Chronic granulomatous disease (CGD) is a group of inherited disorders of host defense caused by a mutation in any of the four components of phagocyte NADPH oxidase, namely gp91-, p22-, p47-, and p67-phox. We have made a precise statistical analysis of 229 registered patients from 195 families in Japan and mutation analysis of 28 and 5 independent patients, respectively, with gp91- and p22-phox deficiency. The gp91- and p22-phox proteins form the membrane cytochrome b558, which plays important roles in the assembly of the active oxidase and electron-transfer reaction, and the lesions in either subunit account for more than 80% of cases. The ratio of male to female patients was 6.6/1, the incidence was calculated to be about 1 out of 220,000 birth, and the life expectancy of the patients born in the 1970s was estimated to be 25-30 years old. For the X-linked gp91-phox deficiency, we found five missense and nine nonsense mutations, seven deletions, three insertions, and four splice site mutations, which included the following novel mutations: four missense, five nonsense, six deletions, one insertion, and two splice site abnormalities. With regard to p22-phox deficiency, two homozygous nonsense mutations and one homozygous deletion, a missense mutation together with a splice site mutation, and two different missense mutations were found. These mutations have not been reported before. Based on the present and reported data from Japan, we discuss the molecular defects of the disease and the difference in statistics between western countries and Japan.

Chronic granulomatous disease (CGD) is an inherited disorder of host defense against microbial infections caused by defective activity of the phagocyte NADPH oxidase. Based on an increase of neutrophil superoxide-generating ability in response to interferon ␥ (IFN-␥) in a single patient with CGD, multicentered group studies demonstrated a beneficial effect of prophylactic IFN-␥. However, no apparent increase of the phagocyte superoxide generation was found in patients enrolled in these studies. The present report offers an additional kindred in whom an IFN-␥-dependent increase in neutrophil superoxide production was observed in 3 affected patients. The defect in the CYBB gene for gp91-phox was identified as an otherwise silent mutation adjacent to the third intron of the CYBB gene that alters messenger RNA splicing. By molecular analysis, significant differences were found in the splicing pattern of CYBB gene transcripts in patient neutrophils between 1 and 25 days after administration of IFN-␥. IntroductionChronic granulomatous disease (CGD) is an inherited disorder of host defense against bacterial and fungal infections; affected patients suffer from severe recurrent and intractable infections beginning in early childhood. 1 Phagocytes from patients with CGD show impaired microbicidal activity due to defects in the superoxidegenerating phagocyte oxidase. 1 It is known that the mutations responsible for CGD reside within the genes for 4 essential components of the oxidase designated as gp91-phox (phagocyte oxidase), p22-phox, p47-phox and p67-phox. 2,3 The gp91-phox forms membrane cytochrome b 558 together with p22-phox and plays an essential role in the transfer of electrons following assembly of the active oxidase with the cytoplasmic p47-and p67-phox components. Patients with CGD with gp91-phox defects account for the majority of cases, and in most instances the cytochrome is reduced or absent in phagocytes and B lymphocytes. The CYBB gene that encodes gp91-phox is localized to Xp21.1 and encompasses 13 exons spanning approximately 30 kilobases (kb). Mutations in the CYBB gene are heterogenous, and include missense, nonsense, deletion, insertion, and splicing defects. 1,4,5 Various cytokines have been studied for enhancement of the neutrophil superoxide generation, showing that IFN-␥ may be an effective agent. 6,7 Ezekowitz and coworkers first demonstrated that phagocytes of a patient with X-linked CGD were responsive to interferon-␥ (IFN-␥), which almost completely corrected the oxidase defect in vitro and in vivo. 8,9 These findings motivated multicenter groups to perform double-blinded clinical studies of IFN-␥ as a prophylactic agent in CGD, which demonstrated its clinical benefit in the majority of patients with CGD. 10,11 In these group studies, however, no apparent increases in phagocyte superoxide generation were observed. The patient studied by Ezekowitz and colleagues, therefore, has been considered to be an exceptional case. Recently, the mutation in this patient has been identified as a single b...