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PubMed2002

Identification of G6PD Mediterranean mutation by amplification refractory mutation system.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X chromosome-linked hereditary enzymopathy in humans. The authors have developed an amplification refractory mutation system (ARMS) to detect the G6PD Mediterranean mutation (nt. 563 C-->T) that is the most frequent among Caucasian population. METHODS: Specific forward polymerase chain reaction (PCR) primers, within exon 6 of the G6PD gene, were designed: ARMS M complementary to the mutated DNA sequence and ARMS N complementary to the wild-type DNA. They were paired with a common reverse primer. The new method was validated using known DNA samples from 72 G6PD-deficient patients carrying the G6PD Mediterranean mutation ascertained by the restriction enzyme analysis. The ARMS test was performed on DNA extracted both from blood or saliva samples. RESULTS: The ARMS test showed an excellent reproducibility and a complete concordance with the endonuclease cleavage reference method. At the same time, it is more rapid and less expensive. CONCLUSIONS: The described molecular test may be a method of choice to identify the G6PD Mediterranean mutation. It could also be helpful to obtain a definite diagnosis of G6PD Mediterranean heterozygotes, which is not feasible by using red blood cell enzyme activity measurements.

DNA Mutational Analysis↗

PubMed1998

Clinical and haematological consequences of recurrent G6PD mutations and a single new mutation causing chronic nonspherocytic haemolytic anaemia.

We have determined the causative mutation in 12 cases of glucose-6-phosphate dehydrogenase deficiency associated with chronic non-spherocytic haemolytic anaemia. In 11 of them the mutation we found had been previously reported in unrelated individuals. These mutations comprise seven different missense mutations and a 24 base pair deletion. G6PD Nara, previously found in a Japanese boy. Repeated findings of the same mutations suggests that a limited number of amino acid changes can produce the CNSHA phenotype and be compatible with normal development. The one new mutation we have found, G6PD Serres, is 1082 C-->T causing a 361 Ala-->Val substitution in the dimer interface where most other severe G6PD mutations are found. Now that several patients with the same mutation have been reported we can compare the resulting clinical phenotypes. For each mutation we find a reasonably consistent clinical picture, ranging from mild (G6PD Clinic) through moderate (G6PD Nashville) to severe (G6PD Beverly Hills and G6PD Nara).

Adolescent↗

PubMed2006

G6PD deficiency with hemolytic anemia due to a rare gene deletion--a report of the first case in Malaysia.

A 2-year-old Chinese boy was referred to Hospital UKM for investigation of recurrent episodes of dark-coloured urine and pallor since birth. He was born prematurely at 34 weeks gestation and developed severe early-onset neonatal jaundice requiring exchange blood transfusion. Screening at birth showed Glucose-6-phosphate dehydrogenase (G6PD) deficiency. On admission, physical examination revealed pallor, jaundice and mild hepatomegaly. Results of laboratory investigations showed a hemoglobin level of 11.0 g/dl with a hemolytic blood picture, reticulocytosis of 20% and red cell G6PD activity reported as undetectable. The patient's DNA was analysed for G6PD mutations by PCR-based techniques and DNA sequencing and results showed a 24 bp deletion of nucleotide 953-976 in the exon 9 of the G6PD gene. DNA analysis was also performed on blood samples of the patient's mother and female sibling confirming their heterozygous status, although both showed normal red cell G6PD activity levels. The patient was discharged well and his parents were appropriately advised on the condition and the importance of taking folic acid regularly. This is a first case report in Malaysia of G6PD deficiency causing chronic-hemolytic anemia. The rare 24 bp deletion causes the G6PD Nara variant, previously reported only in two other unrelated males, a Japanese and a Portuguese both with chronic hemolytic anemia.

Anemia, Hemolytic↗

PubMed2006

Contrasting histories of G6PD molecular evolution and malarial resistance in humans and chimpanzees.

