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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Roosing, S; Hofree, M; Kim, S; Scott, E; Copeland, B; Romani, M; Silhavy, JL; Rosti, RO; Schroth, J; Mazza, T; Miccinilli, E; Zaki, MS; Swoboda, KJ; Milisa-Drautz, J; Dobyns, WB; Mikati, MA; ─░ncecik, F; Azam, M; Borgatti, R; Romaniello, R; Boustany, R-M; Clericuzio, CL; D'Arrigo, S; Strømme, P; Boltshauser, E; Stanzial, F; Mirabelli-Badenier, M; Moroni, I; Bertini, E; Emma, F; Steinlin, M; Hildebrandt, F; Johnson, CA; Freilinger, M; Vaux, KK; Gabriel, SB; Aza-Blanc, P; Heynen-Genel, S; Ideker, T; Dynlacht, BD; Lee, JE; Valente, EM; Kim, J; Gleeson, JG

Published Date

  • May 30, 2015

Published In

Volume / Issue

  • 4 /

Start / End Page

  • e06602 -

PubMed ID

  • 26026149

Pubmed Central ID

  • PMC4477441

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.06602


  • eng

Conference Location

  • England