyna SzymanskaEwan E. MorrisonAlbert E. ChudleyFowzan S. AlkurayaPanagiotis I. SergouniotisPanagiotis I. SergouniotisPatrick FroskJacquelyn BondMiriam SchmidtsSusanne RoosingNicola HornGabrielle WhewaySandra M. BellCarmel ToomesToby J. GibsonMartijn A. HuynenPhilip L. BealesGisela G. SlaatsJulie KennedyClare V. LoganOliver E. BlacquePaul M. K. GordonRachel H. GilesHeymut OmranAizeddin A. MhanniA. James BarkovichDavid A. ParryA. Micheil InnesDorus A. MansJeroen Van ReeuwijkKristin KesslerLouis WolfShamsa AnaziEvan A. BoyleKarsten BoldtRonald RoepmanJoseph G. GleesonAndrew R. WebsterAndrew R. WebsterSelwa A. Al HazzaaSelwa A. Al HazzaaChris F. InglehearnWarren HerridgeChristian ThielChandree L. BeaulieuColin A. JohnsonStef J.f. Letteboersubject
PRPF31Pregnancy ProteinsInbred C57BLCiliopathiesMiceImmunologicCerebellumDatabases GeneticEye AbnormalitiesNon-U.S. Gov'tZebrafishExome sequencingMice KnockoutGeneticsResearch Support Non-U.S. Gov'tCiliumHigh-Throughput Nucleotide SequencingMetabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]GenomicsKidney Diseases CysticPhenotypeKidney DiseasesRNA InterferenceAbnormalitiesMultipleFunctional genomicsCiliary Motility DisordersGenetic MarkersEllis-Van Creveld SyndromeKnockoutJeune syndromeOther Research Radboud Institute for Molecular Life Sciences [Radboudumc 0]BiologyResearch SupportTransfectionRetinaArticlewhole-genome siRNA screenJoubert syndromeN.I.H.DatabasesCysticreverse geneticsResearch Support N.I.H. ExtramuralGeneticCerebellar DiseasesJoubert syndromeCiliogenesisSuppressor FactorsJournal ArticleSuppressor Factors ImmunologicmedicineAnimalsHumansAbnormalities MultipleGenetic Predisposition to DiseasePhotoreceptor CellsCiliaGenetic TestingCaenorhabditis elegansExtramuralMembrane ProteinsProteinsReproducibility of ResultsCell Biologymedicine.diseaseMice Inbred C57BLCytoskeletal ProteinsCiliopathyRenal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]HEK293 CellsMutationciliopathiesGenome-Wide Association Studydescription
Item does not contain fulltext 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-08-01 | Nature Cell Biology |