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

Chronic granulomatous disease is an inherited disease characterized by the inability of phagocytes to generate normal amounts of superoxide, leaving p atients susceptible to opportunistic, life-threatening infections. In the m ajority of cases, cytochrome bas 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 ref erred to as "variant" forms. In three of these six variant patients, a roug hly proportional decrease in cytochrome b(558) expression and production of H2O2 were found. In two cases this phenotype could be well explained by sp ecial splice mutations, whereas in the third case it was caused by a missen se mutation, predicting Ser 193 --> Phe, In the other three variant patient s, cytochrome b(558) expression and H2O2 production were clearly disproport ionate as the generation of H2O2 was much more decreased than cytochrome ex pression, Missense mutations also were found in these cases. One of these m utations, predicting Leu 546 --> Pro and affecting the putative nicotinamid e adenine dinucleotide phosphate binding site, led to normal levels of cyto chrome b(558) expression and reduced H2O2 production. In the other two muta tions, predicting Pro 339 --> His and His 338 --> Tyr, the putative flavin adenine dinucleotide binding site was affected. This could explain the corr esponding uncommon phenotypes, characterized by zero or trace amounts of H2 O2 production and the expression of relatively high amounts of nonfunctiona l or low functional cytochrome b(558), respectively, The only missense muta tion found that prevented the expression of any cytochrome b(558) was cause d by a predicted His 222 --> Arg exchange in one of the three classic cases . The two other classic phenotypes were caused by splice mutations. (C) 199 9 International Society for Experimental Hematology. Published by Elsevier Science Inc.