Hematologically Important Mutations: Glucose-6-Phosphate Dehydrogenase

Vulliamy, Tom; Luzzatto, Lucio; Hirono, Akira; Beutler, Ernest

doi:10.1006/bcmd.1997.0147

Cited by 76 publications

(74 citation statements)

References 57 publications

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“…The Class I variants have the most severe manifestations with less than 5% of residual activity, while Class V are the mildest form [19,28,29]. Measurements of enzyme activity in red cells extracts did not give a reasonable indicator of the altered Michaelis constants of G6PD protein due to either a decreased level of enzyme with normal k cat , or a normal level of enzyme with a decreased k cat .…”

Section: Functional Characterization Of G6pd Variantsmentioning

confidence: 92%

Functional and Biochemical Analysis of Glucose-6-Phosphate Dehydrogenase (G6PD) Variants: Elucidating the Molecular Basis of G6PD Deficiency

et al. 2017

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G6PD deficiency is the most common enzymopathy, leading to alterations in the first step of the pentose phosphate pathway, which interferes with the protection of the erythrocyte against oxidative stress and causes a wide range of clinical symptoms of which hemolysis is one of the most severe. The G6PD deficiency causes several abnormalities that range from asymptomatic individuals to more severe manifestations that can lead to death. Nowadays, only 9.2% of all recognized variants have been related to clinical manifestations. It is important to understand the molecular basis of G6PD deficiency to understand how gene mutations can impact structure, stability, and enzymatic function. In this work, we reviewed and compared the functional and structural data generated through the characterization of 20 G6PD variants using different approaches. These studies showed that severe clinical manifestations of G6PD deficiency were related to mutations that affected the catalytic and structural nicotinamide adenine dinucleotide phosphate (NADPH) binding sites, and suggests that the misfolding or instability of the 3D structure of the protein could compromise the half-life of the protein in the erythrocyte and its activity.

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Section: Functional Characterization Of G6pd Variantsmentioning

confidence: 92%

Functional and Biochemical Analysis of Glucose-6-Phosphate Dehydrogenase (G6PD) Variants: Elucidating the Molecular Basis of G6PD Deficiency

et al. 2017

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“…Genomic DNA was isolated from whole blood using Blood Mini kits (Qiagen) according to the manufacturer's protocol. Specific PCR reactions were performed to isolate exons 3-5 that correspond to the common A/Aallele found in patients of African descent, or exon 6 that corresponds to the Mediterranean mutant allele (39). PCR products were checked for size on agarose gels and purified using a Qiagen PCR Purification kit and sequenced on both forward and reverse strands across the regions of interest to verify presence of mutant allele.…”

Section: Methodsmentioning

confidence: 99%

Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity

Rochford

Ohrt

Baresel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance This article describes the development and validation of a novel mouse model that can be used to predict hemolytic toxicity of drugs that occurs in individuals with an enzyme deficiency known as glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency affects more than 400 million people worldwide. In this model, nonobese diabetic/SCID mice are transfused with human RBCs from G6PD-deficient donors. Treatment with drugs known to cause hemolytic anemia in humans do not cause damage to the mouse RBCs nor to the transfused normal human RBCs; but a robust hemolytic response is observed in the mice transfused with G6PD-deficient human RBCs. The immediate impact of this model will be in advancing the development antimalarial drugs.

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“…In total, we analyzed 963 disease-associated replacement mutations, 50 polymorphic replacement mutations, and 94 silent mutations (Table 1). Furthermore, in the case of G6PD, information on the severity of the disease phenotype (Vulliamy et al 1997) permitted us to separately analyze sets of severe (type I) mutations resulting in chronic non-spherocytic hemolytic anemia and milder (type II, III, and IV) mutations resulting only in enzyme deficiencies. Definitions of the specific amino acid residues contained in domains of each gene were obtained from the sources listed in Table 1 (see also Methods in Miller & Kumar, 2001).…”

Section: Data Acquisitionmentioning

confidence: 99%

Quantifying the Intragenic Distribution of Human Disease Mutations

Miller

Parker²,

Rissing³

et al. 2003

Annals of Human Genetics

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SummaryA wide variety of functional domains exist within human genes. Since different domains vary in their roles regarding overall gene function, the ability for a mutation in a gene region to produce disease varies among domains. We tested two hypotheses regarding distributions of mutations among functional domains by using (1) sets of single nucleotide disease mutations for six genes (CFTR, TSC2, G6PD, PAX6, RS1, and PAH) and (2) sets of polymorphic replacement and silent mutations found in two genes (CFTR and TSC2). First, we tested the null hypothesis that sets of mutations are uniformly distributed among functional domains within genes. Second, we tested the null hypothesis that disease mutations are distributed among gene regions according to expectations derived from the distribution of evolutionary conserved and variable amino acid sites throughout each gene. In contrast to the mainly uniform distribution of sets of silent and polymorphic mutations, sets of disease mutations generally rejected the null hypotheses of both uniform and evolutionary-influenced distributions. Although the disease mutation data showed a better agreement with the evolutionary-derived expectations, disease mutations were found to be statistically overabundant in conserved domains, and under-represented in variable regions, even after accounting for amino acid site variability of domains over long-term evolutionary history. This finding suggests that there is a nonadditive influence of amino acid site conservation on the observed intragenic distribution of disease mutations, and underscores the importance of understanding the patterns of neutral amino acid substitutions permitted in a gene over long-term evolutionary history.

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Hematologically Important Mutations: Glucose-6-Phosphate Dehydrogenase

Cited by 76 publications

References 57 publications

Functional and Biochemical Analysis of Glucose-6-Phosphate Dehydrogenase (G6PD) Variants: Elucidating the Molecular Basis of G6PD Deficiency

Functional and Biochemical Analysis of Glucose-6-Phosphate Dehydrogenase (G6PD) Variants: Elucidating the Molecular Basis of G6PD Deficiency

Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity

Quantifying the Intragenic Distribution of Human Disease Mutations

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