Alternative titles; symbols
HGNC Approved Gene Symbol: SOD2
Cytogenetic location: 6q25.3 Genomic coordinates (GRCh38): 6:159,669,069-159,762,281 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q25.3 | {Microvascular complications of diabetes 6} | 612634 | 3 |
Superoxide dismutase-2 (SOD2; EC 1.15.1.1.) is a mitochondrial matrix enzyme that scavenges oxygen radicals produced by the extensive oxidation-reduction and electron transport reactions occurring in mitochondria. In contrast with cytoplasmic SOD1 (147450), a homodimeric copper- and zinc-containing enzyme, SOD2 (147460) is tetrameric and contains manganese (Beckman et al., 1973; Beck et al., 1987).
Beck et al. (1987) and Heckl (1988) independently cloned human SOD2 from T-lymphocyte and placenta cDNA libraries, respectively. The deduced 222-amino acid protein has a 24-amino acid N-terminal signal sequence. Wan et al. (1994) noted that there is significant sequence variation in the 3-prime UTRs of SOD2 cDNAs, including those reported by Beck et al. (1987) and Heckl (1988).
Wan et al. (1994) determined that the SOD2 gene contains 5 exons and spans almost 20 kb. The 5-prime flanking region contains no TATA or CAAT boxes, but it is GC rich (78%) and contains a cluster of 7 potential SP1 (189906)-binding sites and 3 AP2 (107580) consensus sites. The 3-prime region contains alternate polyadenylation sites, an SP1-binding site, and an NF-kappa-B (see 164011) consensus sequence. Comparison of the genomic sequence with the 5-prime UTRs of reported SOD2 cDNAs suggested that at least 1 alternative transcription initiation site exists.
The locus for mitochondrial SOD has been assigned to chromosome 6 by study of somatic cell hybrids (Creagan et al., 1973). It is syntenic with cytoplasmic malic enzyme (154250).
Church et al. (1992) mapped the SOD2 gene to 6q25 by fluorescence in situ hybridization (FISH). Using a somatic cell hybrid panel containing different segments of chromosome 6, they demonstrated that SOD2 is located in the region 6q25.3-qter which, together with the FISH analysis, indicated that SOD2 is in the distal portion of 6q25.
Figueroa et al. (1988) demonstrated that Sod2 maps in the t complex in the mouse. Since Sod2 is a mitochondrial enzyme and mitochondria are important for sperm motility, Figueroa et al. (1988) were led to speculate that the Sod2 locus may be one of the genes involved in segregation distortion in the mouse. It should be noted that TCP1 (186980), a gene related to the mouse t complex, is located close to SOD2 in man.
Rosenblum et al. (1996) emphasized the importance of polymorphisms in signal peptides that target organelle-specific proteins to their subcellular sites of action. They discovered a polymorphism when they cloned the SOD2 gene from cell lines of normal individuals and patients with genetic diseases of premature aging. The polymorphism consisted of a single nucleotide change in the region of the DNA that encodes the signal sequence such that either an alanine or a valine was present (147460.0001). Rosenblum et al. (1996) suggested that such signal sequence polymorphism could result in diseases of distribution, where essential proteins are not properly targeted, thereby leading to absolute or relative deficiencies of critical enzymes within specific cellular compartments. They suggested that progeria (176670) and related syndromes may be diseases of distribution.
MnSOD, glutathione peroxidase-1 (GPX1; 138320), and catalase (CAT; 115500) are antioxidant enzymes that share a common detoxification pathway. Bastaki et al. (2006) measured the activities of these 3 enzymes in blood cell samples from 231 healthy, nonsmoking student volunteers. Minor allele frequencies ranged from 13% for catalase (T) to 18% for GPX1 (T), and 33% for MnSOD (C) with significant variation between ethnicities. GPX1 activity showed a 6-fold difference between lowest and highest levels. Catalase activity ranged 8-fold, while MnSOD had a 56-fold range of values. MnSOD enzyme activity was 15% higher in females than in males, and 33% higher in individuals with the CT or TT genotype of the 47C-T polymorphism (147460.0001) versus CC individuals. They concluded that interindividual variability of antioxidant enzyme activity in healthy young adults was partially explained by significant associations with 3 known genetic polymorphisms, and was further modified by gender and ethnicity. A substantial component of this variability may be attributable to differences in diet, environmental exposures, and additional genetic factors.
