HGNC Approved Gene Symbol: GSR
Cytogenetic location: 8p12 Genomic coordinates (GRCh38): 8:30,678,066-30,727,846 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p12 | Hemolytic anemia due to glutathione reductase deficiency | 618660 | Autosomal recessive | 3 |
Glutathione reductase (EC 1.6.4.2), a homodimeric flavoprotein, catalyzes the production of glutathione (GSH) from glutathione disulfide (GSSG) at the expense of NADPH. As part of the glutathione redox cycle, the enzyme plays a role in the detoxification of reactive oxygen species. It is also involved in a number of cellular functions including the activation of dormant cells and the regulation of the cell cycle (Tutic et al., 1990).
Tutic et al. (1990) cloned a full-length cDNA of human GSR. The deduced GSR protein contains 478 amino acids. Tutic et al. (1990) also cloned a partial cDNA pf mouse Gsr.
Kelner and Montoya (2000) stated that mammalian GSR activity is present in both the cytosol and the mitochondria.
By genomic cloning, Kelner and Montoya (2000) determined that the GSR gene spans 50 kb, contains 13 coding exons, and is highly similar to the mouse Gsr gene. Human GSR has an N-terminal arginine-rich mitochondrial leader sequence, which shows high homology to the mouse leader sequence, between 2 in-frame start codons in the first exon.
George and Francke (1976) assigned the GSR gene to 8p21-p23 by the gene dosage method. In an infant with terminal deletion of the short arm of chromosome 8, de la Chapelle et al. (1976) found low GSR activity. They concluded that the GSR locus is in the region 8pter-p21. Sinet et al. (1977) narrowed the assignment to 8p21. The GSR locus has also been assigned by somatic cell hybridization; it is one of the enzyme-markers for each chromosome (table 1 in Shows and Sakaguchi, 1980), useful for synteny mapping.
In cases of mosaic trisomy for chromosome 8, de la Chapelle et al. (1976) found elevated glutathione reductase activity, with other enzymes normal.
Hampel et al. (1969) found a markedly increased frequency of chromosomal aberrations in a patient with pancytopenia and absent GSR-II band in the electropherogram. The mother was hematologically normal but had absent GSR-II band and a moderate increase in the frequency of chromosomal aberrations. Addition of chloramphenicol to the cultures increased the number of damaged chromosomes in both the mother and the son.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Hemolytic Anemia due to Glutathione Reductase Deficiency
In 2 sibs, born of consanguineous parents, with hemolytic anemia due to glutathione reductase deficiency (618660), who were previously reported by Loos et al. (1976) and Roos et al. (1979), Kamerbeek et al. (2007) identified a homozygous intragenic 2.246-kb deletion in the GSR gene (138300.0001). The deletion was confirmed by Southern blot analysis; Western blot analysis did not detect any residual protein, suggesting that any mutant protein produced was rapidly degraded. There was no detectable GSR enzyme activity in patient red blood cells or leukocytes. Kamerbeek et al. (2007) also identified compound heterozygous mutations in the GSR gene (W287X, 138300.0002 and G330A, 138300.0003) in an unrelated girl with the disorder. Each unaffected parent was heterozygous for one of the mutations. Patient red blood cells had no detectable GSR activity, but leukocytes retained some residual activity that correlated with weak protein expression. In vitro functional cellular expression studies of the G330A mutation showed that it had decreased GSSG reduction activity and increased thermal instability compared to wildtype. The authors suggested that the clinical features resulted from increased cellular susceptibility to oxidative stress due to absence of GSR activity.
Using a combination of behavioral analysis of 6 inbred mouse strains with quantitative gene expression profiling of several brain regions, Hovatta et al. (2005) identified 17 genes with expression patterns that correlated with anxiety-like behavioral phenotypes. To determine if 2 of the genes, glyoxalase-1 (138750) and glutathione reductase-1, have a causal role in the genesis of anxiety, Hovatta et al. (2005) performed genetic manipulation using lentivirus-mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behavior, while local inhibition of glyoxalase-1 expression by RNA interference decreased the anxiety-like behavior. Hovatta et al. (2005) concluded that both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behavior.
In 2 sibs, born of consanguineous parents, with hemolytic anemia due to glutathione reductase deficiency (618660), who were previously reported by Loos et al. (1976) and Roos et al. (1979), Kamerbeek et al. (2007) identified a homozygous intragenic 2.246-kb deletion in the GSR gene. The deletion, which was found by direct sequencing of the GSR gene, spanned from nucleotide -229 in intron 11 to nucleotide 500 in the 3-prime UTR. The deletion was confirmed by Southern blot analysis; Western blot analysis did not detect any residual protein, suggesting that any mutant protein produced was rapidly degraded. There was no detectable GSR enzyme activity in patient red blood cells or leukocytes.
In a girl with hemolytic anemia due to glutathione reductase deficiency (618660), Kamerbeek et al. (2007) identified compound heterozygous mutations in the GSR gene: a c.861G-A transition in exon 9, resulting in a trp287-to-ter (W287X) substitution, and a c.989G-C transversion in exon 10, resulting in a gly330-to-ala (G330A; 138300.0003) substitution at a highly conserved residue that is part of an FAD-binding motif. Each unaffected parent was heterozygous for one of the mutations. Patient red blood cells had no detectable GSR activity, but leukocytes retained some residual activity that correlated with weak protein expression. In vitro functional cellular expression studies of the G330A mutation showed that it had decreased GSSG reduction activity and increased thermal instability compared to wildtype.
For discussion of the c.989G-C transversion in exon 10 of the GSR gene, resulting in a gly330-to-ala (G330A) substitution, that was found in a girl with hemolytic anemia due to glutathione reductase deficiency (618660) by Kamerbeek et al. (2007), see 138300.0002.
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