ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency

Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency
Literature review current through: Jan 2024.
This topic last updated: Jun 05, 2023.

INTRODUCTION — Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is the most common enzymatic disorder of red blood cells in humans, affecting more 400 to 500 million people worldwide [1-5]. The clinical expression of G6PD variants encompasses a spectrum of hemolytic syndromes. Affected patients are most often asymptomatic, but many patients have episodic anemia, while a few have chronic hemolysis.

With most G6PD variants, hemolysis is induced in children and adults by the sudden destruction of older, more deficient erythrocytes after exposure to drugs having a high redox potential (including the antimalarial drug primaquine and certain sulfa drugs) or to fava beans, selected infections, or metabolic abnormalities (table 1). However, in the neonate with G6PD deficiency, decreased bilirubin elimination may play an important role in the development of jaundice (see 'Jaundice in neonates' below) [6,7].

Normal enzyme function and the genetics and pathophysiology of G6PD deficiency, including its possible role in protecting against severe malaria, will be reviewed here.

The clinical manifestations, diagnosis, and treatment of this disorder, as well as genetic testing, are discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Gene test interpretation: G6PD".)

A historical review of the discovery of this condition, its clinical manifestations, detection, population genetics, and molecular biology, written by Dr. Ernest Beutler, a pioneer in the understanding of this disorder, is available [8].

Other red blood cell (RBC) enzyme disorders are also discussed separately.

Pyruvate kinase deficiency – (See "Pyruvate kinase deficiency".)

Rare RBC enzyme deficiencies – (See "Rare RBC enzyme disorders".)

FUNCTION OF G6PD — G6PD catalyzes the initial step in the hexose monophosphate (HMP or pentose phosphate) shunt, oxidizing glucose-6-phosphate to 6-phosphogluconolactone and reducing nicotinamide adenine dinucleotide phosphate (NADP) to NADPH (figure 1). The HMP shunt is the only red cell source of NADPH, a cofactor important in glutathione metabolism.

The main function of the HMP shunt is to protect red blood cells against oxidative injury via the production of NADPH [5]. Red blood cells contain relatively high concentrations of reduced glutathione (GSH), a sulfhydryl-containing tripeptide that functions as an intracellular reducing agent, thereby protecting against oxidant injury. Oxidants, such as superoxide anion (O2-) and hydrogen peroxide, are formed within red cells via reactions of hemoglobin with oxygen and can also be produced by exogenous factors such as drugs and infection. If these oxidants accumulate within red cells, hemoglobin and other proteins are oxidized (see below), leading to loss of function and cell death.

Under normal circumstances, oxidant accumulation does not occur, since these compounds are rapidly inactivated by GSH in conjunction with glutathione peroxidase. These reactions result in the conversion of GSH to oxidized glutathione (GSSG). GSH levels are restored by glutathione reductase which catalyzes the reduction of GSSG to GSH. This reaction requires the NADPH generated by G6PD.

Thus, tight coupling of the HMP shunt to glutathione metabolism is responsible for protecting intracellular proteins from oxidative injury. Almost all hemolytic episodes related to altered HMP shunt and glutathione metabolism are due to G6PD deficiency. Rarely, hemolysis results from deficiencies in GSH synthetic enzymes. (See "Rare RBC enzyme disorders".)

GENETICS OF G6PD — The gene for G6PD is located on the X chromosome (band X q28) [9] and has been cloned and sequenced [10-12]. Even though females have two X chromosomes per cell, males and females have the same enzyme activity in their red cells because one of the X chromosomes in each cell of the female embryo is inactivated and remains inactive throughout subsequent cell divisions (Lyon hypothesis) [13].

G6PD deficiency is expressed in males carrying a variant gene, while heterozygous females are usually clinically unaffected. However, the mean red blood cell enzyme activity in heterozygous females may be normal, moderately reduced, or grossly deficient depending upon the degree of lyonization and the degree to which the abnormal G6PD variant is expressed [5,14]. A heterozygous female with 50 percent normal G6PD activity has 50 percent normal red cells and 50 percent G6PD-deficient red cells. The deficient cells are as vulnerable to hemolysis as the enzyme-deficient red blood cells in males.

