Two X-linked chronic granulomatous disease patients with unusual NADPH oxidase properties

Background Chronic granulomatous disease (CGD) is an immune deficiency syndrome caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme that generates reactive oxygen species (ROS) in phagocytizing leukocytes. This study evaluates the NADPH oxidase capacity in two X-linked CGD patients with mutations in gp91 ^phox that alter the regions in this membrane-bound NADPH oxidase component involved in docking of the cytosolic component p47 ^phox. Materials and Methods Hydrogen peroxide and superoxide generation, bactericidal activity, and NADPH oxidase protein expression by the patients' neutrophils were measured, and genetic analysis was performed. Results We report two patients, each with a novel missense mutation in CYBB, the gene that encodes gp91 ^phox. Surprisingly, neutrophils from these patients showed total absence of superoxide production, although they retained 13-30% of the hydrogen peroxide production capability. We speculate that this is due to direct electron transfer from flavin adenine dinucleotide (FAD) in gp91 ^phox to oxygen, leading to inefficient hydrogen peroxide formation instead of efficient superoxide production. Conclusions X-linked CGD patients with mutations that alter the gp91 ^phox protein in regions involved in docking of the cytosolic NADPH oxidase component p47 ^phox may have higher than expected hydrogen peroxide generation capability.