Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome
- Howard Hughes Medical Institute, The Rockefeller University, United States
- University of California, San Diego, United States
- Mendel Institute, Italy
- National Research Center, Egypt
- University of Utah School of Medicine, United States
- University of New Mexico, United States
- Seattle Children's Hospital, United States
- Duke Institute for Brain Sciences, Duke University Medical Center, United States
- Cukurova University Medical Faculty, Turkey
- Wah Medical College, Pakistan
- Scientific Institute IRCCS Eugenio Medea, Italy
- American University of Beirut Medical Center, Lebanon
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy
- Oslo University Hospital, Norway
- University Children's Hospital, Switzerland
- Regional Hospital of Bolzano, Italy
- Istituto G. Gaslini, Italy
- Bambino Gesù Children's Research Hospital, IRCCS, Italy
- Bambino Gesù Children's Hospital, IRCCS, Italy
- University Children's Hospital,, Switzerland
- Howard Hughes Medical Institute, Harvard Medical School, United States
- University of Leeds, St. James's University Hospital, United Kingdom
- Medical University Vienna, Austria
- Broad Institute of Harvard and Massachusetts Institute of Technology, United States
- Burnham Institute, United States
- New York University School of Medicine, United States
- Department of Pathology and Cancer Institute, Smilow Research Center, United States
- Sungkyunkwan University, Republic of Korea
- School of Medical Science and Engineering, Republic of Korea
Abstract
Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide siRNA screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.
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Human subjects: Consenting and sampling was performed on both parents and all available genetically informative siblings to include affected and unaffected members, as well as extended family members if appropriate, consistent with IRB guidelines approved by the ethical committee (JGE-0853) and according to the Declaration of Helsinki.
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© 2015, Roosing et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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