CYBA – Autosomal Recessive Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a congenital immunodeficiency in which phagocytes fail to generate superoxide due to defects in the NADPH oxidase complex. The CYBA gene encodes p22-phox, a critical membrane subunit that forms the flavocytochrome b(558) heterodimer with gp91-phox. Mutations in CYBA underlie a rare autosomal recessive (AR) form of CGD, often termed A22(0), accounting for approximately 5% of CGD cases.

AR-CGD due to CYBA exhibits autosomal recessive inheritance with affected individuals harboring homozygous or compound heterozygous variants. Initial gene structure analysis and mutation screening in three unrelated AR-CGD patients identified CYBA mutations in all (n=3 probands) (PMID:2243141). A subsequent survey described nine new kindreds with p22-phox deficiency, confirming CYBA as the disease locus (9 families) (PMID:10910929). Segregation of mutant alleles in consanguineous pedigrees and absence of p22-phox expression in patient neutrophils support AR transmission.

The CYBA variant spectrum includes missense, nonsense, frameshift, splice-site and large deletion alleles. A prototypical AR-CGD case harbors c.467C>A (p.Pro156Gln), resulting in a nonfunctional p22-phox and absent oxidase activity in vitro (PMID:1763037). Other reported alleles include c.557A>T (p.Asn186Ile), c.166dup (p.Arg56fs) and intronic deletions affecting splicing, illustrating diverse mechanisms of gene disruption.

Functional assays demonstrate that CYBA mutations lead to destabilized p22-phox, failure to assemble the cytochrome b(558) heterodimer, and absence of the superoxide-generating NADPH oxidase activity in cell-free and cellular systems. Reconstitution experiments confirm that wild-type p22-phox restores oxidase function, whereas mutant proteins are rapidly degraded or unable to bind gp91-phox.

Clinically, AR-CYBA CGD presents in infancy with recurrent bacterial and fungal infections, notably pneumonia, perianal abscesses, osteomyelitis (HP:0002754), and enterocolitis. Standard immunological assays including dihydrorhodamine flow cytometry and cytochrome c reduction reveal absent or severely reduced respiratory burst, guiding molecular diagnostics and family screening.

Together, genetic and functional data establish a definitive association between CYBA and Chronic Granulomatous Disease. Early molecular diagnosis enables targeted therapy, including antimicrobial prophylaxis and consideration of hematopoietic stem cell transplantation. Key take-home: CYBA mutations cause AR-CGD via loss of p22-phox stability and oxidase assembly, with clear diagnostic and therapeutic implications.

References

• The Journal of Clinical Investigation • 1990 • Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. PMID:2243141
• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Point mutation in the cytoplasmic domain of the neutrophil p22-phox cytochrome b subunit is associated with a nonfunctional NADPH oxidase and chronic granulomatous disease. PMID:1763037
• Blood • 2000 • Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22(phox). PMID:10910929

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