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INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse

Jacoby, M.; Cox, J.J.; Gayral, S.; Hampshire, D.; Ayub, M.; Blockmans, M.; Pernot, E.; Kisseleva, M.V.; Compère, P.; Schiffmann, S.N.; Gergely, F.; Riley, D.; Pérez-Morga, D.; Woods, C.G.; Schurmans, S.

Authors

M. Jacoby

J.J. Cox

S. Gayral

D. Hampshire

M. Ayub

M. Blockmans

E. Pernot

M.V. Kisseleva

P. Compère

S.N. Schiffmann

F. Gergely

D. Riley

D. Pérez-Morga

C.G. Woods

S. Schurmans



Abstract

The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing. 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.

Citation

Jacoby, M., Cox, J., Gayral, S., Hampshire, D., Ayub, M., Blockmans, M., …Schurmans, S. (2009). INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nature Genetics, 41(9), 1027-1031. https://doi.org/10.1038/ng.427

Journal Article Type Article
Publication Date Sep 1, 2009
Deposit Date Jun 22, 2011
Journal Nature Genetics
Print ISSN 1061-4036
Electronic ISSN 1546-1718
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 41
Issue 9
Pages 1027-1031
DOI https://doi.org/10.1038/ng.427