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An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.
- Source :
-
Nature cell biology [Nat Cell Biol] 2015 Aug; Vol. 17 (8), pp. 1074-1087. Date of Electronic Publication: 2015 Jul 13. - Publication Year :
- 2015
-
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.
- Subjects :
- Abnormalities, Multiple
Animals
Caenorhabditis elegans genetics
Caenorhabditis elegans metabolism
Caenorhabditis elegans ultrastructure
Cerebellar Diseases genetics
Cerebellum abnormalities
Cilia metabolism
Cilia pathology
Ciliary Motility Disorders metabolism
Ciliary Motility Disorders pathology
Cytoskeletal Proteins
Databases, Genetic
Ellis-Van Creveld Syndrome genetics
Eye Abnormalities genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
HEK293 Cells
High-Throughput Nucleotide Sequencing
Humans
Kidney Diseases, Cystic genetics
Membrane Proteins deficiency
Membrane Proteins genetics
Mice, Inbred C57BL
Mice, Knockout
Mutation
Phenotype
Pregnancy Proteins genetics
Pregnancy Proteins metabolism
Proteins genetics
Proteins metabolism
Reproducibility of Results
Retina abnormalities
Suppressor Factors, Immunologic genetics
Suppressor Factors, Immunologic metabolism
Transfection
Zebrafish genetics
Zebrafish metabolism
Cilia genetics
Ciliary Motility Disorders genetics
Genetic Markers
Genetic Testing methods
Genomics methods
Photoreceptor Cells metabolism
Photoreceptor Cells ultrastructure
RNA Interference
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4679
- Volume :
- 17
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Nature cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 26167768
- Full Text :
- https://doi.org/10.1038/ncb3201