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The lipid phosphatase  FIG4  is a subunit of the protein complex that regulates biosynthesis of the signaling lipid PI(3,5)P 2 . Mutations of  FIG4  result in juvenile lethality and spongiform neurodegeneration in the mouse, and are responsible for the human disorders Charcot–Marie–Tooth disease, Yunis–Varon syndrome and polymicrogyria with seizures. We previously demonstrated that conditional expression of a wild-type FIG4 transgene in neurons is sufficient to rescue most of the abnormalities of  Fig4  null mice, including juvenile lethality and extensive neurodegeneration. To evaluate the contribution of the phosphatase activity to the  in vivo  function of  Fig4 , we introduced the mutation p.Cys486Ser into the Sac phosphatase active-site motif CX 5 RT. Transfection of the  Fig4 Cys486Ser   cDNA into cultured  Fig4 −/−   fibroblasts was effective in preventing vacuolization. The neuronal expression of an NSE- Fig4 Cys486Ser   transgene  in vivo  prevented the neonatal neurodegeneration and juvenile lethality seen in  Fig4  null mice. These observations demonstrate that the catalytically inactive FIG4 protein provides significant function, possibly by stabilization of the PI(3,5)P 2  biosynthetic complex and/or localization of the complex to endolysosomal vesicles. Despite this partial rescue, later in life the NSE- Fig4 Cys486Ser   transgenic mice display significant abnormalities that include hydrocephalus, defective myelination and reduced lifespan. The late onset phenotype of the NSE- Fig4 Cys486Ser   transgenic mice demonstrates that the phosphatase activity of FIG4 has an essential role  in vivo .

Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene