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Dis Model Mech. 2019 Aug 13;12(8). pii: dmm038174. doi: 10.1242/dmm.038174.

The expanding spectrum of neurological disorders of phosphoinositide metabolism.

Author information

1
Division of Neurology and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
2
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
3
Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman.
4
Department of Neuroscience, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
5
Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
6
Division of Neurology and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada james.dowling@sickkids.ca.

Abstract

Phosphoinositides (PIPs) are a ubiquitous group of seven low-abundance phospholipids that play a crucial role in defining localized membrane properties and that regulate myriad cellular processes, including cytoskeletal remodeling, cell signaling cascades, ion channel activity and membrane traffic. PIP homeostasis is tightly regulated by numerous inositol kinases and phosphatases, which phosphorylate and dephosphorylate distinct PIP species. The importance of these phospholipids, and of the enzymes that regulate them, is increasingly being recognized, with the identification of human neurological disorders that are caused by mutations in PIP-modulating enzymes. Genetic disorders of PIP metabolism include forms of epilepsy, neurodegenerative disease, brain malformation syndromes, peripheral neuropathy and congenital myopathy. In this Review, we provide an overview of PIP function and regulation, delineate the disorders associated with mutations in genes that modulate or utilize PIPs, and discuss what is understood about gene function and disease pathogenesis as established through animal models of these diseases.

KEYWORDS:

ALS; Charcot Marie Tooth disease; Congenital myopathy; Neurogenetic; Phosphoinositides

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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