It is of interest that the incidence of G6PD deficiency in Chinese females ≥80 years of age was several-fold greater than what was expected from population screening at birth [15]. It is thought that this is due to the skewed X-inactivation that occurs with aging.

G6PD and its variants — The monomeric form of G6PD contains 515 amino acids, but the active form of G6PD is a dimer that contains tightly bound NADP [16,17]. Amino acid 205 is the binding site for glucose-6-phosphate, while amino acids 386 and 387 may be involved in binding to NADP [16,18].

The normal or wild-type enzyme is called G6PD B, although over 400 biochemical variant enzymes have been identified [16,17,19,20]. By international agreement, standardized methods have been used to characterize these enzyme variants, which differ on the basis of their biochemical properties, such as kinetic activity and the Michaelis constant for its substrate glucose-6-phosphate and cofactor NADP [21,22]. However, differences between some variants are subtle and may not represent true enzyme differences. In fact, molecular studies indicate many of these variants are due to the same mutation. (See 'Classification of G6PD variants' below.)

The variants are almost all missense point mutations, although a few deletions have been described [16,19]. Large deletions or frame shift mutations have not been identified, suggesting that complete absence of G6PD may be lethal [16]. Most class I variants that are associated with chronic hemolytic anemia have abnormalities in the glucose-6-phosphate binding or NADP binding site of the enzyme (figure 2) [16].

Classification of G6PD variants — The World Health Organization has classified the different G6PD variants according to the magnitude of the enzyme deficiency and the severity of hemolysis [23]. Classes IV and V are of no clinical significance.

Class I variants, which are rare, have severe enzyme deficiency (less than 10 percent of normal) and have chronic hemolytic anemia

Class II variants also have severe enzyme deficiency, but there is usually only intermittent hemolysis associated with infection, drugs, or chemicals

Class III variants have moderate enzyme deficiency (10 to 60 percent of normal) with intermittent hemolysis usually associated with infection, drugs, or chemicals

Class IV variants have no enzyme deficiency or hemolysis

Class V variants have increased enzyme activity

Class I G6PD variants have low in vitro activity and/or marked instability of the molecule, and most have DNA mutations at the glucose-6-phosphate or NADP binding sites (figure 2) [16]. These sites are central to the function of G6PD, which oxidizes glucose-6-phosphate and reduces NADP to NADPH (figure 1). It is presumed that the functional defect is so severe that the red cells cannot withstand even the normal oxidative stresses encountered in the circulation [16].

Clinical consequences of these variants are discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Clinical manifestations'.)

Wild-type enzyme — The normal wild-type enzyme, G6PD B, is found in most individuals with ancestry from Europe, Asia, and Africa. It has normal catalytic activity and is not associated with hemolysis (class IV). A common variant is G6PD A+, which is found in 20 to 30 percent of Black individuals from Africa [24]. It differs from G6PD B by the substitution of a single amino acid, an asparagine for aspartate at the amino acid 126 [25], and has much faster electrophoretic mobility (the letters A and B refer to relative electrophoretic mobilities). G6PD A+ has normal catalytic properties and does not cause hemolysis.

G6PD A- variant — Another common variant, G6PD A-, is the enzyme responsible for primaquine sensitivity in Black individuals, and is the most common variant associated with mild to moderate hemolysis (class III). It is found in 10 to 15 percent of African-Americans, with similar frequencies in western and central Africa [26].

G6PD A- has an electrophoretic mobility identical to that of G6PD A+. However, G6PD A- is an unstable enzyme and its catalytic activity, which is nearly normal in bone marrow cells and reticulocytes [27], decreases markedly in older red cells due to increased catabolism (the "+" and "-" denote enzyme activity) [28].

All cases of G6PD A- have a mutation at nucleotide 376 (A—>G), which also is the nucleotide substitution characteristic of G6PD A+ [16,29,30]. However, the G6PD A- variants have a second mutation, which is usually at nucleotide 202 (G—>A) [16,29] and, less often, at nucleotide 680 (G—>T) or at nucleotide 968 (T—>C) [30].

