Dataset Information

A model of glucose-6-phosphate dehydrogenase deficiency in the zebrafish.

ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic defect and enzymopathy worldwide, affecting approximately 400 million people and causing acute hemolysis in persons exposed to prooxidant compounds such as menthol, naphthalene, antimalarial drugs, and fava beans. Mouse models have not been useful because of a lack of significant response to oxidative challenge. We turned to zebrafish (Danio rerio) embryos, which develop ex utero and are transparent, allowing visualization of hemolysis. We designed morpholinos to zebrafish g6pd that were effective in reducing gene expression as shown by Western blot and G6PD enzyme activity, resulting in a brisk hemolysis and pericardial edema secondary to anemia. Titration of the g6pd knockdown allowed us to generate embryos that displayed no overt phenotype until exposed to the prooxidant compounds 1-naphthol, menthol, or primaquine, after which they developed hemolysis and pericardial edema within 48-72 hours. We were also able to show that g6pd morphants displayed significant levels of increased oxidative stress compared with controls. We anticipate that this will be a useful model of G6PD deficiency to study hemolysis as well as oxidative stress that occurs after exposure to prooxidants, similar to what occurs in G6PD-deficient persons.

SUBMITTER: Patrinostro X

PROVIDER: S-EPMC3856909 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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A model of glucose-6-phosphate dehydrogenase deficiency in the zebrafish.

Patrinostro Xiaobai X Carter Michelle L ML Kramer Ashley C AC Lund Troy C TC

Experimental hematology 20130416 8

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic defect and enzymopathy worldwide, affecting approximately 400 million people and causing acute hemolysis in persons exposed to prooxidant compounds such as menthol, naphthalene, antimalarial drugs, and fava beans. Mouse models have not been useful because of a lack of significant response to oxidative challenge. We turned to zebrafish (Danio rerio) embryos, which develop ex utero and are transparent, allowing visualiz ...[more]

PMID: 23603363

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Project description:BACKGROUNDGlucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient donor RBCs would have inferior storage quality for transfusion as compared with G6PD-normal RBCs.METHODSMale volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed.RESULTSThe mean 24-hour PTR for G6PD-deficient subjects was 78.5% ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways.CONCLUSIONBased on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs.TRIAL REGISTRATIONClinicalTrials.gov NCT04081272.FUNDINGThe Harold Amos Medical Faculty Development Program, Robert Wood Johnson Foundation grant 71590, the National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career Award 2017 by the Boettcher Foundation, and National Heart, Lung, and Blood Institute grants R01HL14644 and R01HL148151.

Dataset Information

A model of glucose-6-phosphate dehydrogenase deficiency in the zebrafish.

Publications

A model of glucose-6-phosphate dehydrogenase deficiency in the zebrafish.

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