The glucose-6-phosphate dehydrogenase (G6PD) deficient variant G6PD union (454 Arg→Cys) has a worldwide distribution possibly due to recurrent mutation

Rovlra, Ana; Vulliamy, Thomas J.; Pujades, Assumpció; Luzzatto, Lucio; Corrons, Joan-Luis Vives

doi:10.1093/hmg/3.5.833

Cited by 18 publications

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“…This could suggest an independent origin of G6PD Mediterranean mutation in Europe and Asia, or it could represent crossover or population admixture (Beutler and Kuhl 1990). G6PD Union has been described worldwide while G6PD Cassano was found in neighboring Italy and Greece (Rovira et al 1994;Menounos et al 2000). Our findings fit into the scheme of world distribution of these mutations.…”

Section: Resultssupporting

confidence: 85%

Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

et al. 2005

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency protects from severe forms of malaria. It is interesting therefore to analyze the molecular basis underlying G6PD deficiency in regions such as the Mediterranean basin where malaria was present for a long time in history. Here we report on the genetic characterization of G6PD deficiency among inhabitants of one Mediterranean region-the Dalmatian region of south Croatia. We analyzed 24 unrelated G6PD-deficient male subjects. Molecular testing revealed several different mutations: G6PD Cosenza 9, G6PD Mediterranean 4, G6PD Seattle 3, G6PD Union 3, and G6PD Cassano 1. Furthermore, we have identified one novel G6PD variant that we named G6PD Split. This variant is caused by a nucleotide change 1442 C fi G leading to the amino acid substitution 481 Pro fi Arg and is characterized by moderate enzyme deficiency (class III variant). This study reveals a higher prevalence (37.5%) of the Cosenza mutation in the Dalmatian region than anywhere else previously investigated and overall shows the considerable molecular heterogeneity underlining G6PD deficiency that can be observed in Mediterranean populations.

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Section: Resultssupporting

confidence: 85%

Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

et al. 2005

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“…In erythrocytes, G6PD Union and G6PD Andalus activities are reportedly about 3 and 0.1% of the wild-type level respectively; in leucocytes, corresponding figures are 9 and 10% (Yoshida et al, 1970;Hsia et al, 1993;VivesCorrons et al, 1990;Rovira et al, 1994). When expressed in E.coli, the mutants also showed 8-9-fold lower activity in crude extracts than the wild type.…”

Section: Discussionmentioning

confidence: 99%

Marked decrease in specific activity contributes to disease phenotype in two human glucose 6-phosphate dehydrogenase mutants, G6PD_Unionand G6PD_Andalus

2005

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Clones overexpressing clinical glucose 6-phosphate dehydrogenase (G6PD) mutants Union (c.1360C>T / p.Arg454Cys) and Andalus (c.1361G>A / p.Arg454His) , have been constructed. These abolish a salt bridge between Arg454 and Asp 286. One mutant is reportedly a Class II clinical variant and the other a Class I. Kinetic studies of the purified proteins reveal that, for both mutants, k cat is about 10-fold decreased, thus giving a 90% decrease in the WHO assay, and also presumably under physiological conditions. In contrast with unfavourable changes in V max for both mutants, K m values for both G6P and NADP + are decreased approximately 5-fold. Measurements with alternative substrates confirm that G6PD Union, like the wild-type enzyme, follows a rapid-equilibrium random-order mechanism, allowing calculation of enzyme-substrate dissociation constants from initial-rate parameters. The mutations result in several-fold tighter binding of glucose 6-phosphate to the free enzyme. Binding, however, is clearly less productive than with normal enzyme. G6PD mutations are thought to cause haemolytic anaemia by compromising enzyme stability. Both these mutants indeed show somewhat decreased thermostability. However, at 37 o C and with NADP + , the stability differences are only moderate. Decreased catalytic efficiency clearly contributes to the disease phenotype of these two mutants, entirely accounting for reported decrease in leukocyte G6PD levels, though not for still lower levels in erythrocytes. Neither the kinetic nor the stability effects appear to justify the different clinical classification of these mutations.

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“…Among these, G6PD Mediterranean (563 C-+T), G6PD A-(376 A+G with either 202 G+A or 968 T-C), G6PD Seattle (844 G+C), G6PD Aures (143 T-C), and G6PD Union (1360 C+T), have been found in Spain (Rovira et al, 1994(Rovira et al, , 1995. Here, the G6PD gene has been characterized in five unrelated Spanish G6PD deficient males who had presented clinically with favism.…”

Section: Mutation Analysismentioning

confidence: 95%

Independent origin of single and double mutations in the human glucose 6-phosphate dehydrogenase gene

et al. 1996

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The glucose-6-phosphate dehydrogenase (G6PD) deficient variant G6PD union (454 Arg→Cys) has a worldwide distribution possibly due to recurrent mutation

Cited by 18 publications

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Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

Marked decrease in specific activity contributes to disease phenotype in two human glucose 6-phosphate dehydrogenase mutants, G6PD_Unionand G6PD_Andalus

Independent origin of single and double mutations in the human glucose 6-phosphate dehydrogenase gene

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The glucose-6-phosphate dehydrogenase (G6PD) deficient variant G6PD union (454 Arg→Cys) has a worldwide distribution possibly due to recurrent mutation

Cited by 18 publications

References 0 publications

Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

Marked decrease in specific activity contributes to disease phenotype in two human glucose 6-phosphate dehydrogenase mutants, G6PDUnionand G6PDAndalus

Independent origin of single and double mutations in the human glucose 6-phosphate dehydrogenase gene

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Marked decrease in specific activity contributes to disease phenotype in two human glucose 6-phosphate dehydrogenase mutants, G6PD_Unionand G6PD_Andalus