Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22(phox)

Chronic granulomatous disease is a rare inherited disorder caused by nonexi stent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxi dase, involves at least 5 protein components. The absence of, or a defect i n, any 1 of 4 of these proteins (p22(phox), P47(phox), p67(phox), or gp91(p hox)) gives rise to the known types of chronic granulomatous disease. One o f the rarest forms of the disease is due to defects in the CYBA gene encodi ng p22(phox), which together with gp91(phox) forms flavocytochrome b(558), the catalytic core of NADPH oxidase, To date, only 9 kindreds with p22phox deficiency have been described in the literature comprising 10 mutant allel es, Four polymorphisms in the CYBA gene have also been reported. Here we de scribe 9 new, unrelated kindreds containing 12 mutations, 9 of which are no vel. In addition, we report 3 new polymorphisms. The novel mutations are (a ) deletion of exons 2 and 3, (6) a missense mutation in exon 3 (T155-->C), (c) a splice site mutation at the 5' end of intron 3, (d) a missense mutati on in exon 2 (G74-->T), (e) a nonsense mutation in exon 1 (G26-->A), (f) a missense mutation in exon 4 (C268-->T), (g) a frameshift in exon 3 due to t he insertion of C at C162, (h) a nonsense mutation in exon 2 (G107-->A), en d (i) a missense mutation in exon 2 (G70-->A). (C) 2000 by The American Soc iety of Hematology.