Although initially thought to be a single homogeneous mutation in Africans, G6PD A- represents at least three different genotypes and a number of G6PD variants originally described in non-Africans have one of the known G6PD A- mutations. As examples, some patients with G6PD Betica, a Spanish variant, or G6PD Matera, an Italian variant, have base substitutions at nucleotides 376 and 202, identical to the more common G6PD A- variant [31,32].

G6PD Mediterranean variant — G6PD Mediterranean is the most common abnormal variant found in individuals from Europe, particularly those whose origins are in the Mediterranean and Mid-Eastern regions [33]. The electrophoretic mobility of G6PD Mediterranean is identical to that of G6PD B, but it is synthesized at a reduced rate, its catalytic activity is markedly reduced [27], and hemolysis can be severe (class II).

Although G6PD Mediterranean involves many different ethnic groups, most affected individuals have the same genetic defect, a single base substitution (C—>T) at nucleotide 563 [31,32]. Many variants previously referred to by different names based on biochemical properties of the enzyme in the laboratory (eg, G6PD Birmingham, G6PD Cagili, G6PD Dallas) are now recognized to have the same molecular defect as G6PD Mediterranean [34,35].

Variants in people with Asian ancestry — Several different G6PD variants occur in people with ancestry from countries in Asia [36,37].

In China, three major variants are recognized. The most common is G6PD Canton (1376G>T), which is usually reported to be a class II variant (similar to G6PD Mediterranean), although sometimes it is considered to be in class III [38]. Another common variant is G6PD Kaiping (1388G>A), which is usually classified as a class III variant, although occasionally considered to be in class II. A third variant is G6PD Gaohe (95A>G), which is almost always considered to be a class II variant. These three variants account for over 70 percent of G6PD deficiency cases in China.

The most common variant in Southeast Asia is G6PD Mahidol (487G>A), a class III variant.

Although India borders China, none of the Chinese G6PD variants are found in India, where the most common type is G6PD Mediterranean (563C>T).

PATHOPHYSIOLOGY OF G6PD DEFICIENCY

Hemolytic anemia — The importance of G6PD for red cell integrity was first recognized following the observation that some African American soldiers taking the antimalarial drug primaquine developed acute hemolytic anemia with hemoglobinuria. Subsequently, the activity of G6PD, one of the enzymes needed to maintain adequate GSH levels, was shown to be deficient in affected red cells [39].

The likelihood of developing hemolysis and the severity of disease are determined by the biochemical characteristics of the G6PD variant. In normal subjects, the activity of G6PD falls exponentially as red cells age, as the normal enzyme (G6PD B) has an in vivo half-life of 62 days [27]. However, normal old red blood cells still contain sufficient G6PD activity to maintain GSH levels in the face of oxidant stress. In contrast, the half-life is much shorter in the G6PD variants associated with hemolysis. As an example, the enzymatic activity of G6PD A- is normal in reticulocytes, but declines rapidly thereafter with a half-life of 13 days [27,40]. G6PD Mediterranean is even more unstable, with a half-life measured in hours [27].

These findings correlate with the clinical degree of hemolysis after oxidant stress (see "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia'). Patients with G6PD A- usually have hemolysis that is mild and limited to older deficient erythrocytes (class III). In contrast, red cells of all ages are grossly deficient in G6PD Mediterranean (class II). Thus, the entire red blood cell population of subjects with G6PD Mediterranean is susceptible to oxidant-induced injury, which can lead to severe hemolytic anemia. However, in the absence of oxidant stress, G6PD Mediterranean red cells have a survival in the circulation that is only modestly shorter than that of normal red cells [41].

G6PD-deficient erythrocytes that are exposed to oxidants (eg, drugs, infection) become depleted of GSH; this change is followed by oxidation of other sulfhydryl-containing proteins with the following consequences [42]:

Oxidation of the sulfhydryl groups on hemoglobin leads to the formation of methemoglobin and then denatured globin or sulfhemoglobin, which form insoluble masses that attach to the red cell membrane (called Heinz bodies) [43]. This oxidative denaturation of hemoglobin leads to its crossbonding; as a result, hemoglobin is no longer free to flow in the cytosol, producing the puddling of hemoglobin and bite or hemiblister cells in the peripheral smear (picture 1).

