The expanding spectrum of neurological disorders of phosphoinositide metabolism

• Main Authors: Jonathan R. Volpatti, Almundher Al-Maawali, Lindsay Smith, Aqeela Al-Hashim, Julie A. Brill, James J. Dowling
• Format: Article
• Language: English
• Published: The Company of Biologists 2019-08-01
• Series: Disease Models & Mechanisms
• Subjects: ALS; Charcot Marie Tooth disease; Congenital myopathy; Neurogenetic; Phosphoinositides
• Online Access: http://dmm.biologists.org/content/12/8/dmm038174

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.