Genetic studies of three Japanese patients with p22-phox-deficient chronicgranulomatous disease: detection of a possible common mutant CYBA allele in Japan and a genotype-phenotype correlation in these patients

Chronic granulomatous disease (CGD) is a disorder caused by defects in the NADPH oxidase responsible for superoxide generation in phagocytes. Cytochro me b558, an essential component of this enzyme, is a heterodimer formed by a 91 kDa glycoprotein (gp91-phox) and a 22 kDa polypeptide (p22-phox). Muta tions in the p22-phox gene (CYBA) locus in 16q24 result in one of the rare autosomal recessive forms of CGD. We performed mutation analysis in three f emale CGD patients suspected of having this form of the disease and found t wo novel mutations in CYBA. Whereas patient 1 with severe phenotype had a h omozygous nonsense mutation in exon 1 (C-35 --> T, Gln-3 --> stop), patient s 2 and 3 with mild phenotype shared the same homozygous missense mutation in exon 2 (G-98 --> A, Gly-24 --> Arg). None of the parents of patients 2 a nd 3 is related. Therefore, this mutation could be a hot-spot or a common m utation in the Japanese population. Patients 2 and 3, but not patient 1, we re demonstrated to have detectable p22-phox expression and significant gran ulocyte respiratory burst (ROB) activity. In this study, we were able to de monstrate an excellent correlation between genotype, p22-phox expression, R OB activity and clinical phenotype in these patients.