Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J.

ABSTRACT: CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositide phosphatase FIG4/SAC3. Affected individuals are compound heterozygotes carrying the missense allele FIG4-I41T in combination with a null allele. Analysis using the yeast two-hybrid system demonstrated that the I41T mutation impairs interaction of FIG4 with the scaffold protein VAC14. The critical role of this interaction was confirmed by the demonstration of loss of FIG4 protein in VAC14 null mice. We developed a mouse model of CMT4J by expressing a Fig4-I41T cDNA transgene on the Fig4 null background. Expression of the mutant transcript at a level 5 × higher than endogenous Fig4 completely rescued lethality, whereas 2 × expression gave only partial rescue, providing a model of the human dis

SUBMITTER: Lenk GM 

PROVIDER: S-EPMC3107197 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature