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

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 Mikati, Faruk İncecik, Matloob Azam, Renato Borgatti, Romina RomanielloRose 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-Blac, Susanne Genel Heynen, Trey Ideker, Brian D. Dynlacht, Ji Eun Lee, Enza Maria Valente, Joon Kim, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1-37
Number of pages37
JournaleLife
Volume4
Issue numberMAY
DOIs
Publication statusPublished - May 30 2015

Keywords

  • Ciliopathy
  • High-content screen
  • Joubert syndrome
  • KIAA0586
  • SiRNA
  • Talpid3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

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