Although mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene result in several blood-related diseases in humans, they also confer resistance to malarial infection. This association between G6PD and malaria was supported by population genetic analyses of the G6PD locus, which indicated that these mutations may have recently risen in frequency in certain geographic regions as a result of positive selection. Here we characterize nucleotide sequence variation in a 5.2-kb region of the G6PD locus in a population sample of 56 chimpanzees, as well as among 7 other nonhuman primates, to compare with that in humans in determining whether other primates that are impacted by malaria also exhibit patterns of G6PD polymorphism or divergence consistent with positive selection. We find that chimpanzees have several amino acid variants but that the overall pattern at G6PD in chimpanzees, as well as in Old and New World primates in general, can be explained by recent purifying selection as well as strong functional constraint dating back to at least 30-40 MYA. These comparative analyses suggest that the recent signature of positive selection at G6PD in humans is unique.

Animals↗

PubMed1996

Unproductive folding of the human G6PD-deficient variant A-.

Human glucose-6-phosphate dehydrogenase (G6PD) deficiency almost invariably results from the presence of missense mutations in the X-linked gene encoding G6PD. The common African deficient variant G6PD A- differs from the normal G6PD B by two amino acid substitutions. Only one of these mutations is found on its own, resulting in the nondeficient variant G6PD A. Deficiency is always associated with decreased G6PD activity in red cells, leading to a variety of clinical manifestations. A group of deficient variants, including A-, have near-normal affinity for the substrates G6P and NADP. In these cases, deficiency is caused by a decreased number of catalytically active molecules per cell due to intracellular instability of the mutated G6PD, although the mechanism for this in vivo instability is unknown. Here we report that in vitro folding of the A- variant mainly renders partially folded polypeptides that do not undergo the dimerization required for activity. Under the same conditions, the nondeficient variants B and A undergo folding to produce active dimers with normal mobilities in native gels and normal kinetic properties. The loss of intrinsic folding determinants in the A- variant may underlie the mechanism of its in vivo instability.

Africa↗

PubMed1986

G6PD-deficiency infectious haemolysis: a complement dependent innocent bystander phenomenon.

Dramatic haemolysis may accompany viral hepatitis and pneumococcal pneumonia in G6PD-deficient patients. Since red blood cells (RBCs) are richly endowed with receptors for activated complement, particularly C3b, we hypothesized that bulky, complement-activating immune complexes (IC) consisting of microbes and antibody might attract granulocytes (PMNs), facilitating oxidative 'innocent bystander' RBC damage. Indeed, opsonization with only two type-2 pneumococcus (PN3)/anti-PN3/C3b complexes per RBC caused agglutination of RBC, a phenomenon termed immune adherence. Addition of as few as one PMN per 20 opsonized RBCs caused the glutathione (GSH) levels of co-incubated G6PD-deficient RBCs to fall by 30% (from 3.5 to 1.8 +/- 0.8 mumoles GSH/g Hb) compared to identically incubated, but nonopsonized, G6PD-deficient RBCs. GSH levels remained normal (5.2 +/- 0.4 mumoles/g Hb) in PMN-exposed opsonized normal RBCs. GSH depletion in G6PD-deficient RBC was directly related to disease severity--falling a mean 33% in RBCs from two Black G6PD A- subjects but 59% in two Caucasian G6PD deficient RBCs. Prevention of C3b generation (with 10 mM EDTA) during opsonization abrogated both immune adherence and PMN-mediated GSH decline in oxidant-sensitive cells. Similarly, removal of C3b receptors by brief trypsin incubation of RBCs eliminated immune adherence and GSH decline. Thus, both phenomena are dependent on IC complement activation and subsequent binding of the bacterial IC to the RBC complement receptors. Although clearance of IC by RBCs may be beneficial in protecting other tissues from inflammatory damage, G6PD-deficient RBCs are vulnerable to oxidants generated by juxtaposed phagocytes--cells attracted to, and stimulated by, the immune complex/C3b combination. It is suggested that this 'Good Samaritan' activity of RBCs may lead to haemolysis during periods of exuberant antibody response to microbes.

Anemia, Hemolytic↗

PubMed1992

Molecular basis of chronic non-spherocytic haemolytic anaemia: a new G6PD variant (393 Arg----His) with abnormal KmG6P and marked in vivo instability.

More than 80 genetic variants of glucose-6-phosphate dehydrogenase (G6PD) are associated with chronic non-spherocytic haemolytic anaemia (CNSHA). In order to help clarify the molecular basis of this association, we have carried out a detailed biochemical and genetic characterization of two G6PD deficient brothers affected by CNSHA. The G6PD from the two patients has altered electrophoretic mobility, abnormally elevated Michaelis constant (Km) for G6P, and extreme instability in vivo and in vitro. By comparison with published information we found that this is a new G6PD variant which we have designated G6PD Portici. The entire coding region of the gene has been sequenced, and a single point mutation, a G----A transition, was found at position 1178 in exon X, causing a substitution of histidine for arginine at residue 393 in the polypeptide chain. By polymerase chain reaction (PCR) amplification followed by diagnostic restriction enzyme analysis and allele-specific oligonucleotide hybridization we have demonstrated the inheritance of this mutation in the patient's family. Our results support the notion of a causative link between this mutation in the G6PD gene and CNSHA. Our data, in combination with previous data in the literature, suggest that the three-dimensional structure of G6PD is such as to cause interaction in the binding of its two substrates, G6P and NADP.

Adolescent↗

PubMed1987

Glutathione reductase activity and its relationship to pyridoxine phosphate activity in G6PD deficiency.

Per cent stimulation of GR activity by FAD in vitro and PNP oxidase activity were measured in G6PD deficiency, heterozygous beta-thalassaemia and controls. It is confirmed that, in contrast to the high stimulation of GR by FAD commonly found in in thalassaemia indicating red-cell deficiency of FAD, and shown here to be greater in the Italian subjects, GR is usually saturated with FAD in G6PD deficiency, leading to high in vitro activity. Unexpectedly, on the other hand, low FMN-dependent PNP oxidase activity due to red-cell deficiency of FMN, confirmed by response to oral riboflavin, was found in the majority of subjects with G6PD deficiency, similar to that found in heterozygous beta-thalassaemia. Whereas this is explained in thalassaemia by an inherited slow red-cell metabolism of riboflavin to FMN, it is suggested that in G6PD deficiency an increased rate of red-cell metabolism of FMN to FAD leads to the low FMN and high FAD. When G6PD deficiency occurs with heterozygous beta-thalassaemia, GR is usually saturated with FAD as in G6PD deficiency alone, unless there is an inherited, very slow red-cell metabolism of riboflavin to FMN. The part played by GR in haemolytic crises in G6PD deficiency is discussed.

Erythrocytes↗

PubMed2001

High prevalence of G6PD deficiency in Vataliya Prajapati community in western India.

OBJECTIVE: Sporadic cases of drug-induced haemolytic anaemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients belonging to Vataliya Prajapati community prompted us to study the prevalence of G6PD deficiency in the community. METHODS: Screening for G6PD deficiency was carried out using the dichlorophenol-indophenol (DPIP) dye decolorization method. RESULTS: A total of 471 individuals were screened. Of these, 385 unrelated individuals were considered to calculate the prevalence of G6PD deficiency. Among 272 unrelated males, 76 persons (27.94%) and among 113 unrelated females, 11 individuals (9.73%) were found to be G6PD deficient. A quantitative assay on 41 of the G6PD deficient samples showed the enzyme activity ranged from 0-0.5 unit/ml RBC/min. CONCLUSION: The prevalence of G6PD deficiency in Vataliya Prajapatis community was found to be the highest ever reported in the Indian caste-groups population studied so far.

Anemia, Hemolytic↗

PubMedDate not supplied

Regional experience with newborn screening for sickle cell disease, other hemoglobinopathies and G6PD deficiency.

