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PubMed1991

Membrane alterations in G6PD- and PK-deficient erythrocytes exposed to oxidizing agents.

After in vitro treatment of normal, glucose-6-phosphate dehydrogenase-deficient or pyruvate kinase-deficient human erythrocytes with three different oxidizing agents, the extent of lipid peroxidative degradation and the alterations of membrane proteins were evaluated. Exposure to tert-butylhydroperoxide induced, most markedly in G6PD- and PK-deficient erythrocytes, a reduction of protein bands 1, 2, 2.1, 3, 4.1, 4.2, and 5, with the appearance of high-molecular-weight aggregates and of "new" polypeptide components in the 29- to 23-kDa region and with a marked increase of membrane-bound globin. Malonyldialdehyde production was highest in G6PD-deficient cells and relatively low in PK-deficient ones. Methylene blue, which had similar but less relevant effects on lipid peroxidation, in G6PD-deficient erythrocytes caused a conspicuous appearance of high-molecular-weight aggregates and a simultaneous relevant decrease of bands 1 and 2 and of membrane-bound globin; it brought about an almost opposite effect in PK-deficient red cells. Acetylphenylhydrazine, which under our conditions appeared the mildest agent, failed, in normal and PK-deficient erythrocytes, to increase malonyldialdehyde production or to alter membrane proteins, whereas it caused, in G6PD-deficient cells, a slight decrease of bands 1 and 2, a more pronounced decrease of band 3, and a marked increase of bands 4.5 and 4.9.

Erythrocyte Membrane↗
PubMed1989

Toward a physical map of the Xq28 region in man: linking color vision, G6PD, and coagulation factor VIII genes to an X-Y homology region.

We are using pulsed-field gel electrophoresis (PFGE) to establish a physical map of the human Xq28 region. We have identified a new probe 35.239 (DXYS64), localized in Xq28 by somatic hybrid mapping and belonging to a region of greater than 99% homology between the X and the Y chromosomes. PFGE data show that probes 35.239 and the polymorphic locus DXS115 (probe 767) map within a common 300-kb BssHII fragment. Both probes, in addition, hybridize to 575-kb BssHII and 590-kb ClaI fragments that contain the gene coding for coagulation factor VIII (F8C). The order F8C-DXS115-DXYS64 could be determined. Our results also provide evidence for linkage between the red/green color vision locus (RCP,GCP) and probes MD13 and T1.7 (GdX, DXS254) within a 750-kb ClaI fragment. Although the latter two probes are located within 50 kb of the 3' end of the G6PD gene, a G6PD cDNA probe did not hybridize to this fragment. G6PD, on the other hand, could be linked to F8C on a 290-kb BssHII fragment. All these data allow us to propose the order (RCP,GCP)-MD13-GdX-G6PD-F8C-DXS115-DXYS 64. We also linked probes St14 (DXS52), MN12 (DXS33), and DX13 (DXS15) to a member of a small family of X-linked dispersed sequences (DNF22S3) within a 575-kb BssHII fragment. The preliminary physical map presented here should be useful for further fine mapping of disease genes in the Xq28 region and should be helpful in orientating efforts toward the cloning of sequences close to the fragile X syndrome.

Animals↗
PubMed2005

Detection of three common G6PD gene mutations in Chinese individuals by probe melting curves.

OBJECTIVE: In order to develop and validate an assay for rapid detection of three common G6PD gene mutations in Chinese individuals. METHODS: In this report we design two sets of primers and fluorescently labeled hybridization probes recognizing adjacent sequences in the amplicon; after annealing, the fluorophores were in resonance energy transfer, providing real-time monitoring of the amplication process. At the completion of PCR, fluorescence was monitored as the temperature increased through the Tm of the probe/product duplex, and a characteristic melting profile for each mutation was obtained. By using the fluorescence method and PCR/RE, a total of 57 samples obtained from two groups of G6PD-deficient individuals were studied. RESULT: A rapid method for detection of three common G6PD gene mutations in Chinese individuals by probe melting curves was developed. This method shows 100% accordance with the traditional method. CONCLUSION: This fluorescent melting curve analysis is a simple, rapid, and effective method for clinical diagnosis and screening of G6PD deficiency.

China↗
PubMed1991

Two commonly occurring nucleotide base substitutions in Chinese G6PD variants.

