Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies.
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.
Bielas
Stephanie L
SL
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, USA.
Silhavy
Jennifer L
JL
Brancati
Francesco
F
Kisseleva
Marina V
MV
Al-Gazali
Lihadh
L
Sztriha
Laszlo
L
Bayoumi
Riad A
RA
Zaki
Maha S
MS
Abdel-Aleem
Alice
A
Rosti
Rasim Ozgur
RO
Kayserili
Hulya
H
Swistun
Dominika
D
Scott
Lesley C
LC
Bertini
Enrico
E
Boltshauser
Eugen
E
Fazzi
Elisa
E
Travaglini
Lorena
L
Field
Seth J
SJ
Gayral
Stephanie
S
Jacoby
Monique
M
Schurmans
Stephane
S
Dallapiccola
Bruno
B
Majerus
Philip W
PW
Valente
Enza Maria
EM
Gleeson
Joseph G
JG
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
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