Somatic triple mosaicism in a carrier of X-linked chronic granulomatous disease.
The X-linked form of chronic granulomatous disease (CGD) is caused by mutations in the CYBB gene, which encodes the 91-kD subunit of the flavocytochrome b558, a component of the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytic leukocytes. Mutations in this gene are very heterogeneous and often unique for one family. Here we report on a family with two patients (brothers), one with a 3-kb deletion comprising exon 5 and the other with a 3.5-kb deletion comprising exons 6 and 7 of the CYBB gene. Sequence analysis of polymerase chain reaction (PCR)-amplified genomic DNA proved these deletions to be overlapping for 35 bp. Analysis by restriction fragment length polymorphism of genomic DNA from the mother's leukocytes showed her to be a carrier of both deletions in addition to the normal CYBB sequence. This triple somatic mosaicism was confirmed with PCR-amplified genomic and complementary DNA. The presence of the normal CYBB gene in the mother was also proven by the finding of normal superoxide-generating neutrophils in addition to cells lacking this ability. Triple X syndrome was excluded. These findings suggest that the mutations are the result of an event in early embryogenesis of the mother, possibly involving a mechanism like sister chromatid exchange.
de Boer
M
M
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, and Laboratory for Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Bakker
E
E
Van Lierde
S
S
Roos
D
D
D000293:Adolescent; D000328:Adult; D003573:Cytochrome b Group / Q000172:deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009030:Mosaicism / Q000235:genetics*; D019255:NADPH Oxidases; D009504:Neutrophils / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012854:Sister Chromatid Exchange; D013481:Superoxides / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics*
D003573:Cytochrome b Group; D013481:Superoxides; C036888:cytochrome b558; D019255:NADPH Oxidases