Spontaneous hypomorphic mutations in antioxidant enzymes of mice.

An antioxidant enzymatic system is pivotal for aerobic animals to minimize the damage induced by reactive oxygen species. Spontaneous mutant animals with altered antioxidant enzyme activity should be useful for the study of the function of these enzymes in vivo. We examined the nucleotide sequences of the genes for the major antioxidant enzymes, including catalase (Cat), superoxide dismutase (Sod1, Sod2, Sod3), glutathione peroxidase (Gpx1, Gpx2, Gpx3, Gpx4, Gpx5), and glutathione reductase (Gsr) in 10 inbred mouse strains. Nonsynonymous nucleotide polymorphisms were identified in all genes, except for Gpx1, Gpx3, and Gpx4. Notably, the SJL/J mouse strain possessed unique nucleotide substitutions in the Gsr and Sod2 genes, which led to Asp39Ala and Val138Met amino acid substitutions in GSR and SOD2, respectively. The specific activity of GSR of SJL/J mice was reduced to 65% of that of NZB/N mice. In vivo activity, however, was higher in SJL/J, due to upregulated expression of the enzyme. The SOD2 activity in SJL/J mice was reduced to half that of other mouse strains. Consistent with this reduction, oxidative damage in the mitochondria was increased as demonstrated by a decrease of total glutathione and an increase in the levels of protein oxidation. These spontaneous hypomorphic alleles would be valuable in the study of free radical biology.