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

View ORCID ProfileAngelo D’Alessandro, Heather L Howie, Ariel M. Hay, Karolina H. Dziewulska, Benjamin 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
doi: https://doi.org/10.1101/2021.05.31.446353
Angelo D’Alessandro
1University of Colorado Denver-Anschutz Medical Campus, Aurora, CO
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Heather L Howie
2Univeristy of Virginia Department of Pathology and Carter Immunology Center, Charlottesville, VA
3Bloodworks NW Research Institute, Seattle, WA
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Ariel M. Hay
2Univeristy of Virginia Department of Pathology and Carter Immunology Center, Charlottesville, VA
3Bloodworks NW Research Institute, Seattle, WA
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Karolina H. Dziewulska
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Benjamin Brown
1University of Colorado Denver-Anschutz Medical Campus, Aurora, CO
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Matthew J Wither
1University of Colorado Denver-Anschutz Medical Campus, Aurora, CO
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Matthew Karafin
4Blood Center of Wisconsin, Milwaukee WI
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Elizabeth F. Stone
5Columbia University, Department of Pathology and Cell Biology, New York, NY
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Steven L Spitalnik
5Columbia University, Department of Pathology and Cell Biology, New York, NY
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Eldad A Hod
5Columbia University, Department of Pathology and Cell Biology, New York, NY
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Richard O Francis
5Columbia University, Department of Pathology and Cell Biology, New York, NY
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Xiaoyun Fu
3Bloodworks NW Research Institute, Seattle, WA
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Tiffany Thomas
5Columbia University, Department of Pathology and Cell Biology, New York, NY
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James C Zimring
2Univeristy of Virginia Department of Pathology and Carter Immunology Center, Charlottesville, VA
3Bloodworks NW Research Institute, Seattle, WA
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  • For correspondence: jcz2k@virginia.edu
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Abstract

Deficiency of Glucose 6 phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (e.g. 5% of humans). 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 G6PD due to promoter mutations, but with stable G6PD. 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 and platelets 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 have increased hemolytic sequalae to oxidant stress. G6PD levels were mildly decreased in non-erythroid organs, consistent with what has been observed in humans. Juxtaposition of G6PD deficient and wild-type mice revealed altered lipid metabolism in multiple organ systems. Together, these findings both establish a new mouse model of G6PD deficiency that more accurately reflects human G6PD deficiency and also advance our basic understanding of altered metabolism in this setting.

Competing Interest Statement

Although unrelated to the studies in the current manuscript, AD is the founder of Omix Technologies and Altis Biosciences LLD. AD and SLS are consultants for Hemanext Inc. BloodworksNW, where the G6PD mouse was generated, has filed intellectual property on use of this animal as a tool for screening toxicology of novel drugs. The authors have no other conflicts of interest to declare.

Footnotes

  • Scientific Category: Red Cells, Iron, Erythropoiesiss

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Hematologic and systemic metabolic alterations due to Mediterranean type II G6PD deficiency in mice
Angelo D’Alessandro, Heather L Howie, Ariel M. Hay, Karolina H. Dziewulska, Benjamin 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
bioRxiv 2021.05.31.446353; doi: https://doi.org/10.1101/2021.05.31.446353
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Hematologic and systemic metabolic alterations due to Mediterranean type II G6PD deficiency in mice
Angelo D’Alessandro, Heather L Howie, Ariel M. Hay, Karolina H. Dziewulska, Benjamin 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
bioRxiv 2021.05.31.446353; doi: https://doi.org/10.1101/2021.05.31.446353

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