Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies
Copyright policy )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.
- University of California, San Diego United States
- University of L'Aquila Italy
- Washington University in St. Louis United States
- University Children's Hospital Zurich Switzerland
- Bambino Gesù Children's Hospital Italy
Serum, 3001 Agricultural biotechnology (for-2020), Genetic Linkage, Fibroblasts (mesh), Fibroblasts -- metabolism, Physical Chromosome Mapping (mesh), Base Sequence (mesh), Catalytic Domain (mesh), Homozygote (mesh), 11 Medical and Health Sciences (for), 3105 Genetics (for-2020), Transgenic, Culture Media, Serum-Free, Consanguinity, Mice, Amino Acid Substitution (mesh), Missense (mesh), Phosphatidylinositol Phosphates, Animals (mesh), Serum-Free (mesh), Pigment Epithelium of Eye, 610 Medicine & health, 5-Diphosphate (mesh), Mice (mesh), Brain, Phosphatidylinositols -- genetics, Sciences bio-médicales et agricoles, Phosphoric Monoester Hydrolases -- genetics, Physical Chromosome Mapping, Phosphatidylinositol 4, 5-Diphosphate, Chromosomes, Human, Pair 9, Human, Protein Structure, Molecular Sequence Data, 612, 618, Rare Diseases (rcdc), 1311 Genetics, Humans, Cilia, Polymorphism, 31 Biological Sciences (for-2020), Fibroblasts, Culture Media, Protein Structure, Tertiary, Serum -- metabolism, Cilia -- pathology, Case-Control Studies, Mutation, Congenital Structural Anomalies, Signal Transduction (mesh), Biochemistry and Cell Biology, Tertiary, 3102 Bioinformatics and computational biology (for-2020), Fibroblasts -- ultrastructure, Phosphatidylinositol Phosphates -- genetics, Pigment Epithelium of Eye -- cytology, Phosphatidylinositols, Medical and Health Sciences, Genetic Linkage (mesh), Serum-Free, Radiography (mesh), Pair 9 (mesh), Tubulin, Phosphoric Monoester Hydrolases -- chemistry, Catalytic Domain, Green Fluorescent Proteins -- metabolism, Phosphatidylinositol 4,5-Diphosphate -- genetics, Developmental Biology (science-metrix), Pediatric, Tubulin -- metabolism, Humans (mesh), Hydrolysis (mesh), Mutation (mesh), Hydrolysis, Homozygote, Linkage (Genetics), Tubulin (mesh), Phosphatidylinositol Phosphates (mesh), Acetylation, Single Nucleotide, Consanguinity (mesh), Biological Sciences, Green Fluorescent Proteins (mesh), Pigment Epithelium of Eye (mesh), 06 Biological Sciences (for), Brain -- radiography, Serum (mesh), Haplotypes (mesh), Signal Transduction, Pair 9, Phosphatidylinositols (mesh), Phosphoric Monoester Hydrolases (mesh), Single Nucleotide (mesh), Green Fluorescent Proteins, Transgenic (mesh), Mutation, Missense, 610 Medicine & health, Mice, Transgenic, Acetylation (mesh), Polymorphism, Single Nucleotide, Case-Control Studies (mesh), Chromosomes, Cell Line, Brain (mesh), Signal Transduction -- genetics, Rare Diseases, Molecular Sequence Data (mesh), Animals, Pediatric (rcdc), Base Sequence, Congenital Structural Anomalies (rcdc), Cilia -- enzymology, Cilia (mesh), Phosphoric Monoester Hydrolases, 3101 Biochemistry and Cell Biology (for-2020), Radiography, Tertiary (mesh), Amino Acid Substitution, Haplotypes, 10036 Medical Clinic, Cell Line (mesh), Missense, Phosphoric Monoester Hydrolases -- metabolism
Serum, 3001 Agricultural biotechnology (for-2020), Genetic Linkage, Fibroblasts (mesh), Fibroblasts -- metabolism, Physical Chromosome Mapping (mesh), Base Sequence (mesh), Catalytic Domain (mesh), Homozygote (mesh), 11 Medical and Health Sciences (for), 3105 Genetics (for-2020), Transgenic, Culture Media, Serum-Free, Consanguinity, Mice, Amino Acid Substitution (mesh), Missense (mesh), Phosphatidylinositol Phosphates, Animals (mesh), Serum-Free (mesh), Pigment Epithelium of Eye, 610 Medicine & health, 5-Diphosphate (mesh), Mice (mesh), Brain, Phosphatidylinositols -- genetics, Sciences bio-médicales et agricoles, Phosphoric Monoester Hydrolases -- genetics, Physical Chromosome Mapping, Phosphatidylinositol 4, 5-Diphosphate, Chromosomes, Human, Pair 9, Human, Protein Structure, Molecular Sequence Data, 612, 618, Rare Diseases (rcdc), 1311 Genetics, Humans, Cilia, Polymorphism, 31 Biological Sciences (for-2020), Fibroblasts, Culture Media, Protein Structure, Tertiary, Serum -- metabolism, Cilia -- pathology, Case-Control Studies, Mutation, Congenital Structural Anomalies, Signal Transduction (mesh), Biochemistry and Cell Biology, Tertiary, 3102 Bioinformatics and computational biology (for-2020), Fibroblasts -- ultrastructure, Phosphatidylinositol Phosphates -- genetics, Pigment Epithelium of Eye -- cytology, Phosphatidylinositols, Medical and Health Sciences, Genetic Linkage (mesh), Serum-Free, Radiography (mesh), Pair 9 (mesh), Tubulin, Phosphoric Monoester Hydrolases -- chemistry, Catalytic Domain, Green Fluorescent Proteins -- metabolism, Phosphatidylinositol 4,5-Diphosphate -- genetics, Developmental Biology (science-metrix), Pediatric, Tubulin -- metabolism, Humans (mesh), Hydrolysis (mesh), Mutation (mesh), Hydrolysis, Homozygote, Linkage (Genetics), Tubulin (mesh), Phosphatidylinositol Phosphates (mesh), Acetylation, Single Nucleotide, Consanguinity (mesh), Biological Sciences, Green Fluorescent Proteins (mesh), Pigment Epithelium of Eye (mesh), 06 Biological Sciences (for), Brain -- radiography, Serum (mesh), Haplotypes (mesh), Signal Transduction, Pair 9, Phosphatidylinositols (mesh), Phosphoric Monoester Hydrolases (mesh), Single Nucleotide (mesh), Green Fluorescent Proteins, Transgenic (mesh), Mutation, Missense, 610 Medicine & health, Mice, Transgenic, Acetylation (mesh), Polymorphism, Single Nucleotide, Case-Control Studies (mesh), Chromosomes, Cell Line, Brain (mesh), Signal Transduction -- genetics, Rare Diseases, Molecular Sequence Data (mesh), Animals, Pediatric (rcdc), Base Sequence, Congenital Structural Anomalies (rcdc), Cilia -- enzymology, Cilia (mesh), Phosphoric Monoester Hydrolases, 3101 Biochemistry and Cell Biology (for-2020), Radiography, Tertiary (mesh), Amino Acid Substitution, Haplotypes, 10036 Medical Clinic, Cell Line (mesh), Missense, Phosphoric Monoester Hydrolases -- metabolism
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