Using a direct PCR sequencing technique, we have identified two DNA base substitutions in 8 different biochemical G6PD variants of Chinese origin. Neither one of these abnormalities has been reported in other ethnic groups. An abnormality (C1) of G to T substitution at cDNA 1376 causing an amino acid change from Arg to Leu has been found in 3 variants. Another abnormality (C2) of G to A substitution at cDNA 1388 causing an amino acid change from Arg to His has been found in 5 variants. Both C1 and C2 are located in exon 12 of the G6PD gene and are only 12 base pairs apart. However, C1 is associated with a significant increase in the deamino-NADP utilization rate, whereas C2 is not. Taken together, our data suggest that C1 and C2 are very common among Chinese with a G6PD deficiency and exon 12 may define an important functional domain of the human G6PD.

Base Sequence↗
PubMed1981

Detection of G6PD and pyruvate kinase deficiencies in reticulocytosis by reference to erythrocyte creatine.

Erythrocyte activities of G6PD and PK, referenced to creatine content, are presented as a means to detect enzyme deficiencies despite the presence of variable proportions of young erythrocytes in the assayed cell population. Lysate enzyme activities, creatine and hemoglobin concentrations, and whole blood reticulocyte counts were determined on 110 samples from 87 patients with a variety of anemias, including two pyruvate kinase deficient, three G6PD deficient, and four proven G6PD heterozygotes. Highest correlations were obtained between log of G6PD activity/g hemoglobin and lysate creatine, and between PK activity/g hemoglobin and lysate creatine. Ninety-five percent limits for this population are presented for creatine concentrations to 28 mg/dl, corresponding to 20% reticulocyte count. In addition to providing reference intervals appropriate to the suspect patient population, the data afford greater confidence in detecting partial enzyme deficiencies concomitant with other hemolytic processes, such as hemoglobinopathies.

Creatine↗
PubMed2002

Moderate G6PD deficiency increases mutation rates in the brain of mice.

Mice that harbored the x-ray-induced low efficiency allele of the major X-linked isozyme of glucose-6-phospate dehydrogenase (G6PD), Gpdx(a-m2Neu), and, in addition, harbored the transgenic shuttle vector for the determination of mutagenesis in vivo, pUR288, were employed to further our understanding of the interdependence of general metabolism, oxidative stress control, and somatic mutagenesis. The Gpdx(a-m2Neu) mutation conferred moderate G6PD deficiency in hemizygous males (Gpdx(a-m2Neu/y)) displaying residual enzyme activities of 27% in red blood cells and 13% in brain (compared to wild-type controls, Gpdx(a/y) males). In spite of this mild phenotype, the brains of G6PD-deficient males exhibited a significant distortion of redox control ( approximately 3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts ( approximately 13-fold increase in ethenodeoxyadenosine and approximately 5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates ( approximately 3-fold increase in mutant frequencies in lacZ, the target and reporter gene of mutagenesis in the shuttle vector, pUR288). The mutation pattern in the brain was dominated by illegitimate genetic recombinations, a presumed hallmark of oxidative mutagenesis. These findings suggested a critical function for G6PD in limiting oxidative mutagenesis in the mouse brain.

Anemia, Hemolytic↗
PubMed2000

Single nucleotide primer extension (SNuPE) analysis of the G6PD gene in somatic cells and oocytes of a kangaroo (Macropus robustus).

cDNA sequence analysis of the X-linked glucose-6-phosphate dehydrogenase (G6PD) gene has shown a base difference between two subspecies of the kangaroo, Macropus robustus robustus (wallaroo) and M. r. erubescens (euro). A thymine residue in the wallaroo at position 358 in exon 5 has been replaced by a cytosine residue in the euro, which accounts for the previously reported electrophoretic difference between the two subspecies. This base difference allowed use of the Single Nucleotide Primer Extension (SNuPE) technique to study allele-specific expression of G6PD at the transcriptional level. We began by examining G6PD expression in somatic cells and observed complete paternal X inactivation in all somatic tissues of adult female heterozygotes, whereas we found partial paternal allele activity in cultured fibroblasts, thus confirming previous allozyme electrophoresis studies. In late dictyate oocytes from an adult heterozygote, the assay also detected expression of both the maternal and paternal alleles at the G6PD locus, with the maternal allele showing preferential expression. Thus reactivation of the inactive paternally derived X chromosome occurs during oogenesis in M. robustus, although the exact timing of reactivation remains to be determined.

Amino Acid Substitution↗
PubMed1975

Distribution of ABO and Rhesus blood groups in G6PD deficient Chinese and Malay newborns.

The distribution of ABO blood groups was studied in 459 Chinese and 65 Malay newborns with deficiency of G6PD, and in 1181 Chinese and 535 Malay newborns with normal levels of the enzyme. Similarly, the distribution of Rhesus blood groups was studied in 248 G6PD deficient Chinese newborns and in 255 normal subjects. No association between the ABO blood groups and G6PD deficiency was observed in either Chinese or Malays. For the Rhesus system there was found to be a statistically significant decrease in the frequency of genotypes containing the complex R1, in G6PD deficient subjects compared with that in normal subjects.