Oxidation of membrane sulfhydryl groups leads to the accumulation of membrane polypeptide aggregates, presumably due to disulfide bond formation between spectrin dimers and between spectrin and other membrane proteins [42,44,45]. The number of aggregates increases with the fall in red cell GSH [44].

The net effect is that the deficient red cells become rigid and nondeformable, making them susceptible to stagnation and destruction by reticuloendothelial macrophages in the marrow, spleen and liver [46,47]. Although this type of hemolysis is predominantly extravascular, intravascular hemolysis also occurs, leading to hemoglobinemia and hemoglobinuria.

Hemolysis occurring after oxidant injury is usually due to G6PD deficiency. However, a similar sequence can occur with hemoglobin H and some unstable hemoglobinopathies, since these abnormal hemoglobins are highly susceptible to mild oxidant stress. (See "Unstable hemoglobin variants" and "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)

Jaundice in neonates — Neonates who are deficient in G6PD have a higher incidence of neonatal jaundice. The clinical picture of neonatal jaundice in this setting differs from classic Rh-related neonatal jaundice in two main respects. First, G6PD deficiency related neonatal jaundice is rarely present at birth; the peak incidence of clinical onset is between days two and three [48]. Second, there is more jaundice than anemia, and the anemia is rarely severe [49]. The severity of jaundice varies widely, from being subclinical to imposing the threat of kernicterus if it is not treated [6,7]. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Neonatal jaundice'.)

The pathogenesis of this type of neonatal jaundice remains uncertain. Some believe that decreased hepatic bilirubin elimination is a key factor [6,16], while others maintain that increased hemolysis causes the hyperbilirubinemia and that there is no need to invoke liver involvement over and above the normal immaturity of the neonatal bilirubin-conjugating mechanism [50].

One study compared the incidence of severe jaundice (ie, bilirubin >15 mg/dL or >257 micromol/L) among infants with varying combinations of G6PD deficiency and the variant Gilbert polymorphism [51]. Neither G6PD deficiency nor presence of the variant Gilbert polymorphism alone increased the incidence of hyperbilirubinemia (incidence: 7 to 15 percent) over subjects with normal alleles at these two loci (incidence: 10 percent), but both defects in combination did (incidence: 32 to 50 percent). (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis" and "Gilbert syndrome".)

G6PD in other hematopoietic cells — Leukocyte and platelet G6PD is regulated by the same gene as that in red cells; as a result, deficient individuals have reduced enzyme activity in these cells, particularly patients with more severe enzyme deficiency such as G6PD Mediterranean [39,52-54]. However, this abnormality is rarely associated with functional impairment of leukocytes and platelets due to their normally short survival. As an example, phagocytic and bactericidal activity of granulocytes are typically normal in deficient subjects [53,54].

Rare kindreds with severe enzymatic deficiency of G6PD (ie, <5 percent of normal) may have decreased respiratory burst activity due to a lack of NADPH production in phagocytes, leading to symptoms of chronic granulomatous disease and increased susceptibility to infection [55,56]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)

Possible protection against malaria — Because of its high prevalence in areas in which malaria was once endemic (figure 3), it has been proposed that G6PD deficiency may have conferred a selective advantage against infection by Plasmodium falciparum [1,57-59]. This issue remains unresolved as some studies have shown conflicting results [16,60], but the following observations are in support of such a relationship. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Evolutionary selection pressure from malaria'.)

G6PD deficiency in Sardinia is more common at sea level than at higher elevations, a pattern that parallels the endemicity of malaria [61].

It has been unclear whether both female heterozygotes and male hemizygotes are protected. In two case-control studies in African children, the common African form of G6PD deficiency (G6PD A-) was associated with a 46 to 58 percent reduction in the risk of severe malaria in the two groups [1]. However, a mathematical model that considered the selective advantage against malaria suggested that there was a counterbalancing disadvantage of male hemizygotes that limited its prevalence in malaria endemic regions.

In female heterozygotes who have both normal and G6PD deficient red cells, there are more malaria parasites in normal compared with G6PD-deficient cells [62]. This is compatible with the demonstration that invasion is normal but in vitro growth of malarial parasites is inhibited in G6PD-deficient red cells in female heterozygotes; there are conflicting data as to inhibition of parasite growth in male hemizygotes [63,64].