BACKGROUND: Newborn screening for sickle cell disease, other hemoglobinopathies and G6PD deficiency is one of the most important means of decreasing mortality and morbidity in high prevalence areas. Nine years experience in newborn screening in Qatif Central Hospital are summarized. PATIENTS AND METHODS: All newborns in Qatif Central Hospital had cord blood screening for sickle cell disease, other hemoglobinopathies and G6PD deficiency using alkaline and electrophoresis, agar gel electrophoresis for sickle cell disease and fluorescent screening technique for G6PD deficiency. Families of infants with minor hemoglobinopathies and G6PD deficiency were informed about the results in the well baby clinic. RESULTS: From December 1992 to December 2001, 24 012 newborn were screened. 21 858 (91.03%) were Saudi and 2154 (8.97%) were non-Saudi. In the Saudi hemoglobin electrophoresis patterns, AF (normal) was found in 49.52%, hemoglobin FS (sickle cell disease) + FS Bart s (sickle cell disease with alpha thalassemia) in 2.57%, hemoglobin AFS (sickle cell trait) + AFS Bart s (sickle cell trait with alpha thalassemia) in 21.14%, and alpha thalassemia (based on elevated Bart s hemoglobin > or = 2%) in 35.68%. G6PD deficiency was found in 37.02% and 21.27% in males and females, respectively. Of 563 Saudi newborn with a presumptive diagnosis of sickle cell disease, 48 (8.5%) did not come to the hematology clinic or were not contactable. The diagnosis of sickle cell anemia or sickle thalassemia was confirmed in 513 patients, and 2 cases were found to have sickle cell trait on repeat testing. Many parents found it hard to accept the initial diagnosis and the resulting impact on their relationship with one another. CONCLUSION: Prevention and early identification of sickle cell disease, other major hemoglobinopathies and G6PD deficiency remains the cornerstone of management of these diseases. The main barriers to successful neonatal screening for hemoglobinopathies are the level of the education and deficiency in manpower. We recommend including newborn screening for hemoglobinopathies and G6PD deficiency in the national hypothyroidism screening program in the eastern province and the establishment of a special center for hemoglobinopathies with a high standard of medical care in Qatif.

Journal Article↗

PubMed1999

[Studies on a G6PD polymorphic site, cDNA C1311T].

OBJECTIVE: To use amplification refractory mutation system(ARMS) method to detect the G6PD cDNA C1311T mutation, estimate its frequency in a normal south Chinese population, and investigate whether IVS-11 C93T mutation is the cause of certain G6PD deficient cases. METHODS: DNA sequencing was used to confirm the C1311T and the IVS-11 C93T mutations. ARMS was set up to detect the C1311T and to estimate its frequency. RESULTS: Three cases of C1311T mutation were found in 40 G6PD deficient samples. The optimal condition for ARMS was established. Using this method, 19 cases of C1311T were detected in 103 normal men, and the frequency of this polymorphic mutation was estimated to be 18.4% in southern Chinese population. Four cases with G6PD deficiency were demonstrated to be C at the IVS-11 93 position. At the same time, a case of IVS-11 93 C-->T was found in a normal man. CONCLUSIONS: ARMS is a simple, time-saving, and reliable method for detecting known G6PD gene point mutation. The frequency of C1311T in a normal south Chinese population is 18.4%. IVS-11 C93T might be another polymorphic site of the G6PD gene, and it is not the cause of enzyme deficiency in certain G6PD deficient cases.

Asian People↗

PubMed2003

Using the fluorescence spot test for neonatal screening of G6PD deficiency.

To establish the neonatal screening method of glucose-6 phosphate dehydrogenase (G6PD) deficiency, G6PD activity was measured using the fluorescence spot test (FST) using dried blood samples on filter paper. The G6PD/6PGD rate test of venous blood samples was further performed for confirmation. The positive G6PD deficiency rate was 4.2% and its detection rates were 3.7% for all neonates and 5.2% only for male newborns when FST was used for neonatal screening. Conformation rates by use of G6PD/ 6PGD ratio test for G6PD deficiency were 86.8% and 100% particularly in the severely deficient groups. Both sensitivity and specificity were very high in the severely deficient groups. FST can be used in neonatal screening of G6PD deficiency because of its high accuracy, applicability, and simplicity. Moreover, a high volume of dried blood samples on filter paper can be tested quickly. It is very favorable to diagnose and treat G6PD deficiency early in high incidence districts.