ABO Blood-Group System↗
PubMed1996

Neonatal jaundice in Saudi newborns with G6PD Aures.

Sixty-five of 3261 (2%) Saudi neonates were found to be severely G6PD-deficient during a cord blood screening programme conducted from April to December, 1992. However, at the time of molecular studies, the blood samples were available from only 20 randomly selected children, aged from 1 to 6 years. DNA analyses showed that seven (three boys, four girls) of these 20 (35%) had G6PD Aures (nt 143 T - > C), a variant associated with favism which was recently reported in an Algerian. Twelve carried the G6PD Mediterranean (563 T) mutation, and in one child the mutation remained unidentified. The medical records of these children showed that all who had G6PD Aures, including a premature baby, were jaundiced during the 1st week of life, but only six full-term infants had moderate-to-severe hyperbilirubinaemia. Two of seven babies had seizures and one of these two developed kernicterus, in spite of timely blood transfusion.

Base Sequence↗
PubMed1983

The effect of DDT on the polymorphism at the G6pd and Pgd loci in Drosophila melanogaster.

For the degradation of DDT and other chlorohydrocarbon insecticides energy in the form of NADPH is needed which for the greater part is supplied by the pentose phosphate shunt. Therefore the influence of DDT on the polymorphism at the G6pd and Pgd loci in Drosophila melanogaster was investigated by studying its effect on egg to adult survival and adult survival. The results show the existence of significant differences in fitness between the different genotypes of the two loci for both components. It is found that the effect of DDT supplementation differs significantly from the effect of sodium octanoate addition. DDT treatment also increases the activity of the pentose phosphate shunt as measured by the activity of G6PD and 6PGD. In larvae a 50% increase in activity is found and in adults a 100% increase. As there is little doubt that the activities of G6PD and 6PGD are somehow correlated with the fitness of flies, the data are discussed in relation to the in vitro and in vivo differences in activity between the different allozymes of both G6PD and 6PGD.

Animals↗
PubMed1985

Targeted selection experiments and enzyme polymorphism: negative evidence for octanoate selection at the G6PD locus in Drosophila melanogaster.

Published studies have reported significant selection with respect to the G6pd locus for Drosophila melanogaster reared on Na-octanoate food. We have reexamined the selective effects of Na-octanoate on egg to adult viability with respect to the G6pd polymorphism using specially constructed X chromosomes. Four experiments were carried out using different 6Pgd backgrounds in two recombinant sets of chromosomes segregating for the G6pd locus but constructed so as to minimize variation over most of the X chromosome. In addition, two measures of viability were used, and the size of the experiments and their associated degrees of freedom are approximately double those reported in the former studies. Our results find no evidence for differential selection on G6pd genotypes (males and females) by Na-octanoate and, therefore, do not corroborate the positive results of selection reported by other investigators. The reasons for our different results are discussed.

Animals↗
PubMed1986

Isolation of human glucose-6-phosphate dehydrogenase (G6PD) cDNA clones: primary structure of the protein and unusual 5' non-coding region.

Glucose-6-phosphate dehydrogenase (G6PD) is an ubiquitous enzyme which by determining the NADPH level has a crucial role in NADPH-mediated reductive processes in all cells (1). The structural gene for G6PD, Gd, is X-linked in mammals and on the basis of its expression in many tissues, it can be regarded as a typical "housekeeping" gene (2). Over 300 variants of the protein are known, many of which have deficient enzyme activity. Nearly 100 of these variants are polymorphic in various populations (3). The mammalian enzyme is a homodimer or a homotetramer with a subunit molecular weight of approximately 56000 daltons (4). Here we report the isolation of cDNA clones from HeLa cells, SV40-transformed human fibroblasts, human placenta and human teratocarcinoma cell lines. These clones have enabled us to sequence the entire coding region of Gd. Thus, the entire amino acid sequence of human G6PD is provided for the first time. This work is the first step for structural analysis of G6PD variants and for an understanding of the biological features of this enzyme at the molecular level.

Amino Acid Sequence↗
PubMed2003

Kernicterus and G6PD deficiency--a case series from Oman.

The relationship between glucose-6 phosphate dehydrogenase (G6PD) deficiency and jaundice in the newborn period is well recognized. However, there is concern about the increasing incidence of kernicterus being reported worldwide, especially due to unrecognized G6PD deficiency and early discharge from hospital after birth. We report a case series of kernicterus from a set-up where the high prevalence rate of G6PD deficiency is known. Fourteen cases of kernicterus were seen during a time period of 6 years, 71 per cent of them had G6PD deficiency. Recent literature is reviewed and possible preventive measures in the light of current information and practices are suggested.

