HGNC Approved Gene Symbol: GPX1
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:49,357,176-49,358,353 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Hemolytic anemia due to glutathione peroxidase deficiency | 614164 | Autosomal recessive | 1 |
Glutathione peroxidase (EC 1.11.1.9) catalyzes the reduction of organic hydroperoxides and hydrogen peroxide by glutathione and thereby protects against oxidative damage (summary by Cohen et al., 1989).
Paglia and Valentine (1967) characterized red cell glutathione peroxidase.
Sukenaga et al. (1987) presented the sequence of GPX cDNA. GPX is one of only a few proteins known in higher vertebrates to contain selenocysteine. This unusual amino acid occurs at the active site of GPX and is coded by the nonsense (stop) codon TGA. Sequence analysis of cDNA clones confirmed previous findings that the unusual amino acid selenocysteine is encoded by the opal terminator codon UGA (Le Beau, 1989). (Note that TGA = UGA; they represent the cDNA and mRNA code, respectively.) There appears to be a selenocysteyl-tRNA that donates selenocysteine to the growing polypeptide chain of GPX, and therefore, selenocysteine becomes the twenty-first naturally occurring amino acid. A tRNA molecule that carries selenocysteine has its own translating factor that delivers it to the translating ribosome (Bock et al., 1991). Bacterial formate dehydrogenase also contains selenocysteine.
Wijnen et al. (1978) presented evidence that GPX1 is on chromosome 3. Johannsmann et al. (1979) concluded that the GPX locus is on 3p. In situ hybridization localized the gene to 3p13-q12 (Johannsmann et al., 1981). McBride et al. (1988) used a cDNA probe to study DNAs isolated from human-rodent somatic cell hybrids. A 609-bp probe containing the entire coding region hybridized to human chromosomes 3, 21, and Xp. An intronic probe detected only the gene on chromosome 3. The sequences on chromosomes X and 21 showed equal conservation of the 3-prime untranslated and coding sequences but did not contain introns, suggesting that they represent processed pseudogenes.
By fluorescence in situ hybridization and PCR analysis, Kiss et al. (1997) mapped the GPX1 gene to 3p21.3. Their results were compatible with the existence of a pseudogene of GPX1 on 3q11-q12 (Chada et al., 1990).
Mehdizadeh et al. (1996) mapped the Gpx1 gene to mouse chromosome 9 in a region of known conserved homology between mouse chromosome 9 and human chromosome 3.
Using a radioimmunoassay for GSHPx, Takahashi et al. (1986) showed that there is a direct relationship between GPX enzyme activity and enzyme protein concentration. Thus, selenium is necessary for the synthesis of protein. Selenium deficiency (see 614164) results in a decrease not only in glutathione peroxidase activity but also in GSHPx protein. Only erythrocytes formed in the presence of selenium contain GSHPx activity. The possibility of confusing genetic and environmental factors is indicated. Takahashi et al. (1987) observed a selenium-dependent GPX in human plasma that is distinct from the one found in erythrocytes.
By electrophoretic means, Beutler and West (1974) demonstrated polymorphism of red cell glutathione peroxidase in Afro-Americans. An electrophoretic polymorphism of glutathione peroxidase was described by Beutler et al. (1974).
Beutler and Matsumoto (1975) found that persons of Jewish ancestry and others of Mediterranean origin have a decrease in red cell GPX activity, but not of leukocyte or fibroblast activity. Oriental populations showed a significantly lower scatter in red cell enzyme levels in comparison with Occidental populations. The authors suggested the existence of a low GPX allele with a frequency of about 0.556 in the Jewish population and 0.181 in the U.S.-Northern European population. They recommended caution in assigning a cause-effect relationship to GPX deficiency (614164) and hemolytic anemia.
