Absence of both the 91kD and 22kD subunits of human neutrophil cytochrome b in two genetic forms of chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a group of inherited disorders in which phagocytic cells fail to generate antimicrobial oxidants. The various forms of CGD can be classified in terms of the mode of inheritance (either X-linked or autosomal recessive), and whether the neutrophils display the absorbance spectrum of a unique b-type cytochrome important for the function of the respiratory burst oxidase. The finding that purified neutrophil cytochrome b is a heterodimer consisting of a 91kD glycosylated and a 22kD nonglycosylated polypeptide has raised the question of which subunits are absent (or defective) in the various types of CGD. To address this question we have studied the expression of the cytochrome b subunits in three genetically distinct forms of CGD: X-linked/cytochrome b-negative (X-), autosomal recessive/cytochrome b-negative (A-), and autosomal recessive/cytochrome b-positive (A+). Using polyclonal antibodies to each of the two subunits, we prepared Western blots of lysates of intact neutrophils from ten CGD patients. In the controls and three patients with A+ CGD, both cytochrome subunits were easily detected. Consistent with the previously reported finding in five X- patients, neither subunit could be identified in neutrophils from three additional X- patients. Both subunits were also undetectable in four patients with A- CGD (three females, one male). This latter group of patients most likely bears a normal 91kD gene, since the patients are genetically distinct from the 91kD-defective X- group. The mutation in A- CGD, therefore, probably involves the 22kD gene and the eventual expression of the 22kD subunit. Furthermore, the expression of the 91kD subunit in this group of patients appears to be prevented due to the 22kD mutation in a manner converse to that seen in the X- CGD patients. Based on these studies, we hypothesize that the stable of expression of either of the two cytochrome subunits is dependent upon the other.
Parkos
C A
CA
Department of Immunology, Research Institute of Scripps Clinic, La Jolla, CA 92037.
Dinauer
M C
MC
Jesaitis
A J
AJ
Orkin
S H
SH
Curnutte
J T
JT
D015153:Blotting, Western; D003573:Cytochrome b Group / Q000172:deficiency* / Q000276:immunology; D006105:Granulomatous Disease, Chronic / Q000235:genetics*; D006801:Humans; D046911:Macromolecular Substances; D008970:Molecular Weight; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics; D019255:NADPH Oxidases; D009504:Neutrophils / Q000201:enzymology*; D014960:X Chromosome
D003573:Cytochrome b Group; D046911:Macromolecular Substances; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases