Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J

Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex

“…How these activities are coordinated within the complex to avoid futile cycles of ATP hydrolysis has been enigmatic. Further mysterious is the observation that PI(3,5)P 2 levels in cells deficient in Fig4 activity, as, for example, in patients with CMT, are reduced rather than upregulated (Chow et al, 2007;Shisheva et al, 2019), as might have been expected, and that catalytically active Fig4 is required for PI(3,5)P 2 upregulation (Duex et al, 2006a(Duex et al, , 2006bStrunk et al, 2020).…”

Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J

“…Another factor for consideration is how soon therapeutic gene delivery must occur to rescue function, as gene therapy fibroblasts and partially extend life span in vivo (11), indicating that FIG4 is most critically required for the integrity of the protein complex and its PIKFYVE kinase activity. Accordingly, analysis of primary fibroblasts from patients with CMT4J showed reductions in PI(5)P and PI(3,5) P2 (16). Importantly, the role of FIG4 is not restricted to development, as induced deletion of the gene in adult mice provokes many facets of the disease (17).…”