Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS

Abstract

Mutations of the lipid phosphatase FIG4 that regulates PI(3,5)P(2) are responsible for the recessive peripheral-nerve disorder CMT4J. We now describe nonsynonymous variants of FIG4 in 2% (9/473) of patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Heterozygosity for a deleterious allele of FIG4 appears to be a risk factor for ALS and PLS, extending the list of known ALS genes and increasing the clinical spectrum of FIG4-related diseases.

Figure 1

Rescue of Vacuole Formation in Null Fig4Δ Yeast (A) Patient missense mutations were introduced into yeast Fig4p and tested for their ability to correct the enlarged vacuole in a Fig4Δ null strain of yeast as previously described. The pathogenic CMT4J variant I41T was included for comparison. The low level of PI(3,5)P₂ in Fig4Δ cells results in enlarged vacuoles, and introduction of wild-type Fig4p restores both PI(3,5)P₂ levels and vacuole morphology. Bars represent the mean from three independent experiments, containing 100–300 cells per experiment. p values for each mutant compared with the wild-type were calculated with the unpaired t test. (B) Locations of patient mutations.