Female↗
PubMed1987

Red-cell GSH regeneration and glutathione reductase activity in G6PD variants in the Ferrara area.

Red-cell studies were carried out on three groups of G6PD-deficient subjects with different G6PD variants from the Ferrara area of Northern Italy. Red-cell GSH and activities of G6PD, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) were measured. A method was developed to measure red-cell GSH regeneration after oxidation of endogenous GSH in whole blood by diamide and only this clearly distinguished the variants from each other and from normal. Regeneration by 1 h was lowest in the Mediterranean variant, 0-10.2% in contrast to 93-98% in normal. A predisposition to a haemolytic crisis after ingestion of fava beans was not clearcut, but subjects appeared to be at risk if GSH regeneration at 1 h was less than 30% of the endogenous level, and red-cell FAD+ was very high indicated by high in vitro GR activity and inhibition by added FAD+. It is suggested that the most informative tests in G6PD deficiency are measurements of GSH regeneration in intact red cells plus GR activity and/or red-cell flavin compounds.

Adolescent↗
PubMed1994

Biochemical and molecular characterization of a new sporadic glucose-6-phosphate dehydrogenase variant described in Italy: G6PD Modena.

A new glucose-6-phosphate dehydrogenase variant detected in an Italian man from the Po delta is described and designated as G6PD Modena. Biochemical characterization of the variant enzyme revealed an activity 21% of normal, a slow electrophoretic mobility, increased Km value for NADP, decreased Km value for G6P and a complete absence of NADPH inhibition, which could account for the apparently nonhaemolytic feature of this variant. The cloning and sequencing of the G6PD Modena allele showed a G-->C transition at nucleotide 844 in exon VIII causing a Asp-->His amino acid substitution. On the basis of biochemical characterization, G6PD Modena is classified as a genuine variant but it has the same mutation as G6PD Seattle-like.

Adult↗
PubMed1993

Alternative splicing of human G6PD messenger RNA in K562 cells but not in cultured erythroblasts.

The biochemical properties of glucose-6-phosphate dehydrogenase (G6PD) vary in different tissues, and different protein isoforms of the enzyme have been described. Alternative splicing of G6PD intron VII has been detected in transformed lymphoblasts, granulocytes and spermatocytes; the function of this mRNA species is still unknown. We developed a PCR for detecting alternatively spliced G6PD mRNA in K562 and in erythroblasts at different stage of maturation obtained from human peripheral BFU-E in order to evaluate a possible physiological role during erythroid maturation. Trace events of alternative splicing of G6PD intron VII sequences were observed in K562 cells but not in BFU-E-derived erythroid precursors; we consider this phenomenon a non-functional activity in the cells analysed.

Base Sequence↗
PubMed2005

Safety of the combination of chloroquine and methylene blue in healthy adult men with G6PD deficiency from rural Burkina Faso.

New drug combinations against falciparum malaria which are both effective and affordable for Sub-Saharan African populations are urgently needed. The combination of the well-known drugs chloroquine (CQ) and methylene blue (MB) is such a promising new regimen. However, there is some concern that MB could cause development of haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition which is prevalent in malaria-endemic regions. Against this background, 74 G6PD-deficient but otherwise healthy adult men were given a 3-day oral regimen of a total of 1500 mg CQ and 780 mg MB in the District Hospital of Nouna in north-western Burkina Faso. Haemolysis did not occur, haemoglobin levels remained stable or even rose in the study participants, and the drug regimen was well tolerated. Therefore, standard dosages of MB appear to be safe in G6PD-deficient African populations with predominantly class III G6PD deficiency.

Adolescent↗
PubMed1982

G6PD Varadero. A new variant of glucose-6-phosphate dehydrogenase associated with congenital nonspherocytic hemolytic anemia.

A glucose-6-phosphate dehydrogenase (G6PD) variant was studied in a mulatto patient with chronic nonspherocytic hemolytic anemia. This variant has reduced activity, increased thermolability, a reduced Michaelis constant for glucose-6-phosphate, slightly increased electrophoretic mobility, a biphasic pH activity profile, high 2-deoxyglucose-6-phosphate utilization, normal diamino nicotinamide adenine dinucleotide phosphate utilization and a peak of elution profile after G6PD B. The electrophoretic, kinetic, and chromatographic properties of this erythrocyte G6PD variant allow the conclusion that G6PD Varadero is probably a new variant.

Anemia, Hemolytic, Congenital↗