Structure, Chromosomal Location, and Analysis of the Canine Cu/Zn Superoxide Dismutase (SOD1) Gene

Abstract

Mutations in Cu/Zn superoxide dismutase (SOD1), a major cytosolic antioxidant enzyme in eukaryotic cells, have been reported in approximately 20% of familial amyotrophic lateral sclerosis (FALS) patients. Hereditary canine spinal muscular atrophy (HCSMA), a fatal inherited motor neuron disease in Brittany spaniels, shares many clinical and pathological features with human motor neuron disease, including FALS. The SOD1 coding region has been sequenced and cloned from several animal species, but not from the dog. We have mapped the chromosomal location, sequenced, and characterized the canine SOD1 gene. Extending this analysis, we have evaluated SOD1 as a candidate for HCSMA. The 462 bp SOD1 coding region in the dog encodes 153 amino acid residues and exhibits more than 83% and 79% sequence identity to other mammalian homologues at both the nucleotide and amino acid levels, respectively. The canine SOD1 gene maps to CFA31 close to syntenic group 13 on the radiation hybrid (RH) map in the vicinity of sodium myo/inositol transporter (SMIT) gene. The human orthologous SOD1 and SMIT genes have been localized on HSA 21q22.1 and HSA 21q21, respectively, confirming the conservation of synteny between dog syntenic group 13 and HSA 21. Direct sequencing of SOD1 cDNA from six dogs with HCSMA revealed no mutations. Northern analysis indicated no differences in steady-state levels of SOD1 mRNA.

Canine degenerative myelopathy: Biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model

“…The sequence for cSOD1 was originally determined from a study looking for mutations in dogs with a form of spinal muscular atrophy and is hypothesized to contain eight beta sheets and a metal-binding active site similar to its human counterpart (Green et al, 2002). As can be seen from the primary amino acid sequence, the E40K mutation falls within connecting loop III and results in a +2 charge shift, while the T18S mutation occurs in the second beta strand and does not change overall protein charge (Figure 2).…”

Motor terminal degeneration unaffected by activity changes in SOD1G93A mice; a possible role for glycolysis

“…Most important among these is a difference in underlying genetic mechanisms. Although the identity of the defective gene in HCSMA remains unknown, it is known that the SOD1 gene is not mutated in HCSMA (Green et al, 2002). As noted earlier, the temporal pattern of motor unit type involvement also differs with slow units showing dysfunction in HCSMA first while fast units are lost first in the SOD1 mouse.…”

Advantages and Pitfalls in Experimental Models Of ALS

“…It shares clinical and pathological features with human ALS (Green et al, 2002). These animals show signs of oxidative stress (Green et al, 2001), but do not have mutations in the SOD1 gene (Green et al, 2002).…”

“…It shares clinical and pathological features with human ALS (Green et al, 2002). These animals show signs of oxidative stress (Green et al, 2001), but do not have mutations in the SOD1 gene (Green et al, 2002). From the histopathological point of view these animals are characterized by aberrant accumulation of extensively phosphorylated heavy (high molecular weight) neurofilament (NFH) and neurodegeneration (Green et al, 2005).…”