Autosomal recessive chronic granulomatous disease caused by defects in NCF-1, the gene encoding the phagocyte p47-phox:: mutations not arising in the NCF-1 pseudogenes

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any one of 4 genes encoding phagocyte NADPH oxidase subunits, Unlike other CGD subtypes, in which there is great heterogeneity among mutations, 97% of affected alleles in patients previously reported with A47(0) CGD carry a single mutation, a GT deletion (Delta GT) in exon 2 of the p47-phox gene, NCF-1, This unusually high incidence results from recombination events between NCF-1 and its highly homologous pseudogenes, in which Delta GT originates. In 50 consecutive patients with A47(0) CGD, 4 were identified who were heterozygous for Delta GT in NCF-1, and for the first time, 2 were identified whose DNA appeared normal at this position. To avoid co-amplification of pseudogene sequence and to enable the identification of mutations in these patients, allele-specific polymerase chain reaction was used to amplify alleles not containing Delta GT. In each of the 4 patients who were hoterozygous for Delta GT, an additional novel mutation was identified, These were 2 missense mutations, G125 --> A in exon 2 (predicting Arg42 --> Gin) and G784 --> A in A47(0) CGD, 4 were identified who were heterozygous for Delta GT in NCF-1, and for the first time, 2 were identified whose DNA appeared normal at this position. To avoid co-amplification of pseudogene sequence and to enable the identification of mutations in these patients, allele-specific polymerase chain reaction was used to amplify alleles not containing Delta GT. In each of the 4 patients who were hoterozygous for Delta GT, an additional novel mutation was identified, These were 2 missense mutations, G125 --> A in exon 2 (predicting Arg42 --> Gln) and G784 - A in exon 8 (Gly262 --> Ser), and 2 splice junction mutations at the 5' end of intron 1, gt at and gtg --> gtt, The first of 2 patients who appeared normal at the GT position was a compound heterozygote with the G125 --> A transition on one allele and a deletion of G811 on the other. In the second of these patients, only a single defect was detected, G574 --> A, which predicts Gly192 --> Ser but is likely to result in defective splicing because it represents the final nucleotide of exon 6, (C) 2001 by The American Society of Hematology.