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

Nature Genetics volume 41, pages 1032–1036 (2009)Cite this article

Abstract

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events1. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly2 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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Figure 1: Missense mutations in the encoded enzymatic domain of INPP5E (inositol polyphate-5-phosphatase E) in individuals linked to the JBTS1 locus.
Figure 2: Impaired 5-phosphatase activity and altered ratio of PtdIns(4,5)P2 to PtdIns(4)P associated with JBTS1 INPP5E mutations.
Figure 3: Ciliary axonemal localization of INPP5E.
Figure 4: Effects of INPP5E mutations on ciliary stability.

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Acknowledgements

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.).

Author information

Author notes

  1. Stephanie L Bielas, Jennifer L Silhavy, Francesco Brancati, Marina V Kisseleva and Lihadh Al-Gazali: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosciences and Pediatrics, Neurogenetics Laboratory, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, USA

    Stephanie L Bielas, Jennifer L Silhavy, Dominika Swistun, Lesley C Scott & Joseph G Gleeson

  2. Casa Sollievo della Sofferenza-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy

    Francesco Brancati, Lorena Travaglini, Bruno Dallapiccola & Enza Maria Valente

  3. Department of Biomedical Sciences and Aging Research Center, Centro Studi sull'Invecchiamento, G. d'Annunzio University Foundation, Chieti, Italy

    Francesco Brancati

  4. Division of Hematology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Marina V Kisseleva & Philip W Majerus

  5. Departments of Pediatrics and Pathology, United Arab Emirates University, Faculty of Medicine and Health Sciences, Al Ain, United Arab Emirates

    Lihadh Al-Gazali

  6. Department of Pediatrics, University of Szeged, Szeged, Hungary

    Laszlo Sztriha

  7. College of Medicine, Sultan Qaboos University, Al-Khoud, Sultanate of Oman

    Riad A Bayoumi

  8. Clinical Genetics Department, National Research Centre, Dokki, Cairo, Egypt

    Maha S Zaki

  9. Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Dokki, Cairo, Egypt

    Alice Abdel-Aleem

  10. Istanbul University, Istanbul Medical Faculty, Medical Genetics, Millet Caddesi, Capa, Fatih, Istanbul, Turkey

    Rasim Ozgur Rosti & Hulya Kayserili

  11. Department of Laboratory Medicine, Unit of Molecular Medicine, Bambino Gesu Children's Research Hospital, Rome, Italy

    Enrico Bertini

  12. Department of Paediatric Neurology, University Children's Hospital of Zurich, Zurich, Switzerland

    Eugen Boltshauser

  13. Department of Child Neurology and Psychiatry, C. Mondino, Pavia, Italy

    Elisa Fazzi

  14. Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, USA

    Seth J Field

  15. Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire (IRIBHM), Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Belgium

    Stephanie Gayral, Monique Jacoby & Stephane Schurmans

  16. Department of Experimental Medicine, Sapienza University, Rome, Italy

    Bruno Dallapiccola

  17. Department of Medical and Surgical Paediatric Sciences, University of Messina, Messina, Italy

    Enza Maria Valente

Authors
  1. Stephanie L Bielas
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Contributions

S.L.B, J.L.S, F.B., L.C.S., L.T., S.G., M.J., S.S. and M.V.K. performed experiments. L.A.-G., L.S., M.S.Z, A.A.-A., O.R., H.K., D.S., L.C.S., E. Bertini, E. Boltshauser and E.F. identified and recruited patients. R.A.B. shared unpublished data and reagents. S.J.F., B.D. and P.W.M. provided advice and helped with data interpretation. S.L.B and J.L.S assembled the figures. S.L.B, E.M.V. and J.G.G. wrote and edited the manuscript.

Corresponding author

Correspondence to Joseph G Gleeson.

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Bielas, S., Silhavy, J., Brancati, F. et al. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41, 1032–1036 (2009). https://doi.org/10.1038/ng.423

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