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A low rate value of G6PD was found in red blood cells from a Cambodian boy. Enzyme mapping was performed according to the WHO standard methods. G6PD presented all the characteristics of the A(-) variant encountered in the Negroes and behaved distinct from fast migrating enzymes described in China. No negro was in the ancestry of the mother.
A new glucose-6-phosphate dehydrogenase (G6PD) variant associated with chronic nonspherocytic hemolytic anemia was found in a 20-year-old Japanese male who showed mild hemolysis after an upper respiratory tract infection. The patient had been noted to have jaundice and reticulocytosis several times before this episode. The enzyme activity of the variant was 1.5% of normal. The enzymatic characteristics were slow anodal electrophoretic mobility, high Km G6P, normal Km NADP, decreased heat stability, and a normal pH optimum. From these results, the enzyme was considered to be a new class 1 variant and was designated G6PD Tsukui.
In order to study the mechanism of X Chromosome (Chr) inactivation in marsupials, the cDNA for glucose-6-phosphate dehydrogenase (G6PD) from an Australian marsupial, the wallaroo (Macropus robustus), was cloned. A partial clone containing the 3' half of the cDNA was obtained by screening a liver cDNA library. The majority of the coding region was obtained by polymerase chain reaction of cDNA with primers designed from regions of conservation between human and opossum G6PD. The 5' end was obtained by rapid amplification of cDNA ends. High homology was observed between mammalian species in the coding region. The 5' untranslated region is highly G+C rich, and appears to be part of a CpG island, as is the case in the human and mouse genes. This is the first report of the full sequence of the cDNA for any marsupial X-linked gene.
The incidence of spontaneous abortions in women with glucose-6-phosphate dehydrogenase (G6PD) deficiency was studied. In 78 families where the wife was a heterozygous carrier of G6PD deficiency the percentage of unsuccessful pregnancies with spontaneous abortions occurring in the first trimester was higher (21.7%, calculated from 258 pregnancies) than in the control group (9.3%, calculated from 678 pregnancies.
The electrophoretic variants of G6PD and 6PGD isolated from the Bogota Drosophila melanogaster population were characterized developmentally and biochemically. Changes in in vitro enzyme activity during development were comparable to those found for other dehydrogenases: an increase in the larval and adult stage and a decrease in the pupal stage. During the whole life cycle the "S" enzyme of both loci showed a higher activity than the "F" enzyme. MgCl2 had a stimulating effect on the activity of both enzymes whereas their heat stability was decreased. The allozymes of 6PGD had different Vmax's but were comparable with respect to Km values, pH optimum, and stability at 45 C. the allozymes of G6PD showed different Vmax's and differed in stability at 35 C, but had similar Km values and pH optima. As the difference in stability was probably due to differences in molecular structure of the allozymes, the differences in activity found at high pH and high MgCl2 concentration were most probably due to this difference in stability.
X chromosome dosage compensation in Marsupials is like that in eutherian mammals except that the paternal X chromosome is always inactive, and silence of this chromosome is not well maintained. We previously showed that the unstable inactivation of the paternal G6PD allele is associated with the lack of DNA methylation in the 5' CpG cluster. Even though this CpG island is unmethylated, the paternal allele (marked by an enzyme variant) is at least partially and often severely repressed in most tissues of the opossum, so that factors other than methylation must inactivate the locus. Here we report that when cell cultures are established from these tissues, the silent G6PD locus is depressed. Although often complete, the extent of derepression differs among tissues and within different cell types in the same tissue, and is not accompanied by obvious changes in the pattern of chromosome replication. Studies of the HPRT locus in these cells show that the paternal HPRT allele also derepresses in cultured cells. These observations suggest that without DNA methylation to maintain the silence of the locus, tissue or cell-specific factors act to repress the silent locus, but are unable to maintain inactivity through cell division, or are lost as cells proliferate in culture.
The nucleotide (nt) sequence of the entire CpG island in the 5' region of the human glucose-6-phosphate dehydrogenase-encoding gene (G6PD) and of the corresponding region in mouse was determined. In comparison to the human gene, the 5' region of the mouse G6PD gene has highly reduced G + C and CpG dinucleotide content, but maintains the functional features of a CpG island, as it is differentially methylated on the active vs. the inactive X chromosome. In addition to the expected conservation of exons, nt sequence comparison showed that several boxes are highly conserved between the two species in the 5' flanking DNA and in the first intron. Moreover, the conservation of the position of most CpG dinucleotides in the promoter region and in one of the upstream boxes, at about -900, gives support to the hypothesis that, in each island, specific CpGs play a major role in the regulation of gene expression.
