–deficient Chronic Granulomatous Disease

The predominant genetic defect causing p47phox –deficient chronic granulomatous disease (A47 8 CGD) is a GT deletion ( D GT) at the beginning of exon 2. No explanation exists to account for the high incidence of this single mutation causing a rare disease in an unrelated, racially diverse population. In each of 34 consecutive unrelated normal individuals, both the normal and mutant D GT sequences were present in genomic DNA, suggesting that a p47phox related sequence carrying D GT exists in the normal population. Screening of genomic bacteriophage and YAC libraries identified 13 p47phox bacteriophage and 19 YAC clones. The GT deletion was found in 11 bacteriophage and 15 YAC clones. Only 5 exonic and 33 intronic differences distinguished all D GT clones from all wild-type clones. The most striking differences were a 30-bp deletion in intron 1 and a 20-bp duplication in intron 2. These results provide good evidence for the existence of at least one highly homologous p47phox pseudogene containing the D GT mutation. The p47phox gene and pseudogene(s) colocalize to chromosome 7q11.23. This close linkage, together with the presence within each gene of multiple recombination hot spots, suggests that the predominance of the D GT mutation in A47 8 CGD is caused by recombination events between the wildtype gene and the pseudogene(s). ( J. Clin. Invest. 1997. 100: 1907–1918.)