CYBB – X-linked Chronic Granulomatous Disease

X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency characterized by defective NADPH oxidase activity in phagocytes, resulting in recurrent bacterial and fungal infections. The CYBB gene (gp91-phox) encodes the catalytic subunit of the oxidase complex; pathogenic CYBB variants abolish or severely impair superoxide production, confirming its causal role in X-CGD.

Genetic studies demonstrate an X-linked recessive inheritance with over 50 unrelated male probands carrying diverse CYBB variants: 6 probands (missense, nonsense) [PMID:1710153], 17 probands (various loss-of-function) [PMID:16569599], 3 variant patients [PMID:7579466], and 24 patients across 24 families [PMID:22562447]. Segregation of pathogenic alleles has been confirmed in maternal carriers across at least 13 families, with heterozygous mothers showing characteristic bimodal neutrophil respiratory burst patterns [PMID:7907031; PMID:9667376].

The variant spectrum includes missense (e.g., c.170C>A (p.Ala57Glu)), nonsense, frameshift, splice-site, and promoter mutations, uniformly leading to absent or nonfunctional gp91-phox protein. Segregation analysis in multiple kindreds further supports X-linked transmission and complete penetrance in affected males [PMID:7756659].

Functional assays in patient neutrophils consistently show absent or markedly reduced superoxide generation. Complementation of CYBB-null PLB-985 cells with wild-type CYBB restores respiratory burst, whereas expression of mutant constructs fails to rescue activity, underscoring a loss-of-function mechanism ([PMID:8234321]; [PMID:7579466]).

Clinically, X-CGD manifests with severe infections, including cholecystitis (HP:0001082) in adults [PMID:29942748] and respiratory failure (HP:0002878) in pediatric cases [PMID:35057749], highlighting the need for early genetic diagnosis.

Integration of extensive genetic and functional data categorizes CYBB–X-CGD as a definitive gene–disease association with clear diagnostic, therapeutic, and genetic counseling implications. Key Take-home: identification of CYBB mutations provides definitive diagnosis of X-CGD, informs carrier testing, and guides potential gene-based therapies.

References

• Blood • 1991 • Point mutations in the beta-subunit of cytochrome b558 leading to X-linked chronic granulomatous disease. PMID:1710153
• Experimental hematology • 2006 • Characterization of 17 new cases of X-linked chronic granulomatous disease with seven novel mutations in the CYBB gene. PMID:16569599
• Blood • 1995 • Molecular analysis in three cases of X91- variant chronic granulomatous disease. PMID:7579466
• Journal of clinical immunology • 2012 • Clinical, functional and genetic analysis of twenty-four patients with chronic granulomatous disease - identification of eight novel mutations in CYBB and NCF2 genes. PMID:22562447
• Pediatric research • 1998 • Genetic analysis of 13 families with X-linked chronic granulomatous disease reveals a low proportion of sporadic patients and a high proportion of sporadic carriers. PMID:9667376
• European journal of haematology • 1994 • Molecular genetic studies of two families with X-linked chronic granulomatous disease: mutation analysis and definitive determination of carrier status in patients' sisters. PMID:7907031
• Proceedings of the National Academy of Sciences of the United States of America • 1993 • Gene targeting of X chromosome-linked chronic granulomatous disease locus in a human myeloid leukemia cell line and rescue by expression of recombinant gp91phox. PMID:8234321
• IDCases • 2018 • Salmonella Enteritidis cholecystitis with chronic granulomatous disease. PMID:29942748
• BMC infectious diseases • 2022 • Overlapping infection of Nocardia farcinica and Aspergillus fumigatus in a child with X-linked chronic granulomatous disease: a case report. PMID:35057749

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