The addition of negroid phenotypes to the already heterogeneous population of Israel caused us to reuse the enzymes G6PD and PGD which are known to have a better discrimination power in a negroid population than in caucasians. We have developed a system for combined phenotyping of G6PD and PGD. This system answers the requirements of the above enzymes and results in a negroid population than in caucasians. We have developed a system for combined phenotype-amount of sample and reagents needed and time spent.
We have mapped HPRT and G6PD loci on the X chromosome in the American opossum, Didelphis virginiana, by in situ hybridization to cells derived from two females by using genomic opossum DNA as probes. The localizations (G6PD to Xp13 and HPRT to Xq21), indicating that the two genes are separated by the centromere, were confirmed by results of hybridization to X chromosomes with deletions that include the HPRT locus and opossum-mouse cell hybrids containing the relevant fragment of the opossum X chromosome.
To investigate the organization of the compact genome of the puffer fish Fugu rubripes at the level of an individual housekeeping gene, we have cloned and sequenced the glucose-6-phosphate dehydrogenase (G6PD) gene from this fish and compared it to the corresponding human gene. The intron/exon structure of the two genes is identical throughout the protein coding regions. The puffer fish gene is four times smaller than the human gene--the difference is accounted for by the fact that the puffer fish gene has smaller introns. Intron 2 is the largest intron in both species. We have constructed a molecular phylogeny for 10 G6PD protein sequences. The sequences fall in the expected arrangement based on established phylogenetic relationships, with the Plasmodium falciparum sequence the most widely diverged.
The electron spin resonance signal of Tempol decays in the presence of red cells. The decay is due to reduction of oxidant, paramagnetic nitroxide group by the metabolic activity of the red cell. In normal red cells, GSH level was stable and Tempol reduction rate followed a first-order kinetics. In G6PD-deficient red cells, GSH dropped and Tempol reduction rate was slower and followed a second-order kinetics. In normal red cells, diamide reversibly oxidized GSH. First-order kinetics of Tempol reduction rate was attained after a delay time proportional to the diamide concentration and corresponding to the full regeneration of GSH. In diamide-treated G6PD deficient, and in NEM-treated, normal red cells, irreversible disappearance of GSH was followed by irreversible dose-dependent decrease in Tempol reduction rate. A correlation between GSH levels and Tempol reduction rate was observed. A correlation was also established between Tempol reduction rate and stimulation of pentosephosphate shunt activity.
In the present study we have assayed the effect of divicine in G6PD-deficient red blood cells in the presence of deferoxamine (iron-chelating drug) and NaN3 (inhibitor of catalase). The effect of divicine has been compared to oxidative stress by H2O2; haemolysis is regarded as an index of cellular toxicity. In addition, we have tested antioxidant enzymatic systems. No significant change in antioxidant enzymatic systems was found in RBCs from subjects with G6PD deficiency when compared to the control group, either in oxidative haemolysis by divicine or by H2O2; a significant decrease in oxidative haemolysis by H2O2 was observed in the presence of deferoxamine, whereas no change was found in oxidative haemolysis by divicine. The replacement of incubation medium by homologous plasma or the supplementation with bovine serum albumin resulted in a marked decrease of percentage of haemolysis by divicine.
A 58-year-old woman was admitted at diagnosis of type 2 diabetes without keto-acidosis. Blood glucose was normalized initially with insulin. Whilst taking glibenclamide, she developed acute haemolysis. She was homozygous for glucose-6-phosphate dehydrogenase (G6PD) deficiency and had no other factors predisposing haemolysis. We reviewed the literature and discuss the relationship between glibenclamide and haemolytic crisis and between G6PD-deficiency and diabetes.
Glucose-6-phosphate dehydrogenase (G6PD) activity was measured in blood from heterozygotes for the normal allele G6pda and the low activity allele G6pda-mlNeu. In adult mice lower activity was found in G6pda/G6pda-mlNeu than in the reciprocal heterozygote G6pda-mlNeu/G6pda (the maternal allele being listed first). Thus, either the paternally derived allele was over-expressed or the maternally derived allele was under-expressed. By contrast, in younger mice the difference in G6PD activity in reciprocal crosses was less marked. The findings are interpreted in terms of differential imprinting of maternally and paternally inherited information. The explanation offered for age related differences is that, as a consequence of imprinting, either the paternal X-chromosome is preferentially reactivated, or cells in which the paternally derived allele is active are at a selective advantage, and proliferate better than those in which the maternally inherited allele is active.
