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Blood, 1 January 2001, Vol. 97, No. 1, pp. 305-311
PHAGOCYTES
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
Deborah Noack,
Julie Rae,
Andrew R. Cross,
Beverly A. Ellis,
Peter E. Newburger,
John T. Curnutte, and
Paul G. Heyworth
From the Department of Molecular and Experimental
Medicine, The Scripps Research Institute, La Jolla, CA; the Department
of Immunology, Genentech, San Francisco, CA; and the Departments of
Pediatrics and Molecular Genetics/Microbiology, University of
Massachusetts Medical School, Worcester, MA.
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 A470 CGD
carry a single mutation, a GT deletion ( 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 GT originates. In 50 consecutive patients with A470 CGD, 4 were identified who
were heterozygous for 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
GT. In each of the 4 patients who were heterozygous for 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.
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