MIM Entry: 138320
+138320 GLUTATHIONE PEROXIDASE; GPX1
GLUTATHIONE PEROXIDASE DEFICIENCY, HEMOLYTIC ANEMIA POSSIBLY DUE TO,
Paglia and Valentine (1967) characterized red cell glutathione
peroxidase (EC 188.8.131.52). Necheles et al. (1968) observed hemolytic
disease of the newborn with hyperbilirubinemia and Heinz bodies,
associated with partial deficiency of red cell glutathione peroxidase.
The clinical manifestations were self-limited; evidence of hemolysis had
disappeared by 3 months of age, although the enzyme deficiency
persisted. Sibs were affected in some instances and 1 parent had
comparably depressed enzyme level and a history of neonatal jaundice.
Necheles et al. (1969) found low levels of glutathione peroxidase in an
18-year-old Puerto Rican male with compensated hemolytic anemia. Both
parents and 1 sib had intermediate enzyme levels. By electrophoretic
means, Beutler and West (1974) demonstrated polymorphism of red cell
glutathione peroxidase in Afro-Americans. Since no male-to-male
transmission was noted, X-linkage could not be excluded but is unlikely.
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 and
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. Paglia (1989) wrote: 'To date,
no defects in glutathione peroxidase have been unequivocally
incriminated in the pathogenesis of hemolytic syndromes, although
several instances of partial deficiency have been reported in patients
with anemias of unknown etiology. This association may be coincidental,
since there is a broad range of ethnic variation in the erythrocyte
enzyme' (Beutler and Matsumoto, 1975).
Perona et al. (1979) presented evidence that neonatal deficiency of the
selenoenzyme glutathione peroxidase, with hematologic consequences, may
result from 'selenium imbalance' during pregnancy. Glutathione
peroxidase is involved in the detoxification of hydrogen peroxide.
Selenium in the form of selenocysteine is part of its catalytic site. In
experimental selenium deficiency in animals and in selenium deficiency
that has developed in patients on long-term total parenteral
alimentation, GSHPx activity in red blood cells, granulocytes, and
platelets is low. Replacement with intravenous selenous acid results in
slow recovery of GSHPx activity in red cells over a 3-month period;
recovery occurs only in cells made in the presence of selenium (Cohen et
Using a radioimmunoassay for GSHPx, Takahashi et al. (1986) showed that
there is a direct relationship between enzyme activity and enzyme
protein concentration. Thus, selenium is necessary for the synthesis of
protein. Selenium deficiency 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.
Selenium deficiency in children with inborn errors of metabolism under
treatment with chemically defined formulas has been reported. Yannicelli
et al. (1992) described a child with biotin-nonresponsive propionic
acidemia (606054) who developed erythrocyte macrocytosis and unusual
texture of the hair with hypopigmentation. Selenium supplementation
resulted in dramatic improvement. Vinton et al. (1987) had reported a
child receiving long-term total parenteral nutrition who developed
erythrocyte macrocytosis and hair and skin depigmentation (referred to
by them as pseudoalbinism) as manifestations of selenium deficiency.
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 which 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.
Glutathione peroxidase activity of red cells was found to be elevated in
patients with trisomy 21 (Sinet et al., 1975). Although confirmation of
the localization of the antiviral protein locus (107450) and the soluble
superoxide dismutase locus (147450) to chromosome 21 has been provided
by dosage effects, misleading results have been provided by this
approach in the case of other loci. Studying nucleated cells
(lymphocytes and polymorphs) from patients with trisomy 21 and monosomy
21, Feaster et al. (1977) could not confirm the suggested assignment of
this locus to that chromosome. 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. 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 in situ
hybridization of a glutathione peroxidase cDNA clone, Le Beau et al.
(1989) sublocalized the gene to 3q11-q13 (see Chada et al., 1990).
Combining this with previous data, the localization becomes 3q11-q12.
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
Kiss et al. (1997) concluded that the GPX1 gene is, in fact, located on
3p21.3; they used fluorescence in situ hybridization and PCR analysis.
They suggested that the probes previously used were not strictly
specific for GPX1 and could amplify other sequences on chromosome 3. The
results were compatible with the existence of a pseudogene of GPX1 on
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).
Cellular antioxidant enzymes such as glutathione peroxidase-1 and
superoxide dismutase have a central role in control of reactive oxygen
species. In a study of 636 patients with suspected coronary artery
disease, Blankenberg et al. (2003) found that erythrocyte GPX1 activity
was among the strongest univariate predictors of the risk of
cardiovascular events. An inverse relationship was found between the
level of GPX1 activity and the risk of cardiovascular events. GPX1
activity was affected by sex (lower in males) and smoking status.
Blankenberg et al. (2003) found no association between risk of
cardiovascular events and superoxide dismutase activity.
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
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.
GLUTATHIONE PEROXIDASE POLYMORPHISM
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.
Board (1983); Boivin et al. (1969); Golan et al. (1980); Johannsmann
et al. (1981); Necheles et al. (1970); Nishimura et al. (1972); Steinberg
et al. (1970); Steinberg and Necheles (1971)
1. Beutler, E.; Matsumoto, F.: Ethnic variation in red cell glutathione
peroxidase activity. Blood 46: 103-110, 1975.
2. Beutler, E.; West, C.: Red cell glutathione peroxidase polymorphism
in Afro-Americans. Am. J. Hum. Genet. 26: 255-258, 1974.
3. Beutler, E.; West, C.; Beutler, B.: Electrophoretic polymorphism
of glutathione peroxidase. Ann. Hum. Genet. 38: 163-169, 1974.
4. 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.
5. Board, P. G.: Further electrophoretic studies of erythrocyte glutathione
peroxidase. Am. J. Hum. Genet. 35: 914-918, 1983.
