Molecular basis of the autosomal recessive forms of chronic granulomatous disease

Abstract

Chronic granulomatous disease (CGD) is an inherited group of disorders in which phagocytic leukocytes (neutrophils, eosinophils, monocytes, and macrophages) fail to undergo a respiratory burst when stimulated. The products of the respiratory burst, which include superoxide and hypochlorous acid, play a critical role in killing pathogenic bacteria, fungi, and parasites. As a result of the failure to activate the respiratory burst in their phagocytes, most CGD patients suffer from severe recurrent infections. While all CGD patients share this severe defect, there is substantial heterogeneity in the molecular mechanisms responsible. The enzyme that catalyzes the respiratory burst, NADPH oxidase, has been extensively characterized and found to consist of at least four subunits: gp91-phox and p22-phox (the two subunits of a low potential cytochrome b that is the terminal electron carrier of the oxidase) as well as p47-phox and p67-phox (two cytosolic oxidase components). CGD is caused by a defect in any one of these four components, thus explaining the previously confusing genetic heterogeneity of this disorder. In approximately thirty reported cases, the underlying mutations involving these oxidase components have been identified. The current understanding of the molecular basis of CGD is reviewed in the context of a recently completed Phase III clinical trial establishing the efficacy of recombinant human interferon gamma in the treatment of CGD.