Table 2.

Different G6PD mutations produce a wide range of biochemical phenotypes

G6PD variantEnzyme activity in red cells, % of normalElectro phoretic mobilityThermal stability in vitro*KmG6P, μMkcat s−1Amino acid changeClassClinical featuresReference/notes
B (“wild type”) 100 Normal Normal 50-70 275 — IV None 71  
A 85 Fast Normal 60 247 N126D IV None 72  
A− 10-23 Fast Low 47-60 137 

  • N126D

  • V68M

 		III AHA 8: Thermostability low at low [NADP]; 73: impaired folding observed 
Orissa 13-28 Normal Increased 135  A44G III AHA 74  
Seattle 17 Slow Normal 20 207† D282H III AHA 70: Accelerated decay in vivo 
Mediterranean <5 Normal Low 12-23 98† S188F II AHA 70: Accelerated decay in vivo 
Andalus 1  Low 14 40 R454H II AHA 71  
Union 3 Fast (exp) Low 10 29 R454C II AHA 71  
Canton 4 Fast (103%) Slightly decreased 28-23 123 R459L II AHA 75; 76: first 3D structure of a human G6PD variant 
Chatham <2 Normal Low 60  A335T II AHA 77  
Viangchan 3 Normal Normal 42 145 V291M II AHA 78  
Mahidol 0.6 Normal Normal 75 207 G163S II AHA 79  
Plymouth <1‡ Fast (exp) Slightly decreased 67 249 G163D I CNSHA, mild 79,80: Also cardiomyopathy 
Nilgiri 2  Low 81 3 R198H II AHA 81  
Santiago <1 Fast (exp) Very low 26 4 R198P I CNSHA 82  
Nashville Portici 1 Slow Very low 144 119 R393H I Severe NNJ; CNSHA, moderate; hepatosplenomegaly; BT+ 83: Accelerated decay in vivo 
Campinas <1‡ Normal (exp) Very low 81 212 G488V I Severe NNJ; CNSHA, severe; BT-dependent 84  
Harilaou <1‡ Normal Very low 90  F216L I Severe NNJ; CNSHA, severe, BT-dependent until splenectomized 85: Stabilized in interspecific hybrid molecule 
Volendam 1 Slow Low 238  P172S I NNJ; mild anemia with infection-related exacerbations 86: Heterozygous woman with skewed X-inactivation with de novo mutation 
G6PD variantEnzyme activity in red cells, % of normalElectro phoretic mobilityThermal stability in vitro*KmG6P, μMkcat s−1Amino acid changeClassClinical featuresReference/notes
B (“wild type”) 100 Normal Normal 50-70 275 — IV None 71  
A 85 Fast Normal 60 247 N126D IV None 72  
A− 10-23 Fast Low 47-60 137 

  • N126D

  • V68M

 		III AHA 8: Thermostability low at low [NADP]; 73: impaired folding observed 
Orissa 13-28 Normal Increased 135  A44G III AHA 74  
Seattle 17 Slow Normal 20 207† D282H III AHA 70: Accelerated decay in vivo 
Mediterranean <5 Normal Low 12-23 98† S188F II AHA 70: Accelerated decay in vivo 
Andalus 1  Low 14 40 R454H II AHA 71  
Union 3 Fast (exp) Low 10 29 R454C II AHA 71  
Canton 4 Fast (103%) Slightly decreased 28-23 123 R459L II AHA 75; 76: first 3D structure of a human G6PD variant 
Chatham <2 Normal Low 60  A335T II AHA 77  
Viangchan 3 Normal Normal 42 145 V291M II AHA 78  
Mahidol 0.6 Normal Normal 75 207 G163S II AHA 79  
Plymouth <1‡ Fast (exp) Slightly decreased 67 249 G163D I CNSHA, mild 79,80: Also cardiomyopathy 
Nilgiri 2  Low 81 3 R198H II AHA 81  
Santiago <1 Fast (exp) Very low 26 4 R198P I CNSHA 82  
Nashville Portici 1 Slow Very low 144 119 R393H I Severe NNJ; CNSHA, moderate; hepatosplenomegaly; BT+ 83: Accelerated decay in vivo 
Campinas <1‡ Normal (exp) Very low 81 212 G488V I Severe NNJ; CNSHA, severe; BT-dependent 84  
Harilaou <1‡ Normal Very low 90  F216L I Severe NNJ; CNSHA, severe, BT-dependent until splenectomized 85: Stabilized in interspecific hybrid molecule 
Volendam 1 Slow Low 238  P172S I NNJ; mild anemia with infection-related exacerbations 86: Heterozygous woman with skewed X-inactivation with de novo mutation 

From the full list (supplemental Table 2) of G6PD variants we have selected, among those for which enzymatic properties are known more extensively, some polymorphic (classes II-IV) and some rare (class I) variants. These properties were reported either in Betke et al9  or when the variant was originally described (references in supplemental Table 2), or in subsequent papers (references in this table). Class I variants are, by definition, associated with CNSHA: but within this diagnosis there is a wide spectrum of severity.

—, no change; 3D, 3-dimensional; BT, blood transfusion; CNSHA, chronic nonspherocytic hemolytic anemia; exp, expected.

*

Thermostability studies must be carried out on purified or recombinant enzyme, and they have been carried out in different ways, making comparisons problematic: hence, we have adopted in this table a semiquantitative terminology. Rather than the time it takes to inactivate the enzyme at a fixed temperature, it is probably more informative to determine T1/2 (temperature at which 50% activity is lost after a fixed exposure time, eg, 7 minutes): this parameter was first introduced in 19658  and found to be highly sensitive to the concentration of NADP. The properties of this arbitrary set of variants illustrate the following: (1) Almost all class I variants show evidence of markedly impaired stability; several of the others are also unstable, and in some this has been found to correlate with accelerated decay in vivo; (2) KmG6P, when increased, affects performance in the steady state; therefore, it is not surprising to find this feature in some class I variants (for example, Portici, Volendam). G6PD Orissa is not in class I (despite high KmG6P) probably thanks to its relatively high residual activity; (3) To determine kcat, pure enzyme (usually obtained by recombinant DNA technology) is required (hence some data are missing): it is moderately decreased in many variants; drastically decreased in G6PD Nilgiri and G6PD Santiago; (4) There is overlap in residual enzyme activity values between class II and class I; however, as a rule, all class I variants have very low activity (1% or less: sometimes undetectable);(5) Comparing variants where the same amino acid is replaced: G6PD Plymouth (class I) differs from G6PD Mahidol (class II) only in reduced thermostability; interestingly, the amino acid replacement in G6PD Plymouth entails a change in charge, whereas that in G6PD Mahidol does not. G6PD Santiago (class I) and G6PD Nilgiri (class II) again differ only in thermostability; and again there is a charge change in the former but not in the latter.

†

Calculated from ratio of activity/cross reacting material compared with G6PD B.

‡

Enzyme activity reported as undetectable.

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