Blood Specimen Collection↗

PubMed2005

[Prevalence and morbidity of G6PD deficiency in sickle cell disease in the homozygote].

Sickle cell disease and G6PD deficiency have similar prevalence of 8 to 10% in Senegalese population. Our objectives were to determine the prevalence of G6PD deficiency in Hb S carriers and normal subjects, and to assess the interaction of G6PD deficiency on clinical severity of sickle cell disease. G6PD activity was measured in 319 sickle cell patients and in 318 subjects without HbS. Clinical severity was compared in male homozygous sickle cell patients (11 with G6PD deficiency and 19 without deficit). In homozygous sickle cell patients, the G6PD status was assessed after correction of reticulocyte count following the micro-centrifugation method of Herz. We found that prevalence of G6PD deficiency was higher in sickle cell disease patients (21.6 %) than in normal subjects (12.3 %) (p = 0.001). No difference was found in the two groups of male sickle cell disease patients concerning number of vaso-occlusive crisis, number of transfusion, frequency of infectious episodes, number of chronic complications, disturbances on patient's activity and total index severity.

Adolescent↗

PubMed2004

Complete molecular characterisation of glucose-6-phosphate dehydrogenase (G6PD) deficiency in a group of Malaysian Chinese neonates.

We performed DNA analysis on cord blood samples of 128 Chinese male neonates diagnosed as G6PD deficiency in Hospital Universiti Kebangsaan Malaysia by a combination PCR-restriction enzyme digest technique, Single Stranded Conformation Polymorphism analysis and DNA sequencing. We found 10 different G6PD-deficient mutations exist. The two commonest alleles were G6PD Canton 1376 G>T (42.3%) and Kaiping 1388 G>A (39.4%) followed by G6PD Gaohe 592 G>A (7.0%), Chinese-5 1024 C>T, Nankang 517 T>C (1.5%), Mahidol 487 G>A (1.6%), Chatham 1003 G>T (0.8%), Union 1360 C>T (0.8%), Viangchan 871 G>A (0.8%) and Quing Yang 392 G>T (0.8%). Sixty eight percent (88/125) neonates in this study had neonatal jaundice and 29.7% developed hyperbilirubinemia >250 micromol/l. The incidence of hyperbilirubinemia >250 micromol/l was higher in G6PD Kaiping (43.8%) than G6PD Canton (22%) (p< 0.05). There was no significant difference in the incidence of neonatal jaundice, mean serum bilirubin, mean age for peak serum bilirubin, percentage of babies requiring phototherapy and mean duration of phototherapy between the two major variants. None of the 88 neonates required exchange transfusion. In conclusion we have completely characterized the molecular defects of a group of Chinese G6PD deficiency in Malaysia. The mutation distribution reflects the original genetic pool and limited ethnic admixture with indigenous Malays.

Asian People↗

PubMed2005

Hematological findings and severity of G6PD deficiency in Vataliya Prajapati subjects.

OBJECTIVES: The present study was undertaken to assess the clinical implication of G6PD deficiency in Vataliya Prajapati (VP) subjects in Surat. METHOD: Blood samples of 954 children and 690 adults were collected in camps. Cord blood samples of 57 neonates born to VP mother were also collected. Medical history and other relevant information of all subjects were obtained. Samples were screened for G6PD deficiency by NBT test and the enzyme activity was estimated by WHO method. Hematological parameters were measured on hematology analyzer while reticulocyte count was measured using new methylene blue dye. RESULTS: The G6PD enzyme deficiency was detected in 27.5% males and 12.8% females. The enzyme levels in deficient subjects suggested class II variant. Hematological studies indicated mild anemia in G6PD deficient persons. Reticulocyte count was slightly raised (p <0.05). Out of eight G6PD deficient neonates one developed mild jaundice. Five deficient male adults gave the history of hemolytic crisis, three of them had typhoid, one tuberculosis and remaining one had fever of unknown origin. CONCLUSION: G6PD deficiency in majority of Vataliya Prajapati subjects is of mild type. However it is essential to test every Vataliya Prajapati subject for G6PD deficiency as certain infections and drugs can cause crisis in deficient person.

