PUBLICATION
An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
- Authors
- Wheway, G., Schmidts, M., Mans, D.A., Szymanska, K., Nguyen, T.M., 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., 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., Gleeson, J.G., Wolfrum, U., Beales, P.L., Gibson, T., Doherty, D., Mitchison, H.M., Roepman, R., Johnson, C.A.
- ID
- ZDB-PUB-170214-152
- Date
- 2015
- Source
- Nature cell biology 17: 1074-87 (Journal)
- Registered Authors
- Lamont, Ryan, Phelps, Ian
- Keywords
- Cilia, Ciliogenesis, RNAi
- MeSH Terms
-
- Animals
- Retina/abnormalities
- Phenotype
- High-Throughput Nucleotide Sequencing
- Proteins/genetics
- Proteins/metabolism
- HEK293 Cells
- Mice, Inbred C57BL
- Genetic Markers*
- Reproducibility of Results
- Cerebellar Diseases/genetics
- Mice, Knockout
- Suppressor Factors, Immunologic/genetics
- Suppressor Factors, Immunologic/metabolism
- Ciliary Motility Disorders/genetics*
- Ciliary Motility Disorders/metabolism
- Ciliary Motility Disorders/pathology
- Genome-Wide Association Study
- Transfection
- Caenorhabditis elegans/genetics
- Caenorhabditis elegans/metabolism
- Caenorhabditis elegans/ultrastructure
- RNA Interference*
- Abnormalities, Multiple
- Humans
- Eye Abnormalities/genetics
- Genetic Testing/methods*
- Databases, Genetic
- Ellis-Van Creveld Syndrome/genetics
- Genetic Predisposition to Disease
- Zebrafish/genetics
- Zebrafish/metabolism
- Pregnancy Proteins/genetics
- Pregnancy Proteins/metabolism
- Mutation
- Cilia/genetics*
- Cilia/metabolism
- Cilia/pathology
- Kidney Diseases, Cystic/genetics
- Photoreceptor Cells*/metabolism
- Photoreceptor Cells*/ultrastructure
- Cerebellum/abnormalities
- Membrane Proteins/deficiency
- Membrane Proteins/genetics
- Genomics/methods*
- PubMed
- 26167768 Full text @ Nat. Cell Biol.
Citation
Wheway, G., Schmidts, M., Mans, D.A., Szymanska, K., Nguyen, T.M., 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., 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., Gleeson, J.G., Wolfrum, U., Beales, P.L., Gibson, T., Doherty, D., Mitchison, H.M., Roepman, R., Johnson, C.A. (2015) An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nature cell biology. 17:1074-87.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping