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Hematologic and systemic metabolic alterations due to Mediterranean class II G6PD deficiency in mice
Angelo D’Alessandro, … , Tiffany Thomas, James C. Zimring
Angelo D’Alessandro, … , Tiffany Thomas, James C. Zimring
Published June 17, 2021
Citation Information: JCI Insight. 2021;6(14):e147056. https://doi.org/10.1172/jci.insight.147056.
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Research Article Hematology

Hematologic and systemic metabolic alterations due to Mediterranean class II G6PD deficiency in mice

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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.

Authors

Angelo D’Alessandro, Heather L. Howie, Ariel M. Hay, Karolina H. Dziewulska, Benjamin C. Brown, Matthew J. Wither, Matthew Karafin, Elizabeth F. Stone, Steven L. Spitalnik, Eldad A. Hod, Richard O. Francis, Xiaoyun Fu, Tiffany Thomas, James C. Zimring

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Figure 8

Metabolic analyses of liver and spleen from WT and G6PDMed- mice.

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Metabolic analyses of liver and spleen from WT and G6PDMed- mice.
(A) Si...
(A) Significant metabolic changes were observed in all the organs tested from G6PDMed- mice, compared with WT controls, (B and C) as highlighted by multivariate principal component and hierarchical clustering analyses (only the top 25 significant metabolites by t test are shown). The majority of metabolic changes in organs of G6PDMed- mice are related to fatty acid metabolism and acyl-carnitines, followed by amino acid metabolism and glycolysis. Lactate levels were significantly lower in all organs of G6PDMed- mice. n = 4 for both groups. (D) Individual data points are shown for lactate in each organ in WT (blue bars) and G6PDMed- (red bars). (E) Organ-to-organ metabolic differences overweighed differences between WT and G6PDMed- mice.

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