In a 61-year-old man with glucose-6-phosphate dehydrogenase (G6PD) deficiency and poorly controlled non-insulin-dependent diabetes mellitus, an episode of acute haemolysis occurred after the administration of glyburide (glibenclamide). Erythrocyte fragmentation, with haemoglobin condensation zones next to clear zones, was observed on peripheral blood smears. Since autoimmune haemolysis was excluded on the basis of laboratory data, acute haemolysis was ascribed to G6PD deficiency.
The available antimalarial drugs for the treatment of Plasmodium falciparum malaria during pregnancy are potentially toxic, especially in the presence of red blood cells (RBC) defects. We describe a case of chloroquine-resistant malaria by P. falciparum in a pregnant woman with glucose-6-phosphate dehydrogenase (G6PD) deficiency successfully treated with pyrimethamine followed by mefloquine administration. The susceptibility of P. falciparum to chloroquine and mefloquine was assessed by an in vitro test before treatment. Pyrimethamine and mefloquine were administered at the 18th and 22nd week of pregnancy, respectively. Mefloquine concentrations were monitored in the mother's blood at 2, 4, 8, 12, 24 and 48 hr after the administration to define effective blood-drug concentrations. Blood smear examination was negative after 48 hr post mefloquine treatment. No histologic lesions of the placenta were observed. The newborn presented normal clinical parameters. The administration of pyrimethamine prevented massive placental infection, thus permitting the fetus to achieve suitable gestational age for further treatment with mefloquine to eradicate P. falciparum malaria without deleterious effects to the newborn. Subsequent studies could contribute to define safe administration of mefloquine in G6PD-deficient pregnant woman.
Proponents of the neutral theory argue that evolution at the molecular level largely reflects a process of random genetic drift of neutral mutations. Under this theory, levels of interspecific divergence and intraspecific polymorphism are expected to be correlated across classes of nucleotide or amino acid sequences with different degrees of functional constraint, such as synonymous and replacement sites. Nucleotide sites with reduced polymorphism should show comparably reduced levels of interspecific divergence. To examine this hypothesis, we have sequenced 32 and 12 copies of the glucose-6-phosphate dehydrogenase (G6pd) gene in Drosophila melanogaster and Drosophila simulans, respectively. Both species exhibit similar levels of nucleotide polymorphism at synonymous sites. D. melanogaster shows two amino acid polymorphisms, one associated with the cosmopolitan allozyme polymorphism and a second with an allozyme polymorphism endemic to European and North African populations. In contrast, D. simulans shows no replacement polymorphism. While synonymous divergence between species is 10%, which is typical of other genes, there are 21 replacement differences. This level of amino acid sequence divergence, when contrasted with levels of amino acid polymorphism, silent polymorphism, and divergence, is in 10-fold excess over that expected under the neutral model of molecular evolution. We propose that this excess divergence reflects episodes of natural selection on G6pd resulting in fixation of advantageous amino acid mutations in these two recently separated lineages.
Several biochemical studies have suggested that in Drosophila melanogaster the two common allozymes of G6PD differ in their in vitro activities and thermal stabilities. Yet, it remains to be shown that these characterizations reflect actual in vivo differences and are not artifacts of the biochemical approach. In this study it is shown that in vivo activity differences must exist between these two variants. This conclusion arises from the observation that the viability of flies bearing a low activity allele of 6PGD is strongly dependent on the genotype at the G6PD (Zw) locus, whereas no measurable difference in viability can be detected between Zw genotypes in a normal activity 6PGD background. These viability interactions are in the direction predicted by the reported in vitro activities of the allozymes and the proposed deleterious effects of 6-phosphogluconate accumulation.--In addition, a genetic scheme is used that uncouples and quantifies the effects of viability modifiers in the region of the Zw locus, while homogenizing 98% of the X chromosome. The viability of different Zw genotypes is measured by examining whole chromosome viabilities relative to the FM6 balancer chromosome. The advantages of this particular scheme are discussed.