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CYBB
cytochrome b-245 beta chain
CYBB encodes the beta chain of an enzyme complex essential for generating antimicrobial molecules in immune cells, with variants causing chronic granulomatous disease. The CYBB gene provides instructions for producing cytochrome b-245 beta chain, a core component of the NADPH oxidase enzyme found in immune cells.
CYBB is located on the short (p) arm of chromosome X, at band Xp21.1-p11.4. Arm ratio per GRCh38 - banding schematic.
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Overview
CYBB is located on the X chromosome and encodes a 570-amino-acid protein known as cytochrome b-245 beta chain, sometimes referred to as p91-phox or gp91-phox. Within the NADPH oxidase complex, this protein operates as a key catalytic element, working alongside other subunits to enable immune defence. The enzyme assembly functions predominantly in phagocytes - specialised immune cells that capture and eliminate pathogens through engulfment. Upon encountering bacteria or fungi, NADPH oxidase drives the production of superoxide from molecular oxygen, launching a sequence of highly reactive antimicrobial compounds. When CYBB function is disrupted, this oxidative burst mechanism fails, leaving affected individuals vulnerable to severe and persistent infections. The gene's position on the X chromosome means that variant inheritance follows an X-linked pattern, predominantly affecting males whilst females may be carriers.
What the gene does
The cytochrome b-245 beta chain serves as a catalytic subunit within the NADPH oxidase complex, partnering with an alpha chain encoded by the CYBA gene to form a functional heterodimer - both must be present for enzymatic activity. Upon detection of foreign invaders, dormant cytosolic components of NADPH oxidase translocate to the membrane and assemble with the cytochrome b-245 heterodimer, creating an active enzyme capable of electron transfer. This complex then reduces oxygen to superoxide anion, a reactive oxygen species that serves as the precursor for additional antimicrobial molecules including hydrogen peroxide and hypochlorous acid. These compounds exhibit potent microbicidal properties, enabling phagocytes to eliminate captured pathogens within specialised compartments. Beyond direct pathogen killing, NADPH oxidase-derived reactive oxygen species also participate in regulating neutrophil activity and modulating inflammatory responses, helping to balance pathogen clearance with tissue preservation during immune reactions.
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Chromosome location
CYBB resides on the short arm of the X chromosome at band Xp21.1-p11.4, a region spanning several megabases. The gene's position on the X chromosome dictates its sex-linked inheritance characteristics, meaning that males carry one copy whilst females carry two. This chromosomal location has been well characterised through genomic mapping studies, establishing CYBB as one of several immune-related genes in this region of the X chromosome.
Protein structure
The 570-amino-acid cytochrome b-245 beta chain contains two principal functional regions. The Ferric oxidoreductase domain extends from amino acids 54 to 286, facilitating electron transfer reactions essential for converting oxygen to superoxide. Downstream, the FAD-binding FR-type domain occupies positions 287 to 397, providing the binding site for flavin adenine dinucleotide, a cofactor critical for the enzyme's oxidoreductase activity. These domains work in concert to enable the protein's role in electron transport across the membrane during the oxidative burst response.
Key variants
More than 650 pathogenic variants have been documented in CYBB. The mutations span the coding sequence and include missense substitutions, nonsense changes, small insertions or deletions, and splice-site disruptions. Many variants impair either protein stability, cofactor binding, or electron transfer capacity, diminishing or abolishing NADPH oxidase activity. The spectrum of variants reflects the gene's extended coding region and the functional importance of both catalytic domains. Evidence indicates that alterations in CYBB account for a substantial proportion of chronic granulomatous disease cases.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1010G>A | p.Trp337Ter | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.1038del | p.Glu347fs | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.1082G>A | p.Trp361Ter | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.1151+2T>C | - | Pathogenic | ★★☆☆ | Chronic granulomatous disease |
c.1315-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.1498G>T | p.Asp500Tyr | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.1629_1630delinsCT | p.Glu544Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.1A>G | p.Met1Val | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.483+1G>A | - | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, X-linked |
c.720_724del | p.Ile241fs | Pathogenic | ★★☆☆ | CYBB-related disorders |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in CYBB are principally associated with chronic granulomatous disease, a primary immunodeficiency characterised by recurrent bacterial and fungal infections alongside episodes of abnormal inflammation. The X-linked form of chronic granulomatous disease arises from CYBB variants and represents the most common genetic subtype of this disorder. Affected individuals experience infections of the lungs, skin, lymph nodes, and liver, often caused by catalase-positive organisms that phagocytes cannot adequately clear. Inflammatory complications such as granuloma formation can also occur in various tissues. Autosomal recessive forms of chronic granulomatous disease result from variants in other NADPH oxidase subunit genes.
- Chronic granulomatous disease
- Chronic granulomatous disease (X-linked) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic CYBB variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CYBB appears on multiple NHS Genomic Medicine Service gene panels reflecting its clinical importance in immune function and infectious disease susceptibility. The gene holds green classification on the COVID-19 research panel, Fetal anomalies panel (version R21), Gastrointestinal epithelial barrier disorders panel, Infantile enterocolitis and monogenic inflammatory bowel disease panel, and Primary immunodeficiency or monogenic inflammatory bowel disease panel (version R15). These memberships indicate that CYBB testing may be considered in the NHS when clinical presentations align with recurrent infections, bowel inflammation, or immunodeficiency phenotypes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is CYBB inherited?
CYBB follows an X-linked recessive inheritance pattern. Males who inherit a pathogenic variant typically develop chronic granulomatous disease, whilst females carrying one altered copy are usually healthy but may experience mild immune-related symptoms in some cases.
What infections are most common in CYBB-related chronic granulomatous disease?
Individuals with CYBB variants are particularly susceptible to infections caused by catalase-positive bacteria and fungi, including Staphylococcus aureus, Burkholderia cepacia complex, Serratia, Nocardia, and Aspergillus species. These organisms can cause pneumonia, abscesses, and invasive infections that recur despite treatment.
Can carrier screening detect CYBB variants?
Carrier screening panels can identify females carrying pathogenic CYBB variants, which is relevant for family planning since male offspring have a 50 per cent chance of inheriting the variant and developing chronic granulomatous disease. Genetic counselling supports interpretation of results and reproductive options.
References
- Roos D, Kuhns DB, Maddalena A. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood cells, molecules & diseases. 2010. PMID: 20729109
- Stasia MJ, Li XJ. Genetics and immunopathology of chronic granulomatous disease. Seminars in immunopathology. 2008. PMID: 18509647
- Sumimoto H. Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. The FEBS journal. 2008. PMID: 18513324
- Kannengiesser C, Gérard B, El Benna J. Molecular epidemiology of chronic granulomatous disease in a series of 80 kindreds: identification of 31 novel mutations. Human mutation. 2008. PMID: 18546332