eLife (May 2015)
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 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
Affiliations
- Susanne Roosing
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- Matan Hofree
- Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States; Department of Medicine, University of California, San Diego, San Diego, United States
- Sehyun Kim
- Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, United States
- Eric Scott
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- Brett Copeland
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- Marta Romani
- IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
- Jennifer L Silhavy
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- Rasim O Rosti
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- Jana Schroth
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- Tommaso Mazza
- IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
- Elide Miccinilli
- IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy
- Maha S Zaki
- Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt
- Kathryn J Swoboda
- Departments of Neurology and Pediatrics, University of Utah School of Medicine, Salt Lake City, United States
- Joanne Milisa-Drautz
- Department of Pediatric Genetics, University of New Mexico, Albuquerque, United States
- William B Dobyns
- Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, United States
- Mohamed A Mikati
- Division of Pediatric Neurology, Department of Pediatrics, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, United States
- Faruk İncecik
- Department of Pediatric Neurology, Cukurova University Medical Faculty, Balcali, Turkey
- Matloob Azam
- Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan
- Renato Borgatti
- Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy
- Romina Romaniello
- Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy
- Rose-Mary Boustany
- Departments of Pediatrics, Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Departments of Biochemistry and Molecular Medicine, American University of Beirut Medical Center, Beirut, Lebanon
- Carol L Clericuzio
- Division of Genetics/Dysmorphology, Department Pediatrics, University of New Mexico, Albuquerque, United States
- Stefano D'Arrigo
- Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- Petter Strømme
- Women and Children's Division, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, University of Oslo, Oslo, Norway
- Eugen Boltshauser
- Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland
- Franco Stanzial
- Department of Pediatrics, Genetic Counselling Service, Regional Hospital of Bolzano, Bolzano, Italy
- Marisol Mirabelli-Badenier
- Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto G. Gaslini, Genoa, Italy
- Isabella Moroni
- Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- Enrico Bertini
- Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, IRCCS, Rome, Italy
- Francesco Emma
- Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Maja Steinlin
- University Children's Hospital, Berne, Switzerland
- Friedhelm Hildebrandt
- Division of Nephrology, Department of Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
- Colin A Johnson
- Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, United Kingdom
- Michael Freilinger
- Neuropediatric group, Department of Paediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria
- Keith K Vaux
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- Stacey B Gabriel
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, United States
- Pedro Aza-Blanc
- High Content Screening Systems, Sanford-Burnham Institute, La Jolla, United States
- Susanne Heynen-Genel
- High Content Screening Systems, Sanford-Burnham Institute, La Jolla, United States
- Trey Ideker
- Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States; Department of Medicine, University of California, San Diego, San Diego, United States
- Brian D Dynlacht
- Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, United States
- Ji Eun Lee
- Samsung Genome Institute, Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea
- Enza Maria Valente
- IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy; Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy
- Joon Kim
- Korea Advanced Institute of Science and Technology, School of Medical Science and Engineering, Daejeon, Republic of Korea
- Joseph G Gleeson
- Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- DOI
- https://doi.org/10.7554/eLife.06602
- Journal volume & issue
-
Vol. 4
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.
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