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 Abdel-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; Stephane Schurmans; Bruno Dallapiccola; Philip W. Majerus; Enza Maria Valente; Joseph G. Gleeson

doi:10.1038/ng.423

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 Abdel-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 JacobyStephane Schurmans, Bruno Dallapiccola, Philip W. Majerus, Enza Maria Valente, Joseph G. Gleeson

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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 language	English
Pages (from-to)	1032-1036
Number of pages	5
Journal	Nature Genetics
Volume	41
Issue number	9
DOIs	https://doi.org/10.1038/ng.423
Publication status	Published - Sept 2009

ASJC Scopus subject areas

Genetics

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Bielas, S. L., Silhavy, J. L., Brancati, F., Kisseleva, M. V., Al-Gazali, L., Sztriha, L., Bayoumi, R. A., Zaki, M. S., Abdel-Aleem, A., Rosti, R. O., Kayserili, H., Swistun, D., Scott, L. C., Bertini, E., Boltshauser, E., Fazzi, E., Travaglini, L., Field, S. J., Gayral, S., ... 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

Bielas, SL, Silhavy, JL, Brancati, F, Kisseleva, MV, Al-Gazali, L, Sztriha, L, Bayoumi, RA, Zaki, MS, Abdel-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

@article{9466e6e36c7c4ebea5230d363adc9710,

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.",

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

note = "Funding Information: We thank the Marshfield Clinic Research Foundation, Center for Inherited Disease Research and University of California Los Angeles Microarray Core (supported by the US National Heart, Lung, and Blood Institute and National Institutes of Health) for genotyping support. J. Meerloo at the University of California San Diego (UCSD) Neuroscience Microscopy Imaging Core (P30NS047101) provided imaging support. Ryan Anderson of the UCSD Material Sciences provided electron microscopy support. We thank members of the the Dixon lab (UCSD) for suggestions and help with protein modeling, and members of the Mitchell lab (Monash University) for reagents. This work was supported by the UCSD Neuroplasticity of Aging Training Grant (to S.L.B.), the Italian Ministry of Health (RC2008 to B.D., Ricerca Finalizzata 2006 to E.M.V.), the Telethon Foundation Italy (GGP08145 to E.B. and E.M.V.), National Institutes of Health grant HL 16634 (to P.W.M. and M.V.K.), American Heart Association grant 0730350N (to M.V.K.), the National Institute of Neurological Disorder and Stroke, the Burroughs Welcome Fund, the March of Dimes and the Howard Hughes Medical Institute (to J.G.G.).",

year = "2009",

month = sep,

doi = "10.1038/ng.423",

language = "English",

volume = "41",

pages = "1032--1036",

journal = "Nature Genetics",

issn = "1061-4036",

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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, Laszlo

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.

N1 - Funding Information: We thank the Marshfield Clinic Research Foundation, Center for Inherited Disease Research and University of California Los Angeles Microarray Core (supported by the US National Heart, Lung, and Blood Institute and National Institutes of Health) for genotyping support. J. Meerloo at the University of California San Diego (UCSD) Neuroscience Microscopy Imaging Core (P30NS047101) provided imaging support. Ryan Anderson of the UCSD Material Sciences provided electron microscopy support. We thank members of the the Dixon lab (UCSD) for suggestions and help with protein modeling, and members of the Mitchell lab (Monash University) for reagents. This work was supported by the UCSD Neuroplasticity of Aging Training Grant (to S.L.B.), the Italian Ministry of Health (RC2008 to B.D., Ricerca Finalizzata 2006 to E.M.V.), the Telethon Foundation Italy (GGP08145 to E.B. and E.M.V.), National Institutes of Health grant HL 16634 (to P.W.M. and M.V.K.), American Heart Association grant 0730350N (to M.V.K.), the National Institute of Neurological Disorder and Stroke, the Burroughs Welcome Fund, the March of Dimes and the Howard Hughes Medical Institute (to J.G.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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Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies

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