Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

• Published in: eLife Vol. 4; p. e06602
• Main Authors: Roosing, Susanne, Hofree, Matan, Kim, Sehyun, Scott, Eric, Copeland, Brett, Romani, Marta, Silhavy, Jennifer L, Rosti, Rasim O, Schroth, Jana, Mazza, Tommaso, Miccinilli, Elide, Zaki, Maha S, Swoboda, Kathryn J, Milisa-Drautz, Joanne, Dobyns, William B, Mikati, Mohamed A, İncecik, Faruk, Azam, Matloob, Borgatti, Renato, Romaniello, Romina, Boustany, Rose-Mary, Clericuzio, Carol L, D'Arrigo, Stefano, Strømme, Petter, Boltshauser, Eugen, Stanzial, Franco, Mirabelli-Badenier, Marisol, Moroni, Isabella, Bertini, Enrico, Emma, Francesco, Steinlin, Maja, Hildebrandt, Friedhelm, Johnson, Colin A, Freilinger, Michael, Vaux, Keith K, Gabriel, Stacey B, Aza-Blanc, Pedro, Heynen-Genel, Susanne, Ideker, Trey, Dynlacht, Brian D, Lee, Ji Eun, Valente, Enza Maria, Kim, Joon, Gleeson, Joseph G
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 30-05-2015; eLife Sciences Publications, Ltd
• Subjects: Abnormalities, Multiple - genetics; Automation; Brain; Brain research; Cell cycle; Cell Cycle Proteins - genetics; Cerebellum; Cerebellum - abnormalities; Children & youth; ciliopathy; Congenital defects; Departments; Developmental Biology and Stem Cells; Eye Abnormalities - genetics; Gene deletion; Gene Frequency; Genes; Genetic Predisposition to Disease; Genetic screening; Genetic Testing; Genetics; Genome-Wide Association Study; Genomes; Genomics; Health sciences; Hedgehog protein; Heterozygote; high-content screen; Hospitals; Human Biology and Medicine; Humans; Joubert syndrome; KIAA0586; Kidney Diseases, Cystic - genetics; Medicine; Mutant Proteins - genetics; Mutation; Nephrology; Neurodevelopmental disorders; Neurology; Neurosciences; Patients; Pediatrics; Proteins; Retina - abnormalities; RNA, Small Interfering - genetics; siRNA; Talpid3; United States > US; Talpid3; human biology; stem cells; KIAA0586; high-content screen; Joubert syndrome; developmental biology; medicine; siRNA; human; ciliopathy
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.06602

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 small interfering RNA (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.