PgmNr M5018: Mutations in PI(3,5)P2 biosynthesis and neurological disease in human and mouse.

Authors:
Miriam Meisler; Guy Lenk


Institutes
Univ Michigan, Ann Arbor, MI.


Abstract:

Positional cloning of a spontaneous insertional mutation of the gene Fig4 in 2007 revealed the mammalian role of this endolysosomal gene first studied in yeast.  The FIG4 protein functions in a protein complex with VAC14 and PIKFYVE to generate the signaling lipid PI(3,5)P2.  Mammalian neurons are particularly susceptible to reduced levels of PI(3,5)P2, which result in cell vacuolization and neurodegeneration.  Knockout of FIG4 specifically in neurons results in neurodegeneration, and expression specifically in neurons rescues the null mouse.  Through a combination of screening and exome sequencing, several human neurological disorders with mutations in this pathway have been identified, including the peripheral neuropathy Charcot-Marie-Tooth Disease and a form of polymicrogyria with seizures.  Studies of mice carrying a common human mutation revealed a defect in myelination that is being studied as a model of neuron/glial interaction.  The cellular vacuolization phenotype is being used in genetic and chemical screens for modifiers of severity.  We have also explored the effects of strain background on Fig4 phenotypes.  The ingls mutation of mouse Vac14 resembles the Fig4 mutant mouse, and analysis human variants of VAC14 is in progress.  The interplay between human and mouse genetics has been essential to our growing understanding of the function of  PI(3,5)P2 signaling in mammalian cells.