Autosomal recessive chronic granulomatous disease caused by novel mutations in NCF-2, the gene encoding the p67-phox component of phagocyte NADPH oxidase

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency di sease that leads to severe recurrent infections. CGD is caused by defects i n the phagocyte NADPH oxidase, a multiprotein enzyme that reduces oxygen to superoxide, a precursor of microbicidal oxidants. Less than 6% of CGD pati ents have an autosomal recessive form of the disease caused by mutations in NCF-2. This gene encodes p67-phox-, a cytosolic oxidase subunit that assoc iates with membrane-bound flavocytochrome b(558) and regulates electron tra nsfer We studied six patients from five families with p67-phox deficiency a nd identified seven different mutant alleles. Patients from three of the ki ndreds were homozygous for their respective mutation, although the parents of only one family were known to be related. Five of the mutations have not previously been identified: (1) a missense mutation (383C-->T) in exon 5, (2) a nonsense mutation (196C-->T) in exon 3, (3) a missense mutation (230G -->A) in exon 3, (4) a nonsense mutation (298C-->T) in exon 4, and (5) a di nucleotide deletion (835-836 AC) from exon 9. Phagocytes from each of the p atients analyzed failed to generate a measurable respiratory burst and had no detectable p67-phox protein. Our results further demonstrate that there is great heterogeneity among the mutations in p67-phox-deficient CGD patien ts, with no evidence for mutational hot-spots or a founder effect. Our data also support the hypothesis that the stability of p67-phox is particularly sensitive to missense mutations that cause amino acid substitutions within its N-terminal domain. In contrast, mutations predicting single amino acid changes elsewhere in the protein generally represent benign polymorphisms.