title: Recombination events between the p47-phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease.
abstract: 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 degrees ) patients, a GT deletion (triangle upGT) 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 degrees 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 triangle upGT 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 triangle upGT into the p47-phox gene, thereby leading to the high frequency of GT deletion in A47 degrees CGD patients. (Blood. 2000;95:2150-2156)
authors.affiliation: Department of Immunology, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: J
authors.initials: J
authors.lastname: Roesler
authors.forename: J T
authors.initials: JT
authors.lastname: Curnutte
authors.forename: J
authors.initials: J
authors.lastname: Rae
authors.forename: D
authors.initials: D
authors.lastname: Barrett
authors.forename: P
authors.initials: P
authors.lastname: Patino
authors.forename: S J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: A
authors.initials: A
authors.lastname: Goerlach
mesh_terms: D001483:Base Sequence; D005091:Exons; D017353:Gene Deletion; D005808:Genes, Recessive; D006105:Granulomatous Disease, Chronic / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D019255:NADPH Oxidases; D010750:Phosphoproteins / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011544:Pseudogenes / Q000235:genetics*; D011995:Recombination, Genetic; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
chemical_list: D010750:Phosphoproteins; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1