The molecular basis of chronic granulomatous disease.
CGD is a rare inherited immunodeficiency syndrome, caused by the phagocytes' inability to produce (sufficient) reactive oxygen metabolites. This dysfunction is due to a defect in the NADPH oxidase, the enzyme responsible for the production of superoxide. It is composed of several subunits, two of which, gp91phox and p22phox, form the membrane-bound cytochrome b558, while its three cytosolic components, p47phox, p67phox and p40phox, have to translocate to the membrane upon activation. This is a tightly and intricately controlled process that involves, among others, several low-molecular weight GTP-binding proteins. Gp91phox is encoded on the X-chromosome and p22phox, p47phox and p67phox on different autosomal chromosomes, and a defect in one of these components leads to CGD. This explains the variable mode of inheritance seen in this syndrome. Clinically CGD manifests itself typically already at a very young age with recurrent and serious infections, most often caused by catalase-positive pathogens. Modern treatment options, including prophylaxis with trimethoprim-sulfamethoxazole and rIFN-gamma as well as early and aggressive anti-infection therapy, have improved the prognosis of this disease dramatically. CGD, as a very well-characterized inherited affection of the hematopoietic stem cells, is predestined to be among the first diseases to profit from the advances in cutting-edge therapeutics, such as gene therapy and in utero stem cell transplantation.
Meischl
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Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands.
Roos
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D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D006579:Heterozygote; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009252:NADPH Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000737:chemistry / Q000378:metabolism; D010586:Phagocytes / Q000201:enzymology / Q000276:immunology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011296:Prenatal Diagnosis; D011994:Recombinant Proteins
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1; D009252:NADPH Dehydrogenase