Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies

Stephanie L. Bielas, Jennifer L. Silhavy, Francesco Brancati, Marina V. Kisseleva, Lihadh Al-Gazali, Laszlo Sztriha, Riad A. Bayoumi, Maha S. Zaki, Alice Kamal Abd El Aleem, Rasim Ozgur Rosti, Hulya Kayserili, Dominika Swistun, Lesley C. Scott, Enrico Bertini, Eugen Boltshauser, Elisa Fazzi, Lorena Travaglini, Seth J. Field, Stephanie Gayral, Monique Jacoby & 5 others Stephane Schurmans, Bruno Dallapiccola, Philip W. Majerus, Enza Maria Valente, Joseph G. Gleeson

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)1032-1036
Number of pages5
JournalNature Genetics
Volume41
Issue number9
DOIs
Publication statusPublished - Sep 2009
Externally publishedYes

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Cilia
Phosphatidylinositols
Phosphoric Monoester Hydrolases
Mutation
Retinal Dystrophies
Polydactyly
Rhombencephalon
Cellular Structures
Mesencephalon
Liver Cirrhosis
Tooth
Phosphotransferases
Phosphates
Genes
Inositol Polyphosphate 5-Phosphatases
Ciliopathies
Joubert syndrome 1

ASJC Scopus subject areas

  • Genetics

Cite this

Bielas, S. L., Silhavy, J. L., Brancati, F., Kisseleva, M. V., Al-Gazali, L., Sztriha, L., ... Gleeson, J. G. (2009). Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nature Genetics, 41(9), 1032-1036. https://doi.org/10.1038/ng.423

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, Laszlo; Bayoumi, Riad A.; Zaki, Maha S.; Kamal Abd El 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 journalArticle

Bielas, SL, Silhavy, JL, Brancati, F, Kisseleva, MV, Al-Gazali, L, Sztriha, L, Bayoumi, RA, Zaki, MS, Kamal Abd El Aleem, A, Rosti, RO, Kayserili, H, Swistun, D, Scott, LC, Bertini, E, Boltshauser, E, Fazzi, E, Travaglini, L, Field, SJ, Gayral, S, Jacoby, M, Schurmans, S, Dallapiccola, B, Majerus, PW, Valente, EM & Gleeson, JG 2009, 'Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies', Nature Genetics, vol. 41, no. 9, pp. 1032-1036. https://doi.org/10.1038/ng.423
Bielas, Stephanie L. ; Silhavy, Jennifer L. ; Brancati, Francesco ; Kisseleva, Marina V. ; Al-Gazali, Lihadh ; Sztriha, Laszlo ; Bayoumi, Riad A. ; Zaki, Maha S. ; Kamal Abd El 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. / Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. In: Nature Genetics. 2009 ; Vol. 41, No. 9. pp. 1032-1036.
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