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

Guy M. Lenk, Christen M. Frei, Ashley C. Miller, Rachel C. Wallen, Yevgeniya A. Mironova, Roman J. Giger, Miriam H. Meisler

Research output: Contribution to journalArticlepeer-review


The lipid phosphatase FIG4 is a subunit of the protein complex that regulates biosynthesis of the signaling lipid PI(3,5)P2. 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 activesite motif CX5RT. Transfection of the Fig4Cys486SercDNA into cultured Fig4-/- fibroblastswas effective in preventing vacuolization. The neuronal expression of an NSE-Fig4Cys486Ser 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)P2 biosynthetic complex and/or localization of the complex to endolysosomal vesicles. Despite this partial rescue, later in life the NSE-Fig4Cys486Ser transgenic mice display significant abnormalities that include hydrocephalus, defective myelination and reduced lifespan. The late onset phenotype of the NSE-Fig4Cys486Ser transgenic mice demonstrates that the phosphatase activity of FIG4 has an essential role in vivo.

Original languageEnglish (US)
Article numberddv480
Pages (from-to)340-347
Number of pages8
JournalHuman molecular genetics
Issue number2
StatePublished - Jan 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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