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

Autor: Roosing S; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Hofree M; Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States., Kim S; Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, United States., Scott E; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Copeland B; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Romani M; IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy., Silhavy JL; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Rosti RO; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Schroth J; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Mazza T; IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy., Miccinilli E; IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy., Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt., Swoboda KJ; Departments of Neurology and Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Milisa-Drautz J; Department of Pediatric Genetics, University of New Mexico, Albuquerque, United States., Dobyns WB; Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, United States., Mikati MA; Division of Pediatric Neurology, Department of Pediatrics, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, United States., İncecik F; Department of Pediatric Neurology, Cukurova University Medical Faculty, Balcali, Turkey., Azam M; Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan., Borgatti R; Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy., Romaniello R; Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy., Boustany RM; Departments of Pediatrics, Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Clericuzio CL; Division of Genetics/Dysmorphology, Department Pediatrics, University of New Mexico, Albuquerque, United States., D'Arrigo S; Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Strømme P; Women and Children's Division, Oslo University Hospital, Oslo, Norway., Boltshauser E; Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland., Stanzial F; Department of Pediatrics, Genetic Counselling Service, Regional Hospital of Bolzano, Bolzano, Italy., Mirabelli-Badenier M; Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto G. Gaslini, Genoa, Italy., Moroni I; Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Bertini E; Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, IRCCS, Rome, Italy., Emma F; Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Steinlin M; University Children's Hospital, Berne, Switzerland., Hildebrandt F; Division of Nephrology, Department of Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States., Johnson CA; 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., Freilinger M; Neuropediatric group, Department of Paediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria., Vaux KK; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States., Gabriel SB; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, United States., Aza-Blanc P; High Content Screening Systems, Sanford-Burnham Institute, La Jolla, United States., Heynen-Genel S; High Content Screening Systems, Sanford-Burnham Institute, La Jolla, United States., Ideker T; Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States., Dynlacht BD; Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, United States., Lee JE; Samsung Genome Institute, Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea., Valente EM; IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy., Kim J; Korea Advanced Institute of Science and Technology, School of Medical Science and Engineering, Daejeon, Republic of Korea., Gleeson JG; Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
Jazyk: angličtina
Zdroj: ELife [Elife] 2015 May 30; Vol. 4, pp. e06602. Date of Electronic Publication: 2015 May 30.
DOI: 10.7554/eLife.06602
Abstrakt: 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.
Databáze: MEDLINE