Chronic granulomatous disease. Molecular genetics.

Chronic granulomatous disease is an inherited disorder of microbial killing characterized by the failure of phagocytic cells to produce superoxide due to a lesion in a membrane-associated NADPH-oxidase. The components of the oxidase have been incompletely characterized and, therefore, a genetic approach has been used to identify the gene affected in the common X-linked form of CGD without reference to a specific protein product. The X-CGD gene was first mapped to Xp21.1. A phagocyte-specific RNA transcript derived from Xp21 was identified and shown to be deficient (or disrupted) in patients with X-CGD. Antisera directed toward the predicted protein product of the X-CGD gene have established its identity as a 90-kD membrane glycoprotein and a component of the phagocyte cytochrome b, recently purified as a heterodimer of a 90-kD species and a 22-kD polypeptide. The more recent genetic and biochemical findings now provide an explanation for the consistent absence of the phagocyte cytochrome b spectrum in X-CGD (now termed "X- -CGD"). Both subunits of the cytochrome b heterodimer are absent in X- -CGD, despite a genetic deficiency of only the larger polypeptide, which indicates that a complete understanding of cytochrome biosynthesis and function will require further characterization of the small subunit. We should anticipate that identification of other functionally associated proteins will aid in analysis of the phagocyte oxidase. Molecular reagents prepared from the cloned X-CGD cDNA or gene may prove to be clinically useful in prenatal diagnosis and may provide a basis for somatic gene therapy in the future.