Somewhat different findings were noted in a study of the Mediterranean variant of G6PD-deficient red cells [65]. With five different strains of P. falciparum, there were no significant differences in either invasion or maturation within deficient and normal red cells. However, among red cells that were parasitized at the ring stage (but not the more mature trophozoite stage), phagocytosis occurred 2.3 times more intensely in the G6PD-deficient cells in association with a marked reduction in reduced glutathione (GSH).

The mechanisms responsible for inhibition of parasite growth or increased phagocytosis in G6PD-deficient red cells are not known. One possibility is that oxidant stress, which causes GSH instability and destroys the host red cells, also kills the parasite [66]. Although the parasite may provide a small amount of G6PD activity [66-68], it is insufficient to compensate for the enzyme deficiency [66]. Similarly, oxidant stress in the presence of diminished GSH in ring stage infected, G6PD-deficient cells may cause membrane damage that promotes phagocytosis [65,69,70].

An alternative explanation is that infected, G6PD-deficient red cells are, due to the low levels of GSH, unable to generate the ribose derivatives needed by the parasite for nucleic acid synthesis [71]. Such a defect would lead to inhibition of parasite growth and does not require oxidative destruction of the parasite.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Glucose-6-phosphate dehydrogenase deficiency (The Basics)")

SUMMARY

Overview – Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is the most common enzymatic disorder of red blood cells in humans. Affected patients are most often asymptomatic, but many patients have episodic anemia, following exposure to infections, drugs, or chemicals, while a few have chronic hemolysis. Clinical manifestations, diagnosis, and management of G6PD deficiency, and genetic testing, are presented separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Gene test interpretation: G6PD".)

Function – The G6PD enzyme catalyzes the initial step in the hexose monophosphate (HMP or pentose phosphate) shunt, oxidizing glucose-6-phosphate to 6-phosphogluconolactone and reducing nicotinamide adenine dinucleotide phosphate (NADP) to NADPH (figure 1). The main function of the HMP shunt is to protect red blood cells against oxidative injury via the production of NADPH. (See 'Function of G6PD' above and 'Pathophysiology of G6PD deficiency' above.)

Variants – G6PD has a number of variants, as follows (see 'Genetics of G6PD' above):

G6PD B – This is the normal wild-type enzyme found in most people with ancestry from Europe, Asia, and a majority from Africa. It has normal catalytic activity and is not associated with hemolysis.

G6PD A+ – This variant is found in 20 to 30 percent of Black people from Africa. It has normal catalytic properties and does not cause hemolysis.

G6PD A- – This variant is responsible for primaquine sensitivity in Black people, is found in 10 to 15 percent of African Americans, with similar frequencies in western and central Africa. Patients usually have mild hemolysis limited to older red cells.

G6PD Mediterranean – This is the most common abnormal variant found in people of European ancestry. Catalytic activity is markedly reduced in red cells of all ages. Thus, the entire red blood cell population is susceptible to oxidant-induced injury.

Variants in people with Asian ancestry – There are several variants seen in people from Asia, including G6PD Canton, G6PD Kaiping, G6PD Gaohe, and G6PD Mahidol.

Mechanisms of complications – The consequences of G6PD deficiency are related to reduced G6PD enzyme function, which affects red blood cell metabolism as well as other blood cells.

Neonatal jaundice – A consequence of hemolytic anemia and decreased hepatic bilirubin metabolism. (See 'Jaundice in neonates' above.)

Hemolytic anemia – Encompasses episodic or chronic Heinz body hemolytic anemia. (See 'Hemolytic anemia' above.)

Infection – Increased susceptibility to infection occurs in kindreds with severe enzymatic deficiency, due to a lack of NADPH production in phagocytes. (See 'G6PD in other hematopoietic cells' above.)

Protection against malaria – Has been proposed based on epidemiology, but the mechanism is unknown. (See 'Possible protection against malaria' above.)

Other red blood cell (RBC) enzyme disorders – (See "Pyruvate kinase deficiency" and "Rare RBC enzyme disorders".)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

  1. Ruwende C, Khoo SC, Snow RW, et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 1995; 376:246.
  2. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008; 371:64.
  3. Glader B, Grace RF. Hereditary hemolytic anemias due to RBC enzyme disorders. In: Wintrobe's Clinical Hematology, 14th edition, Greer JP, Arber D, Glader B, et al (Eds), Lippincott, Williams & Wilkins, Philadelphia 2018. p.742.
  4. Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the genotype-phenotype association. Blood Rev 2007; 21:267.
  5. Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Blood 2020; 136:1225.
  6. Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia. A potential complication of glucose-6-phosphate dehydrogenase deficiency. Clin Perinatol 1998; 25:575.
  7. Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus. Semin Perinatol 2004; 28:356.
  8. Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood 2008; 111:16.
  9. KIRKMAN HN, HENDRICKSON EM. Sex-linked electrophoretic difference in glucose-6-phosphate dehydrogenase. Am J Hum Genet 1963; 15:241.
  10. Martini G, Toniolo D, Vulliamy T, et al. Structural analysis of the X-linked gene encoding human glucose 6-phosphate dehydrogenase. EMBO J 1986; 5:1849.
  11. Persico MG, Viglietto G, Martini G, et al. Isolation of human glucose-6-phosphate dehydrogenase (G6PD) cDNA clones: primary structure of the protein and unusual 5' non-coding region. Nucleic Acids Res 1986; 14:2511.
  12. Takizawa T, Huang IY, Ikuta T, Yoshida A. Human glucose-6-phosphate dehydrogenase: primary structure and cDNA cloning. Proc Natl Acad Sci U S A 1986; 83:4157.
  13. BEUTLER E, YEH M, FAIRBANKS VF. The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker. Proc Natl Acad Sci U S A 1962; 48:9.
  14. Hsia YE, Miyakawa F, Baltazar J, et al. Frequency of glucose-6-phosphate dehydrogenase (G6PD) mutations in Chinese, Filipinos, and Laotians from Hawaii. Hum Genet 1993; 92:470.
  15. Au WY, Lam V, Pang A, et al. Glucose-6-phosphate dehydrogenase deficiency in female octogenarians, nanogenarians, and centenarians. J Gerontol A Biol Sci Med Sci 2006; 61:1086.
  16. Beutler E. G6PD deficiency. Blood 1994; 84:3613.
  17. Mason PJ. New insights into G6PD deficiency. Br J Haematol 1996; 94:585.
  18. Hirono A, Kuhl W, Gelbart T, et al. Identification of the binding domain for NADP+ of human glucose-6-phosphate dehydrogenase by sequence analysis of mutants. Proc Natl Acad Sci U S A 1989; 86:10015.
  19. Miwa S, Fujii H. Molecular basis of erythroenzymopathies associated with hereditary hemolytic anemia: tabulation of mutant enzymes. Am J Hematol 1996; 51:122.
  20. Beutler E. The genetics of glucose-6-phosphate dehydrogenase deficiency. Semin Hematol 1990; 27:137.
  21. Nomenclature of glucose-6-phosphate dehydrogenase in man. Am J Hum Genet 1967; 19:757.
  22. WHO Scientific Group. Standardization of procedures for the study of glucose-6-phosphate dehydrogenase. WHO Tech Rep Ser 366, Geneva 1967.
  23. Beutler E. The molecular biology of enzymes of erythrocyte metabolism. In: The Molecular Basis of Blood Disease, Stamatoyannopoulos G, Nienhus AW, Majerus PW, et al. (Eds), WB Saunders, Philadelphia 1993.
  24. BOYER SH, PORTER IH, WEILBACHER RG. Electrophoretic heterogeneity of glucose-6-phosphate dehydrogenase and its relationship to enzyme deficiency in man. Proc Natl Acad Sci U S A 1962; 48:1868.
  25. Yoshida A. A single amino Acid substitution (asparagine to aspartic Acid) between normal (b+) and the common negro variant (a+) of human glucose-6-phosphate dehydrogenase. Proc Natl Acad Sci U S A 1967; 57:835.
