(mentions CMT) Endosomal phosphoinositides and human diseases

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Endosomal phosphoinositides and human diseases.

Nicot AS, Laporte J.

Department of Neurobiology and Genetics, IGBMC, INSERM U596, CNRS UMR

7104, Université Louis Pasteur de Strasbourg, Collège de France,

67404 Illkirch, France.

Phosphoinositides (PIs) are lipid second messengers implicated in

signal transduction and membrane trafficking. Seven distinct PIs can

be synthetized by phosphorylation of the inositol ring of

phosphatidylinositol (PtdIns) and their metabolism is accurately

regulated by PI kinases and phosphatases.

Two of the phosphoinositides, PtdIns3P and PtdIns(3,5)P(2), are

present on intracellular endosomal compartments and several studies

suggest that they have a role on membrane remodeling and trafficking.

We refer to them as " endosomal phosphoinositides " . An increasing

number of human genetic diseases including myopathy and neuropathies

are due to mutations in enzymes regulating the turn-over of these

endosomal phosphoinositides.

The PtdIns3P and PtdIns(3,5)P(2) 3-phosphatase myotubularin gene is

mutated in X-linked Centronuclear Myopathy whereas its homologs MTMR2

and MTMR13 and the PtdIns(3,5)P(2) 5-phosphatase SAC3/FIG4 are

implicated in Charcot-Marie-Tooth peripheral neuropathies. Mutations

in the gene encoding the PtdIns3P 5-kinase PIP5K3/PIKfyve have been

found in patients affected with François-Neetens Fleck Corneal

Dystrophy.

This review presents the roles of the endosomal phosphoinositides and

their regulators, and proposes defects of membrane remodeling as a

common pathological mechanism for the corresponding diseases.