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

被引：286

作者：

Jacoby, Monique ^{[1
]}

Cox, James J. ^{[2
]}

Gayral, Stephanie ^{[1
]}

Hampshire, Daniel J. ^{[3
]}

Ayub, Mohammed ^{[4
]}

Blockmans, Marianne ^{[1
]}

Pernot, Eileen ^{[1
]}

Kisseleva, Marina V. ^{[5
]}

Compere, Philippe ^{[6
]}

Schiffmann, Serge N. ^{[7
]}

Gergely, Fanni ^{[8
]}

Riley, John H. ^{[9
]}

Perez-Morga, David ^{[10
]}

Woods, C. Geoffrey ^{[2
]}

Schurmans, Stephane ^{[1
]}

机构：

[1] Univ Libre Bruxelles, IRIBHM, IBMM, Gosselies, Belgium

[2] Addenbrookes Hosp, Dept Med Genet, Cambridge Inst Med Res, Cambridge, England

[3] Univ Sheffield, Acad Unit Haematol, Henry Wellcome Labs Med Res, Sch Med & Biomed Sci, Sheffield, S Yorkshire, England

[4] St Lukes Hosp, Middlesbrough, Cleveland, England

[5] Washington Univ, Sch Med, Div Hematol, St Louis, MO USA

[6] Univ Liege, Inst Chim, Liege, Belgium

[7] Univ Libre Bruxelles, Neurophysiol Lab, Brussels, Belgium

[8] Univ Cambridge, Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England

[9] GSK Resp Med Dev Ctr, Uxbridge, Middx, England

[10] Univ Libre Bruxelles, Mol Parasitol Lab, IBMM, Gosselies, Belgium

来源：

NATURE GENETICS | 2009年 / 41卷 / 09期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

INOSITOL-POLYPHOSPHATE; 5-PHOSPHATASE; POLYCYSTIC KIDNEY-DISEASE; FIBROBLASTS; DISORDERS; PROTEINS; NETWORK; BIOLOGY;

D O I：

10.1038/ng.427

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/ differentiated cells and participates in extracellular signal processing(1-3). 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 a (PDGFRa) 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.

引用

页码：1027 / U102

页数：7

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