Defects in gp91-phox, the large subunit of cytochrome b(558) (b(-245))
give rise to X-linked chronic granulomatous disease (CGD), a rare inh
erited condition characterized by an extreme susceptibility to bacteri
al and fungal infection. In the majority of cases, the phagocytes are
unable to generate any superoxide owing to complete absence of the fla
vocytochrome. However, a small minority of these patients do have some
phagocytic oxidase activity. We describe here an analysis of the mole
cular basis of the disease in three such variant patients with lesions
in the gene coding for gp91-phox on the X chromosome. Three different
genetic lesions were found, resulting in the substitution of tyrosine
for cysteine 244, a deletion of one of three lysines 313 through 315,
and the deletion of the six C-terminal amino acids, respectively. The
functional consequences of these defects on oxidase activity was a re
duction to 12%, 3.6%, and 2.1% of the normal levels, respectively. Cor
responding levels of gp91-phox were 20%, 8%, and 16% of normal classif
ying these patients as X91(-). Microbicidal assays showed that killing
of Staphylococcus aureus was grossly impaired in cells in which there
was 12% normal activity. This implies that if gene therapy is to be a
pplied, it must restore oxidase activity to a much higher level than t
hat present in the cells of this patient. The sites of two of the muta
tions were analyzed on a model of the C-terminal half of the gp91-phox
, based on the crystal structure of the homologous protein ferrodoxin
NADP reductase. Possible structural consequences of the mutations were
examined. (C) 1995 by The American Society of Hematology.