Adult↗

PubMed1995

Leukocyte glucose 6 phosphate dehydrogenase (G6PD) as prognostic indicator in children with acute lymphocytic leukemia.

G6PD activity, estimated in 37 patients with acute lymphocytic leukemia (ALL) prior to therapy was found to be significantly decreased in 78.37% of the patients with ALL while it was normal in other patients. Variation in G6PD was found to be dependent on the percentage of myelocytes. Correlation analysis of leukocyte G6PD activity with karyotype indicated that patients with normal karyotype with normal G6PD activity had good prognosis while those with abnormal G6PD with abnormal karyotype had poor prognosis. Subjects with normal karyotype and abnormal G6PD and vice versa had intermediate prognosis. Thus the results clearly indicate that leukocyte G6PD may be used as a diagnostic and prognostic tool.

Child↗

PubMed1987

Nonclonal hemopoietic progenitors in a G6PD heterozygote with chronic myelogenous leukemia revealed after long-term marrow culture.

When marrow cells from Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) patients are placed into long-term culture, Ph-positive progenitor numbers typically decline rapidly. Karyotypically normal cells derived from persisting, but previously undetectable, precursors can then frequently be demonstrated. To investigate the origin of these cytogenetically normal progenitors, long-term cultures were established with marrow from a girl with CML who was also heterozygous for the glucose-6-phosphate dehydrogenase (G6PD) enzyme variants A and B as shown by studies of her skin fibroblasts. Erythroid and granulocytic colonies generated in methylcellulose assays of fresh marrow from this patient were all Ph-positive and expressed the enzyme G6PD-A as found in the mature blood cells. In assays of 4- and 6-week-old long-term cultures, numbers of progenitors present were low and most were Ph-positive, but some (2/11) were Ph-negative. G6PD analysis showed that a similar proportion was not part of the neoplastic clone (4/30 were G6PD-B and 26/30 were G6PD-A). Thus, long-term marrow culture in conjunction with G6PD analysis was able to reveal the presence of a nonclonal hemopoietic progenitor population in a CML patient where such cells would not otherwise have been detected. This approach may offer a novel strategy for the demonstration and selection of populations of normal hemopoietic progenitors in other patients where the malignant cells cannot be distinguished by chromosome analysis.

Bone Marrow↗

PubMed1977

[Regional localization of the genes for human IDHs, MDHs PGK, alphaGAL, G6PD by interspecific hybridization (author's transl)].

22 independent man-hamster (HGPRT-) hybrids using male human cells with balanced reciprocal translocation t(X;2)(p22;q32) were analysed for human genes localized on chromosome 2 (IDHs, MDHs), on chromosome X (PGK, alphaGAL, G6PD) and for the different chromosomes in relation with the balanced reciprocal translocation (chr.2, chr.2q-, chr.Xp+). The following results were obtained: The chromosomes 2 and 2q- are absent in the 22 hybrids. In 9 hybrids, the absence of MDHs in spite of the presence of the chromosome Xp+ indicates that the gene for MDHs is not localized on this chromosome (or that the gene for MDHs is not on the segment 2q32--2qter translocated on X). In 14hybrids, the three markers of X (PGK, alphaGAL, G6PD) and IDHs are expressed in the presence of the chromosome Xp+. This result indicates that the genes for these markers are on Xp+ or that the genes PGK, alphaGAL, G6PD are on X without the Xp22--Xter segment, translocated on the chr.2, and that the gene for IDHs is on the 2q32--2qter segment translocated on X. In 8 hybrids, in the absence of the intack chromosome Xp+, the higher percentage of the presence of G6PD (7 hybrids) and the lower percentage of the presence of IDHs (3 hybrids) are explained by the fact that these hybrids selected in HAT medium had to retain a segment of Xp+ bearing the human gene HGPRT. G6PD appeared very close to HGPRT and IDHs very distant from HGPRT. The study of the different correlations between the presence and the absence of these four markers on Xp+ in the different hybrids indicates the following order on the chromosome Xp+ from p to q: IDHs -- PGK --alphaGAL -- G6PD.

Animals↗