Meera Khan et al. (1986) studied the genetics of red cell GPX1 in the Djuka of Suriname. This group consists of descendants of captives from the Gold Coast (Ghana) of Africa brought to Suriname during the 17th century and of others probably from a wider region of West Africa transported during the 18th century. During successive waves of revolt and following the abolition of slavery, the Djuka escaped into the interior of Suriname and organized themselves into groups which have lived since then as permanent forest dwellers with little or no extra-ethnic mixture. Meera Khan et al. (1986) found that the Djuka have a frequency of the GPX1*2 allele of 0.054 and suggested that the GPX1*2 allele is an African marker. The only non-Africans in whom it is presently found are Ashkenazi Jews living in the United States and the Punjabis of the Indian subcontinent. It was proposed that both groups independently acquired the variant allele through an ancient African mixture. See Meera Khan et al. (1984).
The catalytic activity of GPX1 enzyme in the 2-1 heterozygote is greater than that in the 1-1 homozygote. It may be that individuals with the higher peroxidase activity have an intraerythrocytic environment which is less favorable for the survival of the falciparum parasite and therefore that the 2-1 heterozygote enjoys a selective advantage in a malarious environment. Meera Khan et al. (1986) referred to the electrophoretic variants as electrotypes.
Shen et al. (1994) reported variation in vivo and instability in vitro of an in-frame GCG trinucleotide repeat in the GPX1 gene. In a population study of 110 alleles from 55 unrelated persons, the allele frequencies for 4, 5, and 6 GCG repeats were 0.40, 0.35, and 0.25, respectively. No allele was associated with diminished enzyme activity. Current stocks of HL-60 cells, a human myeloid leukemia cell line, were found to be homozygous for the 6-repeat allele. The expansion of the repeat appears to have developed in the course of multiple passages of the rapidly proliferating cell line because cells frozen in 1976 showed a 4/6 genotype and 'intermediate' passage cells frozen in 1985 contained both 4/6 and 5/6 genotypes.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
De Haan et al. (1998) demonstrated a role for GPX1 in protection against oxidative stress by showing that Gpx1 -/- mice are highly sensitive to the oxidant paraquat. Lethality was detected within 24 hours in mice exposed to paraquat at 10 mg/kg(-1), approximately 1/7 of the LD50 of wildtype controls. The effects of paraquat were dose-related. De Haan et al. (1998) further demonstrated that paraquat transcriptionally upregulates Gpx1 in normal cells, reinforcing a role for GPX1 in protection against paraquat toxicity. Cortical neurons from Gpx1 -/- mice are more susceptible to peroxide; 30% of neurons from Gpx1-deficient mice were killed when exposed to 65 micromolar peroxide, whereas the wildtype controls were unaffected. De Haan et al. (1998) stated that their data established function for GPX1 in protection against some oxidative stressors and in protection of neurons against peroxide.
Reddy et al. (2001) studied the functional role of GPX1 activity in antioxidant mechanisms of lens in vivo by comparing lens changes of Gpx1 knockout mice with age-matched control animals. Slit-lamp images showed increased nuclear light scattering (NLS) in Gpx1 knockout mice compared with control animals. Transmission electron microscopy revealed changes in the nucleus manifested by waviness of fiber membranes as early as 3 weeks of age. The Gpx1 knockout mice developed mature cataracts after 15 months. Reddy et al. (2001) concluded that their results demonstrated the critical role of GPX1 in antioxidant defense mechanisms of the lens nucleus. The increased NLS appeared to be associated with damage to nuclear fiber membranes, which might have been due to formation of lipid peroxides, which serve as substrates for GPX1. Cataract formation appeared to progress from focal opacities, apparent at an early age, to lamellar cataracts between 6 and 10 months, and finally to complete opacification in animals older than 15 months.
Shiomi et al. (2004) created myocardial infarction by left coronary artery ligation in mice overexpressing Gpx1 in the heart and wildtype mice. Although infarct size was comparable, the transgenic mice had an increased survival rate with decreased left ventricular dilatation, dysfunction, and end-diastolic pressure compared to wildtype mice. The improvement in left ventricular function was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis in the noninfarcted left ventricle. Shiomi et al. (2004) concluded that overexpression of Gpx1 protects the heart against post-myocardial infarction remodeling and heart failure in mice.
