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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 6

G6PD-deficient mouse RBCs have comparable metabolism and posttransfusion recovery to WT RBCs at the end of storage.

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G6PD-deficient mouse RBCs have comparable metabolism and posttransfusion...
RBCs from WT and G6PDMed- mice (n = 6) were stored under conditions mimicking storage in the blood bank for 12 days (A). At the end of storage, RBCs were transfused into UbiC-GFP C57BL/6-Tg(UBC-GFP)30Scha/J (Ubi-GFP) mice, and flow cytometry studies were performed to determine the percentage of transfused RBCs circulating at 24 hours from transfusion, which was determined to be comparable between the 2 groups. Transfusing G6PDMed- GFP into WT or G6PDMed- non-GFP recipients did not impact the posttransfusion recovery (PTR) percentage measurement. (B) Metabolic phenotypes of G6PDMed- RBCs showed some significant differences at baseline (especially with respect to glycolysis, the PPP, and glutathione homeostasis). However, these changes were not appreciable by the end of storage. (C) Individual data points for G6P and 6PG are shown (significance calculated by Mann-Whitney unpaired t test). *P < 0.05, **P < 0.01.

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