Journal
NATURE GENETICS
Volume 41, Issue 9, Pages 1032-U108Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.423
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Funding
- Italian Ministry of Health [RC2008]
- Telethon Foundation Italy [GGP08145]
- National Institutes of Health [HL 16634 (]
- American Heart Association [0730350N]
- National Institute of Neurological Disorder and Stroke
- Burroughs Welcome Fund
- March of Dimes and the Howard Hughes Medical Institute
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Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events(1). Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly(2) and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5- phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5) P3 and PtdIns(4,5) P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.
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