title: Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies.
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.
authors: Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, USA.
authors: Stephanie L
authors: SL
authors: Bielas
authors: Jennifer L
authors: JL
authors: Silhavy
authors: Francesco
authors: F
authors: Brancati
authors: Marina V
authors: MV
authors: Kisseleva
authors: Lihadh
authors: L
authors: Al-Gazali
authors: Laszlo
authors: L
authors: Sztriha
authors: Riad A
authors: RA
authors: Bayoumi
authors: Maha S
authors: MS
authors: Zaki
authors: Alice
authors: A
authors: Abdel-Aleem
authors: Rasim Ozgur
authors: RO
authors: Rosti
authors: Hulya
authors: H
authors: Kayserili
authors: Dominika
authors: D
authors: Swistun
authors: Lesley C
authors: LC
authors: Scott
authors: Enrico
authors: E
authors: Bertini
authors: Eugen
authors: E
authors: Boltshauser
authors: Elisa
authors: E
authors: Fazzi
authors: Lorena
authors: L
authors: Travaglini
authors: Seth J
authors: SJ
authors: Field
authors: Stephanie
authors: S
authors: Gayral
authors: Monique
authors: M
authors: Jacoby
authors: Stephane
authors: S
authors: Schurmans
authors: Bruno
authors: B
authors: Dallapiccola
authors: Philip W
authors: PW
authors: Majerus
authors: Enza Maria
authors: EM
authors: Valente
authors: Joseph G
authors: JG
authors: Gleeson
mesh_terms: D000107:Acetylation; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000000981:diagnostic imaging; D016022:Case-Control Studies; D020134:Catalytic Domain; D002460:Cell Line; D002899:Chromosomes, Human, Pair 9; D002923:Cilia / Q000201:enzymology / Q000473:pathology*; D003241:Consanguinity; D016895:Culture Media, Serum-Free; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D008040:Genetic Linkage; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000235:genetics; D010716:Phosphatidylinositols / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020161:Physical Chromosome Mapping; D010857:Pigment Epithelium of Eye / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D011859:Radiography; D044967:Serum / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014404:Tubulin / Q000378:metabolism; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D016895:Culture Media, Serum-Free; D049452:Green Fluorescent Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D014404:Tubulin; D000099182:Phosphoinositide 5-Phosphatases; C060974:phosphatidylinositol 3,4,5-triphosphate