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An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
- 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 :
- Genetic Markers
Ellis-Van Creveld Syndrome
Pregnancy Proteins
Transfection
Retina
Research Support, N.I.H., Extramural
Cerebellar Diseases
Cerebellum
Databases, Genetic
Suppressor Factors, Immunologic
Journal Article
Animals
Humans
Abnormalities, Multiple
Genetic Predisposition to Disease
Photoreceptor Cells
Cilia
Eye Abnormalities
Genetic Testing
Caenorhabditis elegans
Zebrafish
Mice, Knockout
Research Support, Non-U.S. Gov't
High-Throughput Nucleotide Sequencing
Membrane Proteins
Proteins
Reproducibility of Results
Genomics
Kidney Diseases, Cystic
Mice, Inbred C57BL
HEK293 Cells
Phenotype
Mutation
RNA Interference
Ciliary Motility Disorders
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.od.....10691..f3fd7dafc78123d6256feba30d6330af