Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: SOD3
Cytogenetic location: 4p15.2 Genomic coordinates (GRCh38): 4:24,795,573-24,800,842 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p15.2 | [Superoxide dismutase, elevated extracellular] | 3 |
In addition to the soluble (147450) and mitochondrial (147460) forms of superoxide dismutase, an extracellular form is known. EC-SOD (EC 1.15.1.1) is found in plasma, lymph, and synovial fluid as well as in tissues. It is a tetrameric glycoprotein with an apparent subunit molecular mass of about 30 kD. Hjalmarsson et al. (1987) isolated a cDNA for EC-SOD from human placenta and determined the nucleotide sequence. The enzyme is synthesized with a putative 18-amino acid signal peptide preceding the 222 amino acids in the mature enzyme, indicating that the enzyme is a secretory protein. Like SOD1, SOD3 is a CuZn SOD; however, it is distinct from SOD1 in its amino acid sequence, antigenic properties, and tissue distribution.
Marklund (1984) demonstrated that in man the highest levels of SOD3 are found in lung, pancreas, thyroid, and uterus. By RNA gel blot analysis, Folz and Crapo (1994) determined that the highest levels of EC-SOD expression are in adult heart, placenta, pancreas, and lung, followed by moderate expression in kidney, skeletal muscle, and liver. Little EC-SOD mRNA was detected in brain or liver. This pattern of expression is in marked contrast to the relative protein concentration and activity of EC-SOD in these tissues as suggested by Marklund (1984). There may be a substantially higher ratio of enzyme activity to mRNA levels in the brain, pancreas, lung, and kidney, indicating that these tissues have enhanced affinity for circulating EC-SOD or translate the EC-SOD message more efficiently than other tissues. Folz and Crapo (1994) suggested that the EC-SOD gene contains unique transcriptional regulatory elements and that its expression may be regulated at the posttranscriptional or posttranslational level.
Folz and Crapo (1994) reported that the SOD3 gene spans approximately 5,900 bp and contains 3 exons. The entire 720-bp coding region lies within exon 3.
Hendrickson et al. (1990) mapped the SOD3 gene to 4pter-q21 by a study of somatic cell hybrids. Stern et al. (2003) narrowed the assignment to 4p15.3-p15.1 by somatic cell and radiation hybrid analysis, linkage mapping, and FISH.
In the vascular system, SOD3 appears to be located on the endothelial cell surface. The characteristic distinguishing SOD3 from SOD1 and SOD2 is the heparin-binding capacity. SOD3 binds on the surface of endothelial cells through the heparan sulfate proteoglycan and eliminates the oxygen radicals from the NADP-dependent oxidative system of neutrophils. Adachi et al. (1992) developed an immunoassay system for EC-SOD in order to measure EC-SOD levels in the serum of healthy subjects. They found that 6% of these persons had an SOD3 level that was 10- to 15-fold higher than the mean SOD3 level in all subjects. The familial nature of high serum level was established by Adachi et al. (1992).
Sandstrom et al. (1994) reported that about 2% of the plasma donors in Sweden had an 8- to 10-fold higher EC-SOD level and that a single base substitution of C to G at position 760 of the cDNA (185490.0001) was responsible for the high level in plasma. Yamada et al. (1995) performed molecular analysis of the EC-SOD gene from Japanese individuals having a high serum SOD3 level and detected the same C-to-G mutation in healthy persons and hemodialysis patients.
In about 2% of Swedish plasma donors, Sandstrom et al. (1994) found an 8- and 10-fold higher EC-SOD level than the average and demonstrated a C-to-G transversion at nucleotide 760 of their sequence, converting codon 213 from CGG (arg) to GGG (gly).
Yamada et al. (1995) found that 7 of 103 healthy Japanese subjects and 24 of 150 hemodialysis patients had high EC-SOD levels. By molecular analysis, they found the same C-to-G mutation at position 760 of the cDNA as had been found by Sandstrom et al. (1994). Two hemodialysis patients were homozygous; the others in whom the analysis was done were heterozygous. The mutation is located in the region associated with the heparin affinity of the enzyme. The authors speculated that the amino acid substitution may result in a decrease of heparin affinity which favors the presence of EC-SOD in the serum.
In a prospective population-based study of 9,188 Danish individuals, Juul et al. (2004) found an association between the SOD3 gly213 allele and ischemic heart disease, with an age- and gender-adjusted relative risk of 1.5 in heterozygotes compared to noncarriers.
Adachi, T., Ohta, H., Yamada, H., Futenma, A., Kato, K., Hirano, K. Quantitative analysis of extracellular-superoxide dismutase in serum and urine by ELISA with monoclonal antibody. Clin. Chim. Acta 212: 89-102, 1992. [PubMed: 1477980] [Full Text: https://doi.org/10.1016/0009-8981(92)90176-q]
Folz, R. J., Crapo, J. D. Extracellular superoxide dismutase (SOD3): tissue-specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene. Genomics 22: 162-171, 1994. Note: Erratum: Genomics 23: 723 only, 1994. [PubMed: 7959763] [Full Text: https://doi.org/10.1006/geno.1994.1357]
Hendrickson, D. J., Fisher, J. H., Jones, C., Ho, Y.-S. Regional localization of human extracellular superoxide dismutase gene to 4pter-q21. Genomics 8: 736-738, 1990. [PubMed: 2276747] [Full Text: https://doi.org/10.1016/0888-7543(90)90264-u]
Hjalmarsson, K., Marklund, S. L., Engstrom, A., Edlund, T. Isolation and sequence of complementary DNA encoding human extracellular superoxide dismutase. Proc. Nat. Acad. Sci. 84: 6340-6344, 1987. [PubMed: 3476950] [Full Text: https://doi.org/10.1073/pnas.84.18.6340]
Juul, K, Tybjaerg-Hansen, A., Marklund, S., Heegaard, N. H. H., Steffensen, R., Sillesen, H., Jensen, G., Nordestgaard, B. G. Genetically reduced antioxidative protection and increased ischemic heart disease risk: the Copenhagen City Heart Study. Circulation 109: 59-65, 2004. [PubMed: 14662715] [Full Text: https://doi.org/10.1161/01.CIR.0000105720.28086.6C]
Marklund, S. L. Extracellular superoxide dismutase in human tissues and human cell lines. J. Clin. Invest. 74: 1398-1403, 1984. [PubMed: 6541229] [Full Text: https://doi.org/10.1172/JCI111550]
Sandstrom, J., Nilsson, P., Karlsson, K., Marklund, S. L. 10-fold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparin-binding domain. J. Biol. Chem. 269: 19163-19166, 1994. [PubMed: 8034674]
Stern, L.F., Chapman, N. H., Wijsman, E. M., Altherr, M. R., Rosen, D. R. Assignment of SOD3 to human chromosome band 4p15.3-p15.1 with somatic cell and radiation hybrid mapping, linkage mapping, and fluorescent in-situ hybridization. Cytogenet. Genome Res. 101: 178 only, 2003. [PubMed: 14619883] [Full Text: https://doi.org/10.1159/000074178]
Yamada, H., Yamada, Y., Adachi, T., Goto, H., Ogasawara, N., Futenma, A., Kitano, M., Hirano, K., Kato, K. Molecular analysis of extracellular-superoxide dismutase gene associated with high level in serum. Jpn. J. Hum. Genet. 40: 177-184, 1995. [PubMed: 7662997] [Full Text: https://doi.org/10.1007/BF01883574]