Glucose‐6‐phosphate Dehydrogenase (G6PD) Deficiency: Genetics

Abstract

Deficiency of glucose‐6‐phosphate dehydrogenase (G6PD) is the most common enzyme deficiency in humans and is due to many different local variants with point mutations in the X‐linked G6PD gene. In populations that have a history of malaria infection G6PD alleles causing deficiency can reach frequencies of 10% or more. Though often asymptomatic, the enzyme deficiency can lead to acute haemolytic anaemia caused by failure to maintain sufficiently high levels of nicotinamide–adenine dinucleotide phosphate reduced form (NADPH) to prevent oxidative damage in red cells. Rare sporadic variants that can occur in all human populations can cause more severe chronic haemolytic anaemia. G6PD deficiency is also one of the major causes of neonatal jaundice. The prevalence of G6PD‐deficient alleles is likely due to the fact that they confer a selective advantage against malaria infection.

Key Concepts:

  • G6PD deficiency is widespread because deficient individuals have a selective advantage against malaria infection.

  • G6PD in red cells maintains the levels of NADPH, essential for reducing oxidising agents.

  • Deficient variants cannot maintain high NADPH levels and reactive oxygen species cause haemolysis.

  • Deficient variants can reach polymorphic levels and different populations have different variants.

  • This pattern of variation arose recently, coincident with the spread of malaria in human populations.

  • Most deficient variants are unstable in vivo and therefore cause very low levels in red cells, where the enzyme is not turned over.

  • Knowledge of the G6PD variants in a population can be useful in limiting illness caused by G6PD deficiency.

Keywords: polymorphic; chronic nonspherocytic haemolytic anaemia; malaria; evolution; population genetics; red cell

Figure 1.

Mutated amino acids in G6PD. Class I variants are shown as filled circles (amino acid substitutions) and squares (small deletions) below a linear representation of the protein. The nonsense mutation is shown as a bar. Classes II and III variants are shown as open circles above. Widespread polymorphic variants are coloured, as in Figure , and denoted as follows: U: G6PD Union; C: G6PD Canton; M: G6PD Mediterranean; A1: G6PD A– (202 G →A); vl: G6PD Vanua Lava; k: G6PD Kaiping; t: G6PD Taipei; h: G6PD Chatham; m: G6PD Mahidol; v: G6PD Viangchan; i: G6PD Coimbra; o: G6PD Orissa; kk: G6PD Kalyan/Kerala; S: G6PD Seattle; z: G6PD Cosenza; a: G6PD Aures; s: G6PD Santamaria and A2: G6PD A– (968C). Class IV variants are shown as open ellipses. The filled ellipse denotes the only polymorphic Class IV variant, G6PD A.

Figure 2.

Global distribution of the major polymorphic G6PD variants. Coloured circles indicate the location of each variant named as follows – U: G6PD Union; C: G6PD Canton; M: G6PD Mediterranean; A1: G6PD A– (202A); vl: G6PD Vanua Lava; k: G6PD Kaiping; t: G6PD Taipei; h: G6PD Chatham; m: G6PD Mahidol; v: G6PD Viangchan; i: G6PD Coimbra; o: G6PD Orissa; kk: G6PD Kalyan/Kerala; S: G6PD Seattle; z: G6PD Cosenza; a: G6PD Aures; s: G6PD Santamaria and A: G6PD A– (968C).

Figure 3.

Structure of the human G6PD dimer. Provided by Dr S. Glover and Professor M. Adams.

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Further Reading

Beutler E (1996) G6PD: population genetics and clinical manifestations. Blood Reviews 10: 45–52.

Cappellini MD and Fiorelli G (2008) Glucose‐6‐phosphate dehydrogenase deficiency. Lancet 371: 64–74.

Frank JE (2005) Diagnosis and management of G6PD deficiency. American Family Physician 72: 1277–1282.

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Luzzatto L and Poggi V (2009) Glucose‐6‐phosphate dehydrogenase deficiency. In: Orkin S, Nathan D, Ginsburg D, Look A, Fisher D and Lux S (eds) Nathan and Oski's Hematology of Infancy and Childhood, pp. 883–907. Philadelphia, PA: Saunders.

Mason PJ and Vulliamy T (2000) Genetic variation of human glucose‐6‐phosphate dehydrogenase. In: Jean‐King M (ed.) Human Blood Cells: Consequences of Genetic Polymorphisms and Variations, pp. 251–275. London, NY: Imperial College Press.

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Web Links

Glucose‐6‐phosphate dehydrogenase (G6PD); Locus ID: 2539. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2539

Glucose‐6‐phosphate dehydrogenase (G6PD); MIM number: 305900. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?305900

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Mason, Philip J, and Vulliamy, Thomas J(Sep 2010) Glucose‐6‐phosphate Dehydrogenase (G6PD) Deficiency: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006084.pub2]