Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome.
Elife
; 4: e06602, 2015 May 30.
Article
em En
| MEDLINE
| ID: mdl-26026149
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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Base de dados:
MEDLINE
Assunto principal:
Retina
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Cerebelo
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Proteínas de Ciclo Celular
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Predisposição Genética para Doença
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Proteínas Mutantes
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article