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.
| Original language | English |
|---|---|
| Pages (from-to) | 1032-1036 |
| Number of pages | 5 |
| Journal | Nature Genetics |
| Volume | 41 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 2009 |
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ASJC Scopus subject areas
- Genetics
Cite this
Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. / Bielas, Stephanie L.; Silhavy, Jennifer L.; Brancati, Francesco; Kisseleva, Marina V.; Al-Gazali, Lihadh; Sztriha, L.; Bayoumi, Riad A.; Zaki, Maha S.; Abdel-Aleem, Alice; Rosti, Rasim Ozgur; Kayserili, Hulya; Swistun, Dominika; Scott, Lesley C.; Bertini, Enrico; Boltshauser, Eugen; Fazzi, Elisa; Travaglini, Lorena; Field, Seth J.; Gayral, Stephanie; Jacoby, Monique; Schurmans, Stephane; Dallapiccola, Bruno; Majerus, Philip W.; Valente, Enza Maria; Gleeson, Joseph G.
In: Nature Genetics, Vol. 41, No. 9, 09.2009, p. 1032-1036.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies
AU - Bielas, Stephanie L.
AU - Silhavy, Jennifer L.
AU - Brancati, Francesco
AU - Kisseleva, Marina V.
AU - Al-Gazali, Lihadh
AU - Sztriha, L.
AU - Bayoumi, Riad A.
AU - Zaki, Maha S.
AU - Abdel-Aleem, Alice
AU - Rosti, Rasim Ozgur
AU - Kayserili, Hulya
AU - Swistun, Dominika
AU - Scott, Lesley C.
AU - Bertini, Enrico
AU - Boltshauser, Eugen
AU - Fazzi, Elisa
AU - Travaglini, Lorena
AU - Field, Seth J.
AU - Gayral, Stephanie
AU - Jacoby, Monique
AU - Schurmans, Stephane
AU - Dallapiccola, Bruno
AU - Majerus, Philip W.
AU - Valente, Enza Maria
AU - Gleeson, Joseph G.
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=69349094765&partnerID=8YFLogxK
U2 - 10.1038/ng.423
DO - 10.1038/ng.423
M3 - Article
VL - 41
SP - 1032
EP - 1036
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 9
ER -