Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome
| Autor: | Faruk Incecik, Brian David Dynlacht, Enza Maria Valente, Ji Eun Lee, Susanne Roosing, Eric Scott, Brett Copeland, Colin A. Johnson, Trey Ideker, Renato Borgatti, Isabella Moroni, William B. Dobyns, Petter Strømme, Pedro Aza-Blanc, Joseph G. Gleeson, Rasim Ozgur Rosti, Susanne Heynen-Genel, Maja Steinlin, Eugen Boltshauser, Joon Kim, Elide Miccinilli, Joanne Milisa-Drautz, Stefano D'Arrigo, Keith K. Vaux, Carol L. Clericuzio, M. Mirabelli-Badenier, Romina Romaniello, Enrico Bertini, Tommaso Mazza, Michael Freilinger, Sehyun Kim, Matan Hofree, Maha S. Zaki, Jennifer L. Silhavy, Kathryn J. Swoboda, Mohamed A Mikati, Rose-Mary Boustany, Marta Romani, Friedhelm Hildebrandt, Stacey Gabriel, Franco Stanzial, Matloob Azam, Jana Schroth, Francesco Emma |
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| Přispěvatelé: | Çukurova Üniversitesi, University of Zurich, Gleeson, Joseph G |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cell Cycle Proteins
medicine.disease_cause Ciliopathies 0302 clinical medicine Gene Frequency 2400 General Immunology and Microbiology Cerebellum Eye Abnormalities Biology (General) RNA Small Interfering Exome Genetics 0303 health sciences Mutation education.field_of_study General Neuroscience Cilium 2800 General Neuroscience General Medicine Kidney Diseases Cystic high-content screen 3. Good health KIAA0586 Medicine Research Article Heterozygote QH301-705.5 Science Population 610 Medicine & health Biology General Biochemistry Genetics and Molecular Biology Joubert syndrome Retina 03 medical and health sciences 1300 General Biochemistry Genetics and Molecular Biology Talpid3 Ciliogenesis medicine Humans Abnormalities Multiple Genetic Predisposition to Disease human Genetic Testing education Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12] Human Biology and Medicine 030304 developmental biology General Immunology and Microbiology medicine.disease Ciliopathy Developmental Biology and Stem Cells ciliopathy 10036 Medical Clinic siRNA Mutant Proteins 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | eLife eLife, Vol 4 (2015) Elife, 4, pp. e06602 Elife, 4, e06602 |
| ISSN: | 2050-084X |
| Popis: | 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. DOI: http://dx.doi.org/10.7554/eLife.06602.001 eLife digest Joubert syndrome is a rare disorder that affects the brain and causes physical, mental, and sometimes visual impairments. In individuals with this condition, two parts of the brain called the cerebellar vermis and the brainstem do not develop properly. This is thought to be due to defects in the development and maintenance of tiny hair-like structures called cilia, which are found on the surface of cells. Currently, mutations in 25 different genes are known to be able to cause Joubert syndrome. However, these mutations only account for around 50% of the cases that have been studied, and the ‘unexplained’ cases suggest that mutations in other genes may also cause the disease. Here, Roosing et al. used a technique called a ‘genome-wide siRNA screen’ to identify other genes regulating the formation of cilia that might also be connected with Joubert syndrome. This approach identified almost 600 candidate genes. The data from the screen were combined with gene sequence data from 145 individuals with unexplained Joubert syndrome. Roosing et al. found that individuals with Joubert syndrome from 15 different families had mutations in a gene called KIAA0586. In chickens and mice, this gene—known as Talpid3—is required for the formation of cilia. Roosing et al.'s findings reveal a new gene that is involved in Joubert syndrome and also provides a list of candidate genes for future studies of other conditions caused by defects in the formation of cilia. The next challenges are to find out what causes the remaining unexplained cases of the disease and to understand what roles the genes identified in this study play in cilia. DOI: http://dx.doi.org/10.7554/eLife.06602.002 |
| Databáze: | OpenAIRE |
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