Dataset Information

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

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.

SUBMITTER: Roosing S

PROVIDER: S-EPMC4477441 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Roosing Susanne S Hofree Matan M Kim Sehyun S Scott Eric E Copeland Brett B Romani Marta M Silhavy Jennifer L JL Rosti Rasim O RO Schroth Jana J Mazza Tommaso T Miccinilli Elide E Zaki Maha S MS Swoboda Kathryn J KJ Milisa-Drautz Joanne J Dobyns William B WB Mikati Mohamed A MA İncecik Faruk F Azam Matloob M Borgatti Renato R Romaniello Romina R Boustany Rose-Mary RM Clericuzio Carol L CL D'Arrigo Stefano S Strømme Petter P Boltshauser Eugen E Stanzial Franco F Mirabelli-Badenier Marisol M Moroni Isabella I Bertini Enrico E Emma Francesco F Steinlin Maja M Hildebrandt Friedhelm F Johnson Colin A CA Freilinger Michael M Vaux Keith K KK Gabriel Stacey B SB Aza-Blanc Pedro P Heynen-Genel Susanne S Ideker Trey T Dynlacht Brian D BD Lee Ji Eun JE Valente Enza Maria EM Kim Joon J Gleeson Joseph G JG

eLife 20150530

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. Intersectio ...[more]

PMID: 26026149

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Project description:Joubert syndrome (JS) is a ciliopathy associated with mutations in numerous genes encoding cilia components. TALPID3 encoded by KIAA0856 in man (2700049A03Rik in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in KIAA0856 have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11-12 of Talpid3 in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. Talpid3 mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre-derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in Wnt7a expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of Talpid3. The Talpid3 conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for Talpid3 in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

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

Publications

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

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