Redox imbalance and mutagenesis in spleens of mice harboring a hypomorphic allele of Gpdx(a) encoding glucose 6-phosphate dehydrogenase.
Mice harboring the activity-attenuated Gpdx(a-m2Neu) allele and also harboring a chromosomally integrated lacZ reporter gene to study mutagenesis (pUR288) were used to demonstrate that moderate glucose 6-phosphate dehydrogenase (G6PD) deficiency causes elevated mutagenesis and endogenous oxidative stress in the spleen. G6PD-deficient spleens with a residual enzyme activity of 22% exhibited a dramatic shift in the mutational pattern of lacZ (4.6-fold increase in the prevalence of recombination mutations of lacZ) together with a 1.8-fold increase in mutant frequencies in lacZ. A concomitant 3-fold reduction in catalase activity (dependent upon NADPH) indicated that the in vivo supply of G6PD-generated NADPH was insufficient. An additional 3-fold increase in oxidized glutathione suggested that redox control was disturbed in G6PD-deficient spleens. These findings indicate that G6PD is required for limiting oxidative mutagenesis in the mouse spleen. Gpdx(a-m2Neu) is the first hypomorphic allele of a mouse housekeeping gene associated with elevated somatic mutagenesis in vivo.
Felix
Klaus
K
Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Rockwood
Lynne D
LD
Pretsch
Walter
W
Bornkamm
Georg Wilhelm
GW
Janz
Siegfried
S
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011995:Recombination, Genetic / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013154:Spleen / Q000201:enzymology* / Q000378:metabolism*
D005954:Glucosephosphate Dehydrogenase