Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2150-2156
Recombination events between the p47-phox
gene and its highly homologous pseudogenes are the main cause of
autosomal recessive chronic granulomatous disease
Joachim Roesler,
John T. Curnutte,
Julie Rae,
David Barrett,
Pablo Patino,
Stephen J. Chanock, and
Agnes Goerlach
From the Department of Immunology, Genentech Inc, South San
Francisco, CA; The Scripps Research Institute, Department of
Molecular and Experimental Medicine, La Jolla, CA; the Pediatric
Oncology Branch, National Cancer Institute, National Institutes of
Health, Bethesda, MD; and the University of Antioquia School of
Medicine, Medellin, Colombia, South America.
Chronic granulomatous disease (CGD) is an inherited disease caused
by defects in the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of phagocytes. Genetic lesions
in any of 4 components of this antimicrobial enzyme have been detected.
Family-specific mutations are found in 3 of 4 forms of CGD due to
deficiencies of the gp91-phox, p22-phox, and
p67-phox genes. In p47-phox-deficient CGD (autosomal
recessive form A47°) patients, a GT deletion (
GT) at the
beginning of exon 2 of the p47-phox gene has been reported in
19 of 20 alleles. This GT deletion is also characteristic for the
recently identified p47-phox pseudogenes. To explore a possible
link between these findings, a sequence analysis of 28 unrelated,
racially diverse A47° CGD patients and 37 healthy individuals was
performed. The GT deletion in exon 2 was present on all alleles in 25 patients. Only 3 patients but all healthy individuals contained the
GTGT and GT sequences. A total of 22 patients carried additional
pseudogene-specific intronic sequences on all alleles, either only in
intron 1 or in intron 1 and intron 2, which lead to different types of
chimeric DNA strands. It is concluded that recombination events between the p47-phox gene and its highly homologous pseudogenes result in the incorporation of GT into the p47-phox gene, thereby
leading to the high frequency of GT deletion in A47° CGD patients.
