title: Moderate G6PD deficiency increases mutation rates in the brain of mice.
abstract: Mice that harbored the x-ray-induced low efficiency allele of the major X-linked isozyme of glucose-6-phospate dehydrogenase (G6PD), Gpdx(a-m2Neu), and, in addition, harbored the transgenic shuttle vector for the determination of mutagenesis in vivo, pUR288, were employed to further our understanding of the interdependence of general metabolism, oxidative stress control, and somatic mutagenesis. The Gpdx(a-m2Neu) mutation conferred moderate G6PD deficiency in hemizygous males (Gpdx(a-m2Neu/y)) displaying residual enzyme activities of 27% in red blood cells and 13% in brain (compared to wild-type controls, Gpdx(a/y) males). In spite of this mild phenotype, the brains of G6PD-deficient males exhibited a significant distortion of redox control ( approximately 3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts ( approximately 13-fold increase in ethenodeoxyadenosine and approximately 5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates ( approximately 3-fold increase in mutant frequencies in lacZ, the target and reporter gene of mutagenesis in the shuttle vector, pUR288). The mutation pattern in the brain was dominated by illegitimate genetic recombinations, a presumed hallmark of oxidative mutagenesis. These findings suggested a critical function for G6PD in limiting oxidative mutagenesis in the mouse brain.
authors.affiliation: Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Felix
authors.forename: Lynne D
authors.initials: LD
authors.lastname: Rockwood
authors.forename: Walter
authors.initials: W
authors.lastname: Pretsch
authors.forename: Jagadeesan
authors.initials: J
authors.lastname: Nair
authors.forename: Helmut
authors.initials: H
authors.lastname: Bartsch
authors.forename: Georg Wilhelm
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
mesh_terms: D000743:Anemia, Hemolytic / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology*; D018736:DNA Adducts / Q000235:genetics; D004252:DNA Mutational Analysis; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics*; D005978:Glutathione / Q000378:metabolism; D007763:Lac Operon / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D018384:Oxidative Stress; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic
chemical_list: D018736:DNA Adducts; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione