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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 1

Generation of a G6PD-deficient mouse model.

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Generation of a G6PD-deficient mouse model.
(A) Schematic representation...
(A) Schematic representation of the WT G6PD locus (top) and related modifications (bottom). (B) Predicted protein sequence of knocked-in G6PD gene. (C) G6PD activity in RBCs from WT versus G6PDMed- mice. n = 5–7 mice per group. Unpaired, 2-tailed t test. (D) Mouse versus human mRNA levels in G6PDMed- and WT mice; assay 1 detects both WT and G6PDMed- mRNA, assay 2 detects only WT, and assays 3 and 4 detect only G6PDMed- mRNA (details of assay primers and probes shown in Supplemental Figure 2A). n = 5 for both groups for the Pol2RA experiment; n = 3 for WT and G6PD. Data shown as mean ± SD in C and D. (E) Western blot analysis of cytoplasm from RBCs. Because the G6PD gene is X linked, males were used in all experiments. G6PDMed- mice are hemizygous for the knocked-in human gene; WT mice are littermate controls with the mouse WT G6PD. n = 3 for each group.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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