Genetic Variants of Chronic Granulomatous Disease: Prevalence of Deficiencies of Two Cytosolic Components of the NADPH Oxidase System

Robert A. Clark, Harry L. Malech, John Gallin, Hiroyuki Nunoi, Bryan D. Volpp, Doran W. Pearson, William M. Nauseef, John T. Curnutte

Research output: Contribution to journalArticlepeer-review

212 Scopus citations


Chronic granulomatous disease, a syndrome of recurrent infections and failure of oxidative microbicidal activity in phagocytes, results from defects in the gene for one of several components of an oxidase system that can undergo activation. To determine the relative prevalence of certain of the genetic variants of this disorder, we used immunoblotting to detect two specific neutrophil cytosolic proteins of 47 and 67 kd recently shown to be required for oxidase activation. Chronic granulomatous disease is usually an X-linked disorder associated with the absence of membrane cytochrome b558. Of our 94 patients with chronic granulomatous disease, however, 36 had a phenotype characterized by autosomal inheritance, normal membrane oxidase components (including cytochrome b558),and functionally defective cytosolic activity in a cell-free oxidase system. We studied 25 of these 36 patients and found that 22 lacked the 47-kd cytosolic protein, and the remaining 3 were missing the 67-kd component. Patients with chronic granulomatous disease whose functional defect was localized to the neutrophil membrane (classic X-linked cytochrome b–negative type and two other rare variants) had normal amounts of both cytosolic components. We estimate that approximately 33 percent of all patients with chronic granulomatous disease are missing the 47-kd cytosolic oxidase component and about 5 percent of patients are missing the 67-kd component. Chronic granulomatous disease caused by a defect in any cytosolic factors other than the 47-kd and 67-kd proteins, if it exists, is apparently rare. (N Engl J Med 1989; 321:647–52.), THE polymorphonuclear leukocyte (neutrophil) is a critical element in the host response to bacterial and fungal infections. Its microbicidal activity depends to a large extent on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which can be activated and which generates Superoxide anion and other highly reactive forms of reduced oxygen.1 2 3 4 5 Patients with chronic granulomatous disease have recurrent severe infections because of a defective NADPH oxidase system that fails to generate Superoxide. It has become apparent that the oxidase consists of several components and that the phenotype of chronic granulomatous disease can result from different genetic lesions affecting one or another of….

Original languageEnglish (US)
Pages (from-to)647-652
Number of pages6
JournalNew England Journal of Medicine
Issue number10
StatePublished - Sep 7 1989
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


Dive into the research topics of 'Genetic Variants of Chronic Granulomatous Disease: Prevalence of Deficiencies of Two Cytosolic Components of the NADPH Oxidase System'. Together they form a unique fingerprint.

Cite this