Mutations in phosphoinositide metabolizing enzymes and human disease

Abstract

Phosphoinositides are implicated in the regulation of a wide variety of cellular functions. Their importance in cellular and organismal physiology is underscored by the growing number of human diseases linked to perturbation of kinases and phosphatases that catalyze interconversion from one phosphoinositide to another. Many such enzymes are attractive targets for therapeutic interventions. Here, we review diseases linked to inheritable or somatic mutations of these enzymes.

FIGURE 1. Phosphoinositide metabolism and associated disease

A: chemical structure of phosphatidylinositol with numbered positions of the inositol ring indicated. B: depiction of the main pathways of phosphoinositide synthesis and degradation. Diseases associated with the kinases and phosphatases that regulate this interconversion are indicated.

FIGURE 2. Subcellular distribution of the seven phosphoinositides

A: each phosphoinositide is thought to have its own predominant subcellular localization, as indicated (modified from a drawing by Andrea Raimondi). B: localization of PI(4,5)P₂, PI4P, and PI3P, as revealed by transfected GFP fusion of protein modules that selectively bind these phosphoinositides. The localization of the fusion protein is shown in green: plasma membrane for PI(4,5)P₂, the Golgi complex for PI4P, and endosomes for PI3P. (Reprinted with permission from Ref. .)