ClinVar Genomic variation as it relates to human health

In affected members of a family with amyotrophic lateral sclerosis (105400), Rosen et al. (1993) identified a G-to-C transversion in exon 4 of the SOD1 gene, resulting in a gly93-to-ala (G93A) substitution. Yim et al. (1996) observed that overexpression of mutant human H93A SOD1 in Sf9 insect cells resulted in enhanced generation of free radicals compared to wildtype SOD1, as measured by the spin trapping method. The effect was more intense at lower peroxide concentrations due to a small, but reproducible, decrease in the value of K(m) for peroxide for the G93A mutant, while the k(cat) was identical for the mutant and wildtype. The G93A mutant and wildtype enzymes had identical dismutation activity. Yim et al. (1996) concluded that ALS symptoms observed in G93A transgenic mice were not caused by the reduction of SOD1 activity, but rather were induced by a gain-of-function enhancement of the free radical-generating function. The findings were consistent with x-ray crystallographic studies showing that the active channel of the G93A mutant is slightly larger than that of the wildtype enzyme, rendering it more accessible to peroxide. See also Kostic et al. (1997). Wiedau-Pazos et al. (1996) showed that the G93A mutant SOD1 enzyme catalyzed the oxidation of a model substrate (spin trap 5,5-prime-dimethyl-1-pyrroline N-oxide) by hydrogen peroxide at a higher rate than that seen with the wildtype enzyme. Catalysis of this reaction by the mutant enzyme was more sensitive to inhibition by the copper chelators diethyldithiocarbamate and penicillamine than was catalysis by wildtype SOD1. The same 2 chelators reversed the apoptosis-inducing effect of the mutant enzyme expressed in a neural cell line. The findings were interpreted to mean that oxidative reactions catalyzed by mutant SOD1 enzymes initiate the neuropathologic changes in familial ALS. (less)