Uncommon missense and splice mutations and resulting biochemical phenotypes in German patients with X-linked chronic...

Chronic granulomatous disease is an inherited disease characterized by the inability of phagocytes to generate normal amounts of superoxide, leaving patients susceptible to opportunistic, life-threatening infections. In the majority of cases, cytochrome b558 is absent in the X-chromosomal form of CGD. However, the neutrophils from six of nine X-linked CGD patients, reported here, expressed normal or decreased amounts of this cytochrome and are referred to as "variant" forms. In three of these six variant patients, a roughly proportional decrease in cytochrome b558 expression and production of H2O2 were found. In two cases this phenotype could be well explained by special splice mutations, whereas in the third case it was caused by a missense mutation, predicting Ser 193-->Phe. In the other three variant patients, cytochrome b558 expression and H2O2 production were clearly disproportionate as the generation of H2O2 was much more decreased than cytochrome expression. Missense mutations also were found in these cases. One of these mutations, predicting Leu 546-->Pro and affecting the putative nicotinamide adenine dinucleotide phosphate binding site, led to normal levels of cytochrome b558 expression and reduced H2O2 production. In the other two mutations, predicting Pro 339-->His and His 338-->Tyr, the putative flavin adenine dinucleotide binding site was affected. This could explain the corresponding uncommon phenotypes, characterized by zero or trace amounts of H2O2 production and the expression of relatively high amounts of nonfunctional or low functional cytochrome b558, respectively. The only missense mutation found that prevented the expression of any cytochrome b558 was caused by a predicted His 222-->Arg exchange in one of the three classic cases. The two other classic phenotypes were caused by splice mutations.