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CYBA
cytochrome b-245 alpha chain
The CYBA gene provides instructions for a protein vital to the immune system's ability to fight off infections, particularly through the NADPH oxidase enzyme complex. The CYBA gene encodes the cytochrome b-245 alpha chain, also known as p22-phox, a subunit of the NADPH oxidase enzyme.
CYBA is located on the long (q) arm of chromosome 16, at band 16q24.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The CYBA gene is responsible for producing the cytochrome b-245 alpha chain protein, often referred to as p22-phox. This protein plays a fundamental role within the immune system as a component of the NADPH oxidase enzyme complex. The NADPH oxidase enzyme is primarily active in phagocytes, which are specialised immune cells that engulf and destroy harmful microorganisms such as bacteria and fungi.
Effective functioning of the NADPH oxidase complex is critical for mounting a robust immune response against pathogens. When this process is compromised, individuals may experience an increased susceptibility to severe and recurrent infections.
What the gene does
The protein encoded by the CYBA gene, the cytochrome b-245 alpha chain, is an integral part of the NADPH oxidase enzyme complex. This enzyme system is primarily found in phagocytes, a type of immune cell, where it is crucial for host defence. Within the NADPH oxidase complex, the cytochrome b-245 alpha chain partners with a beta chain, encoded by the CYBB gene, and both are necessary for the enzyme's activity.
Upon encountering foreign invaders, phagocytes are stimulated, leading to the assembly and activation of NADPH oxidase. This enzyme facilitates a chemical reaction that converts oxygen into superoxide, a reactive oxygen species. Superoxide is then further processed to generate other potent antimicrobial compounds, including hydrogen peroxide and hypochlorous acid. These highly reactive substances are used by phagocytes to eliminate pathogens, preventing their proliferation and subsequent illness.
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Chromosome location
The CYBA gene is situated on chromosome 16 at position 16q24.2. This specific genomic location provides the instructions for synthesising the cytochrome b-245 alpha chain protein. The gene's location is consistent across individuals and is a fixed point within the human genome.
Protein structure
The protein produced from the CYBA gene consists of 195 amino acids. One notable feature of its structure is a Disordered region, spanning amino acids 134-195. This region indicates a segment of the protein that lacks a stable three-dimensional structure under physiological conditions, which can be important for protein interactions or flexibility.
Key variants
Genetic variations within the CYBA gene can impact the structure and function of the cytochrome b-245 alpha chain protein. These changes may disrupt the normal activity of the NADPH oxidase enzyme complex, potentially leading to impaired immune responses. Such variants are typically categorised based on their predicted effect on protein function, ranging from benign to pathogenic.
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.108G>A | p.Trp36Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chronic granulomatous disease |
c.18G>A | p.Trp6Ter | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative |
c.196G>T | p.Glu66Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative |
c.1A>G | p.Met1Val | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative |
c.267del | p.Arg90fs | Pathogenic/Likely pathogenic | ★★☆☆ | Chronic granulomatous disease |
c.287+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative |
c.288-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Chronic granulomatous disease |
c.295_301del | p.Val99fs | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative |
c.467dup | p.Pro157fs | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative |
c.58+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Chronic granulomatous disease |
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
Variants in the CYBA gene are associated with inherited conditions that primarily affect the immune system. One notable condition linked to CYBA variants is chronic granulomatous disease. This condition is characterised by a weakened immune system, leading to an increased risk of developing severe, recurrent infections and inflammatory complications. Most cases of this condition stem from other genetic causes, with CYBA variants accounting for a smaller proportion.
Inheritance pattern
Conditions caused by pathogenic CYBA 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
The CYBA gene is recognised within the UK's National Genomic Test Directory, indicating its relevance for diagnostic testing in specific clinical contexts. It is included in several green-lighted PanelApp panels, signifying strong evidence for its association with certain conditions. These panels include 'COVID-19 research', 'Gastrointestinal epithelial barrier disorders', 'Infantile enterocolitis & monogenic inflammatory bowel disease', and 'Primary immunodeficiency or monogenic inflammatory bowel disease (R15)'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the CYBA gene?
The CYBA gene produces the cytochrome b-245 alpha chain, a crucial component of the NADPH oxidase enzyme complex. This enzyme is essential for immune cells, particularly phagocytes, to generate reactive oxygen species that destroy invading pathogens.
How do variants in the CYBA gene affect health?
Variants in the CYBA gene can impair the function of the NADPH oxidase enzyme, leading to a compromised immune system. This can result in conditions such as chronic granulomatous disease, characterised by an increased susceptibility to severe and recurrent infections.
Is CYBA associated with any specific genetic conditions?
Yes, pathogenic variants in the CYBA gene are known to cause a form of chronic granulomatous disease. This condition affects the immune system's ability to effectively combat certain bacterial and fungal infections.
References
- Roos D, Kuhns DB, Maddalena A. Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). Blood cells, molecules & diseases. 2010. PMID: 20167518
- 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