2. Academic Validation
  3. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies

Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies

  • Nat Genet. 2009 Sep;41(9):1032-6. doi: 10.1038/ng.423.
Stephanie L Bielas 1,  Jennifer L Silhavy,  Francesco Brancati,  Marina V Kisseleva,  Lihadh Al-Gazali,  Laszlo Sztriha,  Riad A Bayoumi,  Maha S Zaki,  Alice Abdel-Aleem,  Rasim Ozgur Rosti,  Hulya Kayserili,  Dominika Swistun,  Lesley C Scott,  Enrico Bertini,  Eugen Boltshauser,  Elisa Fazzi,  Lorena Travaglini,  Seth J Field,  Stephanie Gayral,  Monique Jacoby,  Stephane Schurmans,  Bruno Dallapiccola,  Philip W Majerus,  Enza Maria Valente,  Joseph G Gleeson
Affiliations

Affiliation

  • 1 Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, USA.
PMID: 19668216 DOI: 10.1038/ng.423
Abstract

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly 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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