  26. Reys L, Manso C, Stamatoyannopoulos G. Genetic studies on southeastern Bantu of Mozambique. I. Variants of glucose-6-phosphate dehydrogenase. Am J Hum Genet 1970; 22:203.
  27. Piomelli S, Corash LM, Davenport DD, et al. In vivo lability of glucose-6-phosphate dehydrogenase in GdA- and GdMediterranean deficiency. J Clin Invest 1968; 47:940.
  28. Morelli A, Benatti U, Gaetani GF, De Flora A. Biochemical mechanisms of glucose-6-phosphate dehydrogenase deficiency. Proc Natl Acad Sci U S A 1978; 75:1979.
  29. Hirono A, Beutler E. Molecular cloning and nucleotide sequence of cDNA for human glucose-6-phosphate dehydrogenase variant A(-). Proc Natl Acad Sci U S A 1988; 85:3951.
  30. Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT. Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-. Blood 1989; 74:2550.
  31. Beutler E. Glucose-6-phosphate dehydrogenase: new perspectives. Blood 1989; 73:1397.
  32. Vulliamy TJ, D'Urso M, Battistuzzi G, et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A 1988; 85:5171.
  33. Oppenheim A, Jury CL, Rund D, et al. G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews. Hum Genet 1993; 91:293.
  34. Glader BE. Glucose-6-phosphate dehydrogenase deficiency and related disorders of hexose monophosphate shunt and glutathione metabolism. In: Wintrobe's Clinical Hematology, 10th ed, Lee GR, Foerster J, Lukens J, et al. (Eds), Williams & Wilkins, Baltimore 1176.
  35. Cappellini MD, Martinez di Montemuros F, De Bellis G, et al. Multiple G6PD mutations are associated with a clinical and biochemical phenotype similar to that of G6PD Mediterranean. Blood 1996; 87:3953.
  36. Jiang W, Yu G, Liu P, et al. Structure and function of glucose-6-phosphate dehydrogenase-deficient variants in Chinese population. Hum Genet 2006; 119:463.
  37. He Y, Zhang Y, Chen X, et al. Glucose-6-phosphate dehydrogenase deficiency in the Han Chinese population: molecular characterization and genotype-phenotype association throughout an activity distribution. Sci Rep 2020; 10:17106.
  38. McCurdy PR, Kirkman HN, Naiman JL, et al. A Chinese variant of glucose-6-phosphate dehydrogenase. J Lab Clin Med 1966; 67:374.
  39. ALVING AS, CARSON PE, FLANAGAN CL, ICKES CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 1956; 124:484.
  40. Yoshida A, Stamatoyannopoulos G, Motulsky AG. Negro variant of glucose-6-phosphate dehydrogenase deficiency (A-) in man. Science 1967; 155:97.
  41. Corash L, Spielberg S, Bartsocas C, et al. Reduced chronic hemolysis during high-dose vitamin E administration in Mediterranean-type glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1980; 303:416.
  42. Arese P, De Flora A. Pathophysiology of hemolysis in glucose-6-phosphate dehydrogenase deficiency. Semin Hematol 1990; 27:1.
  43. Jacob HS. Mechanisms of Heinz body formation and attachment to red cell membrane. Semin Hematol 1970; 7:341.
  44. Allen DW, Flynn TP, Johnson GJ. Erythrocyte membrane protein changes in glucose-6-phosphate dehydrogenase mutants with chronic hemolytic disease: an example of postsynthetic modification of membrane proteins. Prog Clin Biol Res 1982; 97:33.
  45. Coetzer T, Zail S. Membrane protein complexes in GSH-depleted red cells. Blood 1980; 56:159.
  46. Rifkind RA. Heinz body anemia: an ultrastructural study. II. Red cell sequestration and destruction. Blood 1965; 26:433.
  47. Tizianello A, Pannacciulli I, Ajmar F, Salvidio E. Sites of destruction of red cells in G-6-PD deficient Caucasians and in phenylhydrazine treated patients. Scand J Haematol 1968; 5:116.
  48. DOXIADIS SA, VALAES T. THE CLINICAL PICTURE OF GLUCOSE 6-PHOSPHATE DEHYDROGENASE DEFICIENCY IN EARLY INFANCY. Arch Dis Child 1964; 39:545.
