Abstract
Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (approximately 5%). Its prevalence is hypothesized to be due to conferring resistance to malaria. However, G6PD deficiency also results in hemolytic sequelae from oxidant stress. Moreover, G6PD deficiency is associated with kidney disease, diabetes, pulmonary hypertension, immunological defects, and neurodegenerative diseases. To date, the only available mouse models have decreased levels of WT stable G6PD caused by promoter mutations. However, human G6PD mutations are missense mutations that result in decreased enzymatic stability. As such, this results in very low activity in red blood cells (RBCs) that cannot synthesize new protein. To generate a more accurate model, the human sequence for a severe form of G6PD deficiency, Med(-), was knocked into the murine G6PD locus. As predicted, G6PD levels were extremely low in RBCs, and deficient mice had increased hemolytic sequelae to oxidant stress. Nonerythroid organs had metabolic changes consistent with mild G6PD deficiency, consistent with what has been observed in humans. Juxtaposition of G6PD-deficient and WT mice revealed altered lipid metabolism in multiple organ systems. Together, these findings both establish a mouse model of G6PD deficiency that more accurately reflects human G6PD deficiency and advance our basic understanding of altered metabolism in this setting.
Highlights
Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-determining enzyme in the pentose phosphate pathway (PPP), which utilizes glucose to generate NADPH; the latter is the major reducing equivalent that fuels multiple pathways by which cells handle oxidative stress
We describe a murine model of G6PD deficiency that overcomes the limitations of existing models and has allowed an exploration into metabolomics of both red blood cells (RBCs) and solid organs
The extent of the decreased activity in G6PDMed- mice, as compared with WT, approximated what is seen in humans (i.e., 5%–10% of normal activity), and, as is the classic finding in humans, pharmacological oxidative stress induced brisk hemolysis in vivo with hemoglobinuria
Summary
Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-determining enzyme in the pentose phosphate pathway (PPP), which utilizes glucose to generate NADPH; the latter is the major reducing equivalent that fuels multiple pathways by which cells handle oxidative stress. Based upon the mutation and resulting G6PD levels, disease can range from mild to severe deficiency [2, 3]. RBCs from humans with G6PD deficiency are susceptible to oxidant stress for 2 prevailing reasons. When G6PD-deficient humans encounter an illness or consume a drug or food that increases oxidant stress (e.g., antimalarial quinone drugs or fava beans), they can manifest symptoms of acute hemolysis, ranging from mild to lethal [4, 5]. Recent findings have linked G6PD deficiency to many other diseases outside the RBC compartment, including immunological [1], cardiovascular [6], endocrine [7], renal [7], neurological [8], and pulmonary pathologies [9]
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