Polyphosphoinositide phosphatase

FIG4 encodes a dual specificity phosphatase that regulates phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) homeostasis. The protein catalyzes dephosphorylation of PtdIns(3,5)P2 and acts as a serine-protein phosphatase on PIKfyve to modulate lipid kinase activity and PI(3,5)P2 production (UniProt: Q92562). It can also hydrolyze other polyphosphoinositides including PtdIns(3,4,5)P3 and PtdIns(4,5)P2 in vitro.

FIG4 mutations cause peripheral nervous system and neurological disorders. UniProt-curated disease associations include Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis 11 (ALS11), Yunis-Varon syndrome, and bilateral temporooccipital polymicrogyria (UniProt: Q92562). These conditions reflect the protein's critical role in neuronal function and membrane dynamics.

In Alzheimer's disease, FIG4 is upregulated in post-mortem AD brain tissue relative to age-matched controls (mean log2FC: 0.50; Chaparral AD proteomics). This upregulation was detected in human post-mortem AD brain using TMT-labeled proteomics across subcellular fractions, suggesting altered phosphoinositide signaling may contribute to AD pathology.