Back to Search Start Over

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

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

Authors :
Susanne Roosing
Matan Hofree
Sehyun Kim
Eric Scott
Brett Copeland
Marta Romani
Jennifer L Silhavy
Rasim O Rosti
Jana Schroth
Tommaso Mazza
Elide Miccinilli
Maha S Zaki
Kathryn J Swoboda
Joanne Milisa-Drautz
William B Dobyns
Mohamed A Mikati
Faruk İncecik
Matloob Azam
Renato Borgatti
Romina Romaniello
Rose-Mary Boustany
Carol L Clericuzio
Stefano D'Arrigo
Petter Strømme
Eugen Boltshauser
Franco Stanzial
Marisol Mirabelli-Badenier
Isabella Moroni
Enrico Bertini
Francesco Emma
Maja Steinlin
Friedhelm Hildebrandt
Colin A Johnson
Michael Freilinger
Keith K Vaux
Stacey B Gabriel
Pedro Aza-Blanc
Susanne Heynen-Genel
Trey Ideker
Brian D Dynlacht
Ji Eun Lee
Enza Maria Valente
Joon Kim
Joseph G Gleeson
Source :
eLife, Vol 4 (2015)
Publication Year :
2015
Publisher :
eLife Sciences Publications Ltd, 2015.

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.

Details

Language :
English
ISSN :
2050084X
Volume :
4
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.3d923b71f264930947bb9ecf4abf7f9
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.06602