Forsberg et al. (1999) searched the human EST database to determine new polymorphisms in the antioxidant enzymes superoxide dismutase (see 147450), glutathione peroxidases, catalase (115500), and microsomal glutathione transferase-1 (138330). When any mutation, indicated by the search, gave rise to a nonconservative amino acid change, they performed PCR restriction analysis and/or sequence analysis of genomic DNA from human subjects in order to verify these potential polymorphisms. In this way, they identified a pro197-to-leu substitution in the GPX1 gene, resulting from a C-to-T transition at nucleotide 593. The corresponding allele frequencies were approximately 70% for pro197 and 30% for leu197.
Beutler, E., Matsumoto, F. Ethnic variation in red cell glutathione peroxidase activity. Blood 46: 103-110, 1975. [PubMed: 1131421]
Beutler, E., West, C., Beutler, B. Electrophoretic polymorphism of glutathione peroxidase. Ann. Hum. Genet. 38: 163-169, 1974. [PubMed: 4467780] [Full Text: https://doi.org/10.1111/j.1469-1809.1974.tb01947.x]
Beutler, E., West, C. Red cell glutathione peroxidase polymorphism in Afro-Americans. Am. J. Hum. Genet. 26: 255-258, 1974. [PubMed: 4823031]
Blankenberg, S., Rupprecht, H. J., Bickel, C., Torzewski, M., Hafner, G, Tiret, L., Smieja, M., Cambien, F., Meyer, J., Lackner, K. J. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. New Eng. J. Med. 349: 1605-1613, 2003. [PubMed: 14573732] [Full Text: https://doi.org/10.1056/NEJMoa030535]
Board, P. G. Further electrophoretic studies of erythrocyte glutathione peroxidase. Am. J. Hum. Genet. 35: 914-918, 1983. [PubMed: 6193709]
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Boivin, P., Galand, C., Hakim, J. Anemie hemolytique avec deficit en glutathion-peroxydase chez un adulte. Enzymol. Biol. Clin. 10: 68-80, 1969.
Chada, S., Le Beau, M. M., Casey, L., Newburger, P. E. Isolation and chromosomal localization of the human glutathione peroxidase gene. Genomics 6: 268-271, 1990. [PubMed: 2307470] [Full Text: https://doi.org/10.1016/0888-7543(90)90566-d]
Cohen, H. J., Brown, M. R., Hamilton, D., Lyons-Patterson, J., Avissar, N., Liegey, P. Glutathione peroxidase and selenium deficiency in patients receiving home parenteral nutrition: time course for development of deficiency and repletion of enzyme activity in plasma and blood cells. Am. J. Clin. Nutr. 49: 132-139, 1989. [PubMed: 2492138] [Full Text: https://doi.org/10.1093/ajcn/49.1.132]
de Haan, J. B., Bladier, C., Griffiths, P., Kelner, M., O'Shea, R. D., Cheung, N. S., Bronson, R. T., Silvestro, M. J., Wild, S., Zheng, S. S., Beart, P. M., Hertzog, P. J., Kola, I. Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide. J. Biol. Chem. 273: 22528-22536, 1998. [PubMed: 9712879] [Full Text: https://doi.org/10.1074/jbc.273.35.22528]
Forsberg, L., de Faire, U., Morgenstern, R. Low yield of polymorphisms from EST Blast searching: analysis of genes related to oxidative stress and verification of the P197L polymorphism in GPX1. Hum. Mutat. 13: 294-300, 1999. [PubMed: 10220143] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<294::AID-HUMU6>3.0.CO;2-5]
Golan, R., Ezzer, J. B., Szeinberg, A. Red cell glutathione peroxidase in various Jewish ethnic groups in Israel. Hum. Hered. 30: 136-141, 1980. [PubMed: 7358403] [Full Text: https://doi.org/10.1159/000153116]
Johannsmann, R., Hellkuhl, B., Grzeschik, K.-H. Regional assignment of a gene for glutathione peroxidase on human chromosome 3. (Abstract) Cytogenet. Cell Genet. 25: 167 only, 1979.
