Chronic granulomatous disease and glutathione peroxidase deficiency, revisited

Peter E. Newburger, Stephen E. Malawista, Mary C. Dinauer, Terri Gelbart, Richard C. Woodman, Sunil Chada, Qichang Shen, Gretchen Van Blaricom, Paul G. Quie, John T. Curnutte

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


We have restudied two kindreds that formed the basis of the original report of autosomal recessive chronic granulomatous disease (CGD) associated with leukocyte glutathione peroxidase deficiency. Case 1 from the original study and the surviving brother of the originally reported case 2 both have severe CGD, with no detectable respiratory burst activity in purified intact neutrophils. However, their leukocytes exhibit normal glutathione peroxidase enzyme activity and gene expression. Examination of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase components known to be defective in CGD reveals no detectable cytochrome b558 nor any membrane activity in a cell-free NADPH oxidase assay system. Molecular analysis of the genes encoding cytochrome b558 subunits shows, in case 1, a C → T substitution at nucleotide 688 of the gene encoding the gp91-phox subunit of cytochrome b558, resulting in a termination signal in place of Arginine- 226. Levels of gp91-phox mRNA are markedly decreased despite normal levels of gene transcription, indicating a post-transcriptional effect of the nonsense mutation on mRNA processing or stability. The X-linked form of CGD developed in this cytogenetically normal female due to the uniform inactivation of the normal X chromosome in her granulocytes, indicated by the expression in her granulocyte mRNA of only one allele of a glucose-6-phosphate dehydrogenase polymorphisms for which she is heterozygous in genomic DNA. Case 2 (of the present study) has distinct mutations in each allele of the p22-phox gene. Thus, the CGD phenotype in both kindreds now appears to be caused not by leukocyte glutathione peroxidase deficiency, but rather by mutations of the same subunits of phagocyte NADPH oxidase that are involved in all other cases of cytochrome b-negative CGD. Glutathione peroxidase deficiency should no longer be considered a possible cause of the CGD phenotype.

Original languageEnglish
Pages (from-to)3861-3869
Number of pages9
Issue number11
StatePublished - Dec 1 1994


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