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General Comment |
Expression of this gene decreases in oocyte of aging primate ovaries (Wang et al 2020). ///////////Glutathione peroxidases have been thought to function in cellular antioxidant defense.
NCBI Summary:
The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Other studies indicate that H2O2 is also essential for growth-factor mediated signal transduction, mitochondrial function, and maintenance of thiol redox-balance; therefore, by limiting H2O2 accumulation, glutathione peroxidases are also involved in modulating these processes. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is the most abundant, is ubiquitously expressed and localized in the cytoplasm, and whose preferred substrate is hydrogen peroxide. It is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. This gene contains an in-frame GCG trinucleotide repeat in the coding region, and three alleles with 4, 5 or 6 repeats have been found in the human population. The allele with 4 GCG repeats has been significantly associated with breast cancer risk in premenopausal women. Alternatively spliced transcript variants have been found for this gene. Pseudogenes of this locus have been identified on chromosomes X and 21. [provided by RefSeq, Aug 2017]
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Comment |
Nakamura T, et al 2001 reported the down-regulation of glutathione peroxidase causes bovine
luteal cell apoptosis during structural luteolysis.
Prostaglandin (PG) F-2 alpha is known to initiate luteal cell apoptosis in the
bovine corpus luteum (CL) via its specific receptor (FP) on the luteal
membrane by inducing intracellular Ca2+ mobilization and the activation of
PKC, In order to identify the signaling components involved in cell apoptosis,
mRNA levels and activities of antioxidative enzymes were analyzed using bovine
CL at different stages of the estrous cycle. Northern blot analysis revealed
that the levels of two isozymes of superoxide dismutase (SOD), the Mn and
Cu/Zn types, and catalase are highly enriched in the middle estrous phase,
whereas glutathione peroxidase (GPx) levels gradually decrease as the estrous
cycle progresses. The incubation of bovine luteal cells with H2O2 and
mercaptosuccinate (MS), a specific inhibitor of GPx, resulted in an increase
in chromatin DNA condensation and apoptotic DNA fragmentation. Analyses of the
enzymatic activities of GPx and catalase support the RNA data, indicating that
H2O2 produced due to the lack of GPx is a potent inducer of luteal cell
apoptosis.
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Comment |
Changes in the expression of steroidogenic and antioxidant genes in the mouse corpus luteum during luteolysis Foyouzi N, ET AL .
Luteal cell death plays a key role in the regulation of the reproductive process in all mammals. It is also known that prostaglandin (PG) F(2alpha) is one of the main factors that cause luteal demise; still, the effects of PGF(2alpha) on luteal gene transcription have not been fully explored. Using microarray and reverse transcription-polymerase chain reaction, we have profiled gene expression in the corpus luteum (CL) of wild-type and PGF(2alpha) receptor knockout mice on Day 19 of pregnancy. Western blot analysis of selected genes was also performed. Because luteolysis has been shown to be associated with increased oxygen radical production and decreased progesterone synthesis, we report here changes observed in the expression of antioxidant and steroidogenic genes. We found that luteal cells express all genes necessary for progesterone synthesis, whether or not they had undergone luteolysis; however, an increase in mRNA levels of enzymes involved in androgen production, along with a decrease in the expression of enzymes implicated in estrogen synthesis, was observed. We also identified six genes committed to the elimination of free radical species that are dramatically down-regulated in the CL of wild-type animals with respect to PGF(2alpha) receptor knockout mice. Similar changes in the expression of steroidogenic and antioxidant genes were found in the CL of wild-type animals between Days 15 and 19 of pregnancy. It is proposed that an increase in the androgen:estrogen biosynthesis ratio, along with a significantly reduced expression of free radical scavenger proteins, may play an important role in the luteolytic process.
The results also showed that the mRNA of all members of the peroxiredoxin (Prdx) family of proteins are expressed in the CL. Prdx1, Prdx2, Prdx3, and Prdx6 mRNA were found to be highly expressed, while Prdx4 and Prdx5 were found to be present at low levels (Fig. 3B, lower). Low relative expression levels of catalase (Cat) were found (Fig. 3, lower). Messenger RNA levels of Prdx6 were significantly lower in wild-type mice compared with PGF2 receptor knockout animals (Fig. 3B, top).
High luteal mRNA levels for glutathione peroxidase (Gpx) types 1, 3, and 4 were found in both wild-type and PGF2 receptor knockout mice (Fig. 3B, lower), and no differences were found in mRNA levels of these enzymes between these two groups (Fig. 3B, top).
It was also found that luteal cells express the mRNA for the -tocopherol transfer protein (Ttpa). Levels of Ttpa mRNA were 10-fold higher in luteal cells of PGF2 receptor knockout mice than in cells of wild-type animals (Fig. 3B). In wild-type mice, a significant decrease in microsomal glutathione S-transferase (Mgst) 2 mRNA levels was found compared with levels in PGF2 receptor knockout mice, but no differences were found in the expression of Mgst1 and Mgst3 (Fig. 3B, top). Mgst1 mRNA was found to be expressed at very high relative levels, whereas Mgst2 and Mgst3 were expressed at moderate and low relative levels, respectively.
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Mutations |
2 mutations
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Association of GPx1 P198L and CAT C-262T Genetic Variations With Polycystic Ovary Syndrome in Chinese Women. Sun Y et al. (2019) Background: Oxidative stress plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). Glutathione peroxidase 1 (GPx1) and catalase (CAT) are the major intracellular antioxidant enzymes that can detoxify hydrogen peroxide into water, preventing cellular injury from reactive oxygen species. The aim of the present study was to investigate the association of GPx1 P198L (Pro198Leu, C559T, rs1050450) and CAT C-262T (rs1001179) genetic polymorphisms with the risk of PCOS and evaluate the effects of the genotypes on clinical, hormonal, metabolic and oxidative stress parameters in Chinese women. Methods: This is a case-control study of 654 patients with PCOS and 535 controls. The GPx1 P198L, CAT C-262T, and superoxide dismutase 2 (SOD2) A16V genotypes were determined by polymerase chain reaction amplification and restriction analysis. Clinical, hormonal, metabolic and oxidative stress parameters were also analyzed. Results: The frequencies of the PL + LL genotype (14.1 vs. 8.4%) and L allele (7.3 vs. 4.4%) of GPx1 P198L polymorphism were significantly higher in patients with PCOS than in control subjects. Genotype (PL + LL) remained a significant predictor for PCOS in prognostic models including age, body mass index (BMI), insulin resistance index, total cholesterol, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol as covariates (OR = 2.105, 95%CI: 1.330-3.331, P = 0.001). Patients carrying the L allele had relatively high average ovarian volume, waist circumference, and malondialdehyde levels (P < 0.07) compared with patients with the PP genotype. We also demonstrated that the subjects with both GPx1 L and SOD2 A alleles further increase the risk of PCOS compared with the individuals carrying the PP/VV genotype after adjusting for age and BMI (OR = 5.774, 95%CI: 2.243-14.863, P < 0.001). However, no significant differences were observed in the frequencies of the CAT C-262T genotypes and alleles between PCOS and control groups. Conclusions: The GPx1 P198L, but not CAT C-262T, genetic polymorphism is associated with the risk of PCOS in Chinese women.//////////////////
Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: 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. de Haan JB et al. (1998) Glutathione peroxidases have been thought to function in cellular antioxidant defense. However, some recent studies on Gpx1 knockout (-/-) mice have failed to show a role for Gpx1 under conditions of oxidative stress such as hyperbaric oxygen and the exposure of eye lenses to high levels of H2O2. These findings have, unexpectedly, raised the issue of the role of Gpx1, especially under conditions of oxidative stress. Here we demonstrate a role for Gpx1 in protection against oxidative stress by showing that Gpx1 (-/-) mice are highly sensitive to the oxidant paraquat. Lethality was already detected within 24 h in mice exposed to paraquat at 10 mg.kg-1 (approximately (1)/(7) the LD50 of wild-type controls). The effects of paraquat were dose-related. In the 30 mg.kg-1-treated group, 100% of mice died within 5 h, whereas the controls showed no evidence of toxicity. We further demonstrate that paraquat transcriptionally up-regulates Gpx1 in normal cells, reinforcing a role for Gpx1 in protection against paraquat toxicity. Finally, we show that cortical neurons from Gpx1 (-/-) mice are more susceptible to H2O2; 30% of neurons from Gpx1 (-/-) mice were killed when exposed to 65 microM H2O2, whereas the wild-type controls were unaffected. These data establish a function for Gpx1 in protection against some oxidative stressors and in protection of neurons against H2O2. Further, they emphasize the need to elucidate the role of Gpx1 in protection against different oxidative stressors and in different disease states and suggest that Gpx1 (-/-) mice may be valuable for studying the role of H2O2 in neurodegenerative disorders.//////////////////
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