  49. Meloni T, Costa S, Cutillo S. Haptoglobin, hemopexin, hemoglobin and hematocrit in newborns with erythrocyte glucose-6-phosphate dehydrogenase deficiency. Acta Haematol 1975; 54:284.
  50. Valaes T. Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr Suppl 1994; 394:58.
  51. Kaplan M, Renbaum P, Levy-Lahad E, et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A 1997; 94:12128.
  52. RAMOT B, FISHER S, SZEINBERG A, et al. A study of subjects with erythrocyte glucose-6-phosphate dehydrogenase deficiency. II. Investigation of leukocyte enzymes. J Clin Invest 1959; 38:2234.
  53. Miller DR, Wollman MR. A new variant of glucose-6-phosphate dehydrogenase deficiency hereditary hemolytic anemia, G6PD Cornell: erythrocyte, leukocyte, and platelet studies. Blood 1974; 44:323.
  54. Schilirò G, Russo A, Mauro L, et al. Leukocyte function and characterization of leukocyte glucose-6-phosphate dehydrogenase in Sicilian mutants. Pediatr Res 1976; 10:739.
  55. Vives Corrons JL, Feliu E, Pujades MA, et al. Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with chronic hemolytic anemia, granulocyte dysfunction, and increased susceptibility to infections: description of a new molecular variant (G6PD Barcelona). Blood 1982; 59:428.
  56. van Bruggen R, Bautista JM, Petropoulou T, et al. Deletion of leucine 61 in glucose-6-phosphate dehydrogenase leads to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 2002; 100:1026.
  57. Luzzatto L. Genetics of red cells and susceptibility to malaria. Blood 1979; 54:961.
  58. Nagel RL, Roth EF Jr. Malaria and red cell genetic defects. Blood 1989; 74:1213.
  59. Tishkoff SA, Varkonyi R, Cahinhinan N, et al. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 2001; 293:455.
  60. Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med (Berl) 1998; 76:581.
  61. Siniscalco, M, et al. Favism and thalassemia in Sardinia and their relationship to malaria. Nature 1961; 190:1179.
  62. Luzzatto L, Usanga FA, Reddy S. Glucose-6-phosphate dehydrogenase deficient red cells: resistance to infection by malarial parasites. Science 1969; 164:839.
  63. Luzzatto L, Sodeinde O, Martini G. Genetic variation in the host and adaptive phenomena in Plasmodium falciparum infection. Ciba Found Symp 1983; 94:159.
  64. Roth EF Jr, Raventos-Suarez C, Rinaldi A, Nagel RL. Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum. Proc Natl Acad Sci U S A 1983; 80:298.
  65. Cappadoro M, Giribaldi G, O'Brien E, et al. Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 1998; 92:2527.
  66. Roth EF Jr, Schulman S, Vanderberg J, Olson J. Pathways for the reduction of oxidized glutathione in the Plasmodium falciparum-infected erythrocyte: can parasite enzymes replace host red cell glucose-6-phosphate dehydrogenase? Blood 1986; 67:827.
  67. Usanga EA, Luzzatto L. Adaptation of Plasmodium falciparum to glucose 6-phosphate dehydrogenase-deficient host red cells by production of parasite-encoded enzyme. Nature 1985; 313:793.
  68. Yoshida A, Roth EF Jr. Glucose-6-phosphate dehydrogenase of malaria parasite Plasmodium falciparum. Blood 1987; 69:1528.
  69. Giribaldi G, Ulliers D, Mannu F, et al. Growth of Plasmodium falciparum induces stage-dependent haemichrome formation, oxidative aggregation of band 3, membrane deposition of complement and antibodies, and phagocytosis of parasitized erythrocytes. Br J Haematol 2001; 113:492.
  70. Griffiths MJ, Ndungu F, Baird KL, et al. Oxidative stress and erythrocyte damage in Kenyan children with severe Plasmodium falciparum malaria. Br J Haematol 2001; 113:486.
  71. Roth EF Jr, Ruprecht RM, Schulman S, et al. Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum. J Clin Invest 1986; 77:1129.
Topic 7109 Version 26.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