Microvascular Complications of Diabetes 6
Among Japanese patients with type 2 diabetes (125853), Nomiyama et al. (2003) found a significantly higher frequency of the SOD2-VV genotype (147460.0001) than the AA or VA genotypes in patients with diabetic nephropathy (MVCD6; 612634) and concluded that the A16V polymorphism may be unrelated to the etiology of type 2 diabetes, but is associated with diabetic nephropathy in Japanese patients with type 2 diabetes.
Mollsten et al. (2007) analyzed the SOD2 A16V polymorphism (rs4880) in 1,510 Finnish and Swedish patients with type 1 diabetes (222100) and found that the VV genotype was associated with an increase in the risk of diabetic nephropathy. Logistic regression analysis showed that the high-risk group, VV patients who had ever smoked, had a 2.52-fold increased risk for diabetic nephropathy compared to the low-risk group, supporting the hypothesis that oxidative stress contributes to the development of diabetic nephropathy.
Associations Pending Confirmation
To reveal genetic risk factors of nonfamilial idiopathic dilated cardiomyopathy (CMD; see 115200) in Japanese, Hiroi et al. (1999) investigated polymorphisms in the SOD2 and HLA-DRB1 (142857) genes in 86 patients and 380 healthy controls. There was a significant excess of homozygotes for the V allele (the presence of valine vs alanine (A type) in the leader peptide of SOD2 at position 16; 147460.0001). Nishi et al. (1995) had demonstrated an increase in the frequency of the HLA-DRP1*1401 allele in patients with dilated cardiomyopathy; Hiroi et al. (1999) confirmed this finding. A 2-locus analysis suggested that these 2 genetic markers (SOD2-VV genotype and DRB1*1401) may play a synergistic role in controlling the susceptibility to nonfamilial idiopathic cardiomyopathy. In addition, processing efficiency of the V-type SOD2 leader peptide in the presence of mitochondria was significantly lower than that of the A type by 11 +/- 4%, suggesting that this lower processing efficiency was in part an underlying mechanism of the association between SOD2-VV genotype and nonfamilial idiopathic cardiomyopathy.
For a discussion of a possible association between variation in the SOD2 gene and lethal neonatal dilated cardiomyopathy, see 147460.0002.
Yoshimitsu et al. (1987) found low leukocyte SOD2 in a patient with a ring chromosome 6. The breakpoints seemed to be p24 (or p25) and q26 (or q27).
The SOD2 gene encodes an intramitochondrial free radical scavenging enzyme that is the first line of defense against superoxide produced as a byproduct of oxidative phosphorylation. Li et al. (1995) inactivated the Sod2 gene in transgenic mice by homologous recombination. Homozygous mutant mice died within the first 10 days of life with a dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, and metabolic acidosis. Cytochemical analysis revealed a severe reduction in succinate dehydrogenase (complex II; 600857) and aconitase (a tricarboxylic acid cycle enzyme; 100850) activities in the heart and to a lesser extent in other organs. The findings suggested to Li et al. (1995) that MnSOD is required for normal biologic function of tissues by maintaining the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide.
Reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemic heart disease, Alzheimer disease, Parkinson disease, and aging. ROS are generated by mitochondria as the toxic by-products of oxidative phosphorylation, their energy generating pathway. As noted above, genetic inactivation of the mitochondrial form of SOD in mice results in dilated cardiomyopathy, hepatic lipid accumulation, and early neonatal death (Li et al., 1995). Melov et al. (1998) reported that treatment with an SOD mimetic, MnTBAP, rescued Sod2 -/- mutant mice from this systemic pathology and dramatically prolonged their survival. Surviving animals developed a pronounced movement disorder progressing to total debilitation by 3 weeks of age. Neuropathologic evaluation showed a striking spongiform degeneration of the cortex and specific brainstem nuclei, associated with gliosis and intramyelinic vacuolization similar to that observed in cytotoxic edema and disorders associated with mitochondrial abnormalities such as Leigh disease and Canavan disease. Melov et al. (1998) suggested that because of the failure of MnTBAP to cross the blood-brain barrier progressive neuropathology is caused by excessive mitochondrial production of ROS.
Oxidative stress has been implicated in many diseases. The chief source of reactive oxygen species within the cell is the mitochondrion. Melov et al. (1999) characterized a variety of biochemical and metabolic effects of inactivation of the mouse gene for mitochondrial superoxide dismutase. The Sod2 mutant mice exhibited a tissue-specific inhibition of the respiratory chain enzymes NADH-dehydrogenase (complex I) and succinate dehydrogenase (complex II), inactivation of the tricarboxylic acid cycle enzyme aconitase, development of a urinary organic aciduria in conjunction with a partial defect in 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL; 613898), and accumulation of oxidative DNA damage. These results indicated that the increase in mitochondrial reactive oxygen species can result in biochemical aberrations with features reminiscent of mitochondrial myopathy, Friedreich ataxia, and HMGCL deficiency.
To develop an animal model system for study of oxidative injury to the optic nerve, Qi et al. (2003) designed hammerhead ribozymes to degrade SOD2 mRNA, thereby decreasing mitochondrial defenses against reactive oxygen species (ROS). Several potential ribozymes were analyzed in vitro. The one with the best kinetic characteristics was cloned into a recombinant adeno-associated virus (rAAV) vector for delivery and testing in cells and animals. The rAAV ribozyme was then injected into the eyes of DBA/1J mice, and the effect on the optic nerve was evaluated by ocular histopathologic examination. The AAV-expressing ribozyme decreased SOD2 mRNA and protein levels by as much as 85%, increased cellular superoxide, reduced mitochondrial membrane potential, and culminated in the death of infected cell lines by apoptosis without significantly altering complex I and III activity, somewhat spared in the most common LHON mutation (G11778A; 516003.0001) although ATP synthesis is markedly reduced. When inoculated into the eyes of mice, the AAV-expressing ribozyme led to loss of axons and myelin in the optic nerve and ganglion cells in the retina, the hallmarks of optic nerves examined at autopsy of patients with LHON. The striking similarity of the mouse model's optic neuropathy to the histopathology of LHON patients is evidence supporting ROS as a key factor in the pathogenesis of LHON.
Qi et al. (2004) created a mouse model of severe complex I deficiency (252010) by targeted disruption of Ndufa1 (300078) mRNA using ribozymes. In vitro complex I activity was reduced by more than 80%, and reactive oxygen species were increased by 21 to 24% in cells from affected mice. The mice showed damage to the optic nerve and retina. Adeno-associated viral delivery of the human SOD2 gene resulted in suppression of optic nerve degeneration and rescue of retinal ganglion cells. The findings suggested that reactive oxygen species contributed to retinal cell death and optic nerve damage in mice with complex I deficiency, and that expression of SOD2 attenuated the disease process.
Pauling (1979) pointed out that superoxide dismutase had been discovered only about 10 years earlier and that during the previous 5 years more papers had appeared on SOD than on any other single enzyme.
Rosenblum et al. (1996) identified a 47C-T transition in the SOD2 gene, which resulted in a change from GCT (alanine) to GTT (valine) at codon 16 (ala16 to val; A16V).
Hiroi et al. (1999) observed that processing efficiency of the V-type SOD2 leader peptide in the presence of mitochondria was significantly lower than that of the A type, by 11 +/- 4%.
