Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome
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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
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
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.7554/eLife.06602Metadata
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Roosing, S., M. Hofree, S. Kim, E. Scott, B. Copeland, M. Romani, J. L. Silhavy, et al. 2015. “Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome.” eLife 4 (1): e06602. doi:10.7554/eLife.06602. http://dx.doi.org/10.7554/eLife.06602.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 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. DOI: http://dx.doi.org/10.7554/eLife.06602.001Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477441/pdf/Terms of Use
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