Letter abstract
Nature Genetics 41, 1027 - 1031 (2009)
Published online: 9 August 2009 | doi:10.1038/ng.427
INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse
Monique Jacoby1,11, James J Cox2,11, Stéphanie Gayral1,11, Daniel J Hampshire3, Mohammed Ayub4, Marianne Blockmans1, Eileen Pernot1, Marina V Kisseleva5, Philippe Compère6, Serge N Schiffmann7, Fanni Gergely8, John H Riley9, David Pérez-Morga10, C Geoffrey Woods2,11 & Stéphane Schurmans1,11
The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing1, 2, 3. Here, we report that mice deficient for the lipid 5-phosphatase Inpp5e develop a multiorgan disorder associated with structural defects of the primary cilium. In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. Inpp5e inactivation did not impair ciliary assembly but altered the stability of pre-established cilia after serum addition. Blocking phosphoinositide 3-kinase (PI3K) activity or ciliary platelet-derived growth factor receptor 
(PDGFR) restored ciliary stability. In human INPP5E, we identified a mutation affecting INPP5E ciliary localization and cilium stability in a family with MORM syndrome, a condition related to Bardet-Biedl syndrome. Together, our results show that INPP5E plays an essential role in the primary cilium by controlling ciliary growth factor and PI3K signaling and stability, and highlight the consequences of INPP5E dysfunction.
- Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Belgium.
- Department of Medical Genetics, Cambridge Institute of Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge, UK.
- Academic Unit of Haematology, Henry Wellcome Laboratories for Medical Research, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK.
- Psychiatry of Learning Disability, St. Lukes Hospital, Middlesbrough, UK.
- Division of Hematology, Washington University School of Medicine, St. Louis, USA.
- Cellule d'Appui Technologique en Microscopie, Institut de Chimie, Université de Liège, Liège, Belgium.
- Laboratoire de Neurophysiologie, Université Libre de Bruxelles, Bruxelles, Belgium.
- Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
- GSK Respiratory Medicines Development Centre, Stockley Park, Uxbridge, UK.
- Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Belgium.
- These authors contributed equally to this work.
Correspondence to: Serge N Schiffmann7 e-mail: sschurma@ulb.ac.be
Correspondence to: C Geoffrey Woods2,11 e-mail: cw347@cam.ac.uk