Johannsmann, R., Hellkuhl, B., Grzeschik, K.-H. Regional mapping of human chromosome 3: assignment of a glutathione peroxidase-1 gene to 3p13-3q12. Hum. Genet. 56: 361-363, 1981. [PubMed: 7239518] [Full Text: https://doi.org/10.1007/BF00274693]
Kiss, C., Li, J., Szeles, A., Gizatullin, R. Z., Kashuba, V. I., Lushnikova, T., Protopopov, A. I., Kelve, M., Kiss, H., Kholodnyuk, I. D., Imreh, S., Klein, G., Zabarovsky, E. R. Assignment of the ARHA and GPX1 genes to human chromosome bands 3p21.3 by in situ hybridization and with somatic cell hybrids. Cytogenet. Cell Genet. 79: 228-230, 1997. [PubMed: 9605859] [Full Text: https://doi.org/10.1159/000134729]
Le Beau, M. M. Personal Communication. Chicago, Ill. 1/23/1989.
McBride, O. W., Mitchell, A., Lee, B. J., Mullenbach, G., Hatfield, D. Gene for selenium-dependent glutathione peroxidase maps to human chromosomes 3, 21 and X. BioFactors 1: 285-292, 1988. [PubMed: 3255357]
Meera Khan, P., Verma, C., Wijnen, L. M. M., Jairaj, S. Red cell glutathione peroxidase (GPX1) variation in Afro-Jamaican, Asiatic Indian, and Dutch populations: is the GPX1*2 allele of 'Thomas' variant an African marker? Hum. Genet. 66: 352-355, 1984. [PubMed: 6586636] [Full Text: https://doi.org/10.1007/BF00287640]
Meera Khan, P., Verma, C., Wijnen, L. M. M., Wijnen, J. T., Prins, H. K., Nijenhuis, L. E. Electrotypes and formal genetics of red cell glutathione peroxidase (GPX1) in the Djuka of Surinam. Am. J. Hum. Genet. 38: 712-723, 1986. [PubMed: 3717160]
Mehdizadeh, S., Warden, C. H., Wen, P.-Z., Xia, Y.-R., Mehrabian, M., Lusis, A. J. The glutathione peroxidase gene, Gpx1, maps to mouse chromosome 9. Mammalian Genome 7: 465-466, 1996. [PubMed: 8662233] [Full Text: https://doi.org/10.1007/s003359900135]
Paglia, D. E., Valentine, W. N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. 70: 158-169, 1967. [PubMed: 6066618]
Reddy, V. N., Giblin, F. J., Lin, L.-R., Dang, L., Unakar, N. J., Musch, D. C., Boyle, D. L., Takemoto, L. J., Ho, Y.-S., Knoernschild, T., Juenemann, A., Lutjen-Drecoll, E. Glutathione peroxidase-1 deficiency leads to increased nuclear light scattering, membrane damage, and cataract formation in gene-knockout mice. Invest. Ophthal. Vis. Sci. 42: 3247-3255, 2001. [PubMed: 11726630]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Shen, Q., Townes, P. L., Padden, C., Newburger, P. E. An in-frame trinucleotide repeat in the coding region of the human cellular glutathione peroxidase (GPX1) gene: in vivo polymorphism and in vitro instability. Genomics 23: 292-294, 1994. [PubMed: 7829093] [Full Text: https://doi.org/10.1006/geno.1994.1499]
Shiomi, T., Tsutsui, H., Matsusaka, H., Murakami, K., Hayashidani, S., Ikeuchi, M., Wen, J., Kubota, T., Utsumi, H., Takeshita, A. Overexpression of glutathione peroxidase prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 109: 544-549, 2004. [PubMed: 14744974] [Full Text: https://doi.org/10.1161/01.CIR.0000109701.77059.E9]
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Takahashi, K., Avissar, N., Whitin, J., Cohen, H. Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme. Arch. Biochem. Biophys. 256: 677-686, 1987. [PubMed: 3619451] [Full Text: https://doi.org/10.1016/0003-9861(87)90624-2]
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Wijnen, L. M., Monteba-van Heuvel, M., Pearson, P. L., Meera Khan, P. Assignment of a gene for glutathione peroxidase (GPX-1) to human chromosome 3. Cytogenet. Cell Genet. 22: 232-238, 1978. [PubMed: 752481] [Full Text: https://doi.org/10.1159/000130944]