6. Bock, A.; Forchhammer, K.; Heider, J.; Leinfelder, W.; Sawers,
G.; Veprek, B.; Zinoni, F.: Selenocysteine: the 21st amino acid. Molec.
Microbiol. 5: 515-520, 1991.
7. Boivin, P.; Galand, C.; Hakim, J.: Anemie hemolytique avec deficit
en glutathion-peroxydase chez un adulte. Enzym. Biol. Clin. 10:
8. Chada, S.; Le Beau, M. M.; Casey, L.; Newburger, P. E.: Isolation
and chromosomal localization of the human glutathione peroxidase gene. Genomics 6:
9. Cohen, H. J.; Chovaniec, M. E.; Mistretta, O.; Baker, S. S.: Selenium
repletion and glutathione peroxidase-differential effects on plasma
and red cell enzyme activity. Am. J. Clin. Nutr. 41: 735-747, 1985.
10. 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,
11. Feaster, W. W.; Kwok, L. W.; Epstein, C. J.: Dosage effects for
superoxide dismutase-1 in nucleated cells aneuploid for chromosome
21. Am. J. Hum. Genet. 29: 563-570, 1977.
12. 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:
13. Golan, R.; Ezzer, J. B.; Szeinberg, A.: Red cell glutathione
peroxidase in various Jewish ethnic groups in Israel. Hum. Hered. 30:
14. 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.
15. 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.
16. 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,
17. Le Beau, M. M.: Personal Communication. Chicago, Ill. 1/23/1989.
18. Le Beau, M. M.; Chada, S.; Casey, L.; Newburger, P. E.: Chromosomal
sublocalization of the human glutathione peroxidase gene. (Abstract) Cytogenet.
Cell Genet. 51: 1030 only, 1989.
19. 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.
20. 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.
21. 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.
22. 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.
23. Necheles, T. F.; Boles, T. A.; Allen, D. M.: Erythrocyte glutathione-peroxid ase
deficiency and hemolytic disease of the newborn infant. J. Pediat. 72:
24. Necheles, T. F.; Maldonado, N. I.; Barquet-Chediak, A.; Allen,
D. M.: Homozygous erythrocyte glutathione-peroxidase deficiency:
clinical and biochemical studies. Blood 33: 164-169, 1969.
25. Necheles, T. F.; Steinberg, M. H.; Cameron, D.: Erythrocyte glutathione-pero xidase
deficiency. Brit. J. Haemat. 19: 605-612, 1970.
26. Nishimura, Y.; Chida, N.; Hayashi, T.; Arakawa, T. S.: Homozygous
glutathione-peroxidase deficiency of erythrocytes and leukocytes. Tohoku
J. Exp. Med. 108: 207-218, 1972.
27. Paglia, D. E.: Erythroenzymopathies: 1960s in retrospect. Curr.
Contents 32: 17 only, 1989.
28. 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.
29. Perona, G.; Guidi, G. C.; Piga, A.; Cellerino, R.; Milani, G.;
Colautti, P.; Moschini, G.; Stievano, B. M.: Neonatal erythrocyte
glutathione peroxidase deficiency as a consequence of selenium imbalance
during pregnancy. Brit. J. Haemat. 42: 567-574, 1979.
30. 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:
31. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.
32. 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:
33. 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:
34. Sinet, P. M.; Michelson, A. M.; Bazin, A.; Lejeune, J.; Jerome,
H.: Increase in glutathione peroxidase activity in erythrocytes from
trisomy 21 subjects. Biochem. Biophys. Res. Commun. 67: 910-915,
35. Steinberg, M. H.; Brauer, M. J.; Necheles, T. F.: Acute hemolytic
anemia associated with erythrocyte glutathione-peroxidase deficiency. Arch.
Intern. Med. 125: 302-303, 1970.
36. Steinberg, M. H.; Necheles, T. F.: Erythrocyte glutathione peroxidase
deficiency: biochemical studies on the mechanisms of drug-induced
hemolysis. Am. J. Med. 50: 542-546, 1971.
37. Sukenaga, Y.; Ishida, K.; Takeda, T.; Takagi, K.: cDNA sequence
coding for human glutathione peroxidase. Nucleic Acids Res. 15:
7178 only, 1987.
38. Takahashi, K.; Avissar, N.; Whitin, J.; Cohen, H.: Purification
and characterization of human plasma glutathione peroxidase: a selenoglycoprotei n
distinct from the known cellular enzyme. Arch. Biochem. Biophys. 256:
39. Takahashi, K.; Newburger, P. E.; Cohen, H. J.: Glutathione peroxidase
protein: absence in selenium deficiency states and correlation with
enzymatic activity. J. Clin. Invest. 77: 1402-1404, 1986.
40. Vinton, N. E.; Dahlstrom, K. A.; Stobel, C. T.; Ament, M. E.:
Macrocytosis and pseudoalbinism: manifestations of selenium deficiency. J.
Pediat. 111: 711-717, 1987.
41. 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.
42. Yannicelli, S.; Hambidge, K. M.; Picciano, M. F.: Decreased selenium
intake and low plasma selenium concentrations leading to clinical
symptoms in a child with propionic acidaemia. J. Inherit. Metab.
Dis. 15: 261-268, 1992.
Hemolytic disease of the newborn;
Compensated hemolytic anemia
Glutathione peroxidase deficiency;
Selenium deficiency interaction
Autosomal recessive (3q11-q12)
Marla J. F. O'Neill - updated: 11/3/2005
Victor A. McKusick - updated: 11/3/2003
Jane Kelly - updated: 7/2/2002
Ada Hamosh - updated: 7/28/2000
Victor A. McKusick - updated: 5/14/1999
Victor A. McKusick - updated: 5/28/1998
Victor A. McKusick: 3/9/1989