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. Epub 2009 Aug 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Brain / diagnostic imaging
  • Case-Control Studies
  • Catalytic Domain
  • Cell Line
  • Chromosomes, Human, Pair 9
  • Cilia / enzymology
  • Cilia / pathology*
  • Consanguinity
  • Culture Media, Serum-Free
  • Fibroblasts / metabolism
  • Fibroblasts / ultrastructure
  • Genetic Linkage
  • Green Fluorescent Proteins / metabolism
  • Haplotypes
  • Homozygote
  • Humans
  • Hydrolysis
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Phosphatidylinositol 4,5-Diphosphate / genetics
  • Phosphatidylinositol Phosphates / genetics
  • Phosphatidylinositols / genetics*
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Physical Chromosome Mapping
  • Pigment Epithelium of Eye / cytology
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • Radiography
  • Serum / metabolism
  • Signal Transduction / genetics*
  • Tubulin / metabolism

Substances

  • Culture Media, Serum-Free
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Tubulin
  • phosphatidylinositol 3,4,5-triphosphate
  • Green Fluorescent Proteins
  • Phosphoric Monoester Hydrolases
  • phosphoinositide 5-phosphatase