Bastaki et al. (2006) analyzed SOD2 activity in isolated mitochondria from healthy nonsmokers and found that activity was 15% higher in females than in males, and 33% higher in individuals with the CT or TT genotype of the 47C-T polymorphism versus CC individuals.
Susceptibility to Microvascular Complications of Diabetes 6
Among Japanese patients with type 2 diabetes (125853), Nomiyama et al. (2003) found a significantly higher frequency of the VV genotype than the AA or VA genotypes in patients with diabetic nephropathy (MVCD6; 612634). They concluded that the A16V polymorphism may be unrelated to the etiology of type 2 diabetes, but is associated with diabetic nephropathy in Japanese patients with type 2 diabetes.
Mollsten et al. (2007) analyzed the SOD2 A16V polymorphism (rs4880) in 1,510 Finnish and Swedish patients with type 1 diabetes (222100), including 955 patients with diabetic nephropathy and 555 controls with diabetes for more than 20 years without albuminuria or antihypertensive treatment. After controlling for age at onset, diabetes duration, hemoglobin A1C, smoking, and gender, the VV genotype was associated with an increase in the risk of diabetic nephropathy (odds ratio, 1.32; p = 0.049). Logistic regression analysis showed that the high-risk group, VV patients who had ever smoked, had a 2.52-fold increased risk for diabetic nephropathy compared to the low-risk group, supporting the hypothesis that oxidative stress contributes to the development of diabetic nephropathy.
Associations Pending Confirmation
Hiroi et al. (1999) found an increased frequency for the SOD2-VV genotype (homozygosity for the valine (V) allele vs the alanine allele) in Japanese with nonfamilial idiopathic dilated cardiomyopathy (CMD; see 115200) and suggested that this polymorphism may collaborate with the DRP1*1401 allele of the HLA-DRB1 gene (142857) in controlling the susceptibility to nonfamilial idiopathic cardiomyopathy.
The val16 allele disrupts the alpha-helix structure of SOD2 and causes the protein to be retained at the level of the mitochondrial inner membrane. The mutant protein has 30 to 40% lower activity and increases susceptibility to oxidative stress. Valenti et al. (2004) found a significantly increased frequency of the val16 allele among 217 unrelated patients with hereditary hemochromatosis (235200) who developed dilated or nondilated cardiomyopathy compared to HH patients without cardiomyopathy and controls (frequencies of 0.67, 0.45, and 0.52, respectively). The val/val genotype conferred a 10.1-fold increased risk for cardiomyopathy in the HH patients. The association was independent of cirrhosis, diabetes, arthropathy, and hypogonadism, and did not apply to ischemic heart disease. Valenti et al. (2004) concluded that the val16 allele increased the risk of cardiomyopathy due to iron overload toxicity and oxidation in HH patients as a result of decreased activity of the SOD2 enzyme.
This variant is classified as a variant of unknown significance because its contribution to lethal neonatal dilated cardiomyopathy (CMD; see 115200) has not been confirmed.
In a Dutch female infant who died at 4 days of life with severe biventricular dilated cardiomyopathy, who was negative for mutation in genes known to be associated with early-onset CMD, Almomani et al. (2020) performed whole-exome sequencing and identified homozygosity for a c.542G-T transversion (c.542G-T, NM_000636.3) in the SOD2 gene, resulting in a gly181-to-val (G181V) substitution at a highly conserved residue. Her unaffected distantly consanguineous parents were heterozygous for the variant, which was not found in the GoNL database but was present in 1 of 248,906 alleles in the gnomAD database. Analysis of patient fibroblasts revealed a significant increase in superoxide anion levels compared to control, and patient-derived muscle cells showed reduced total SOD activity compared to control. Analysis of transfected patient fibroblasts showed a clear reduction in superoxide dismutase activity in the mitochondria-enriched fraction compared to controls, and after transduction of patient cells with wildtype SOD2 cDNA, mitochondrial superoxide dismutase activity was completely restored.
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