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NCF2
neutrophil cytosolic factor 2
The NCF2 gene provides instructions for producing the p67-phox protein, a key component of the NADPH oxidase enzyme complex vital for immune responses, particularly in fighting infections. The NCF2 gene encodes neutrophil cytosolic factor 2, also known as p67-phox.
NCF2 is located on the long (q) arm of chromosome 1, at band 1q25.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The NCF2 gene, or neutrophil cytosolic factor 2, is crucial for a healthy immune system. It directs the production of a protein called p67-phox, which is a subunit of the NADPH oxidase enzyme complex. This enzyme is vital for immune cells to effectively neutralise pathogens like bacteria and fungi, preventing illness.
What the gene does
The NCF2 gene produces the p67-phox protein, an integral part of the NADPH oxidase enzyme complex. This enzyme is predominantly active in phagocytes, a type of immune cell that engulfs and destroys foreign invaders. When pathogens are detected, NADPH oxidase assembles and initiates a chemical reaction that converts oxygen into superoxide. Superoxide is then used to produce other potent reactive oxygen species, such as hydrogen peroxide and hypochlorous acid, which are highly toxic to microorganisms. These reactive substances allow phagocytes to kill pathogens, preventing their proliferation and reducing the risk of infection. The p67-phox protein is also thought to help regulate neutrophils, immune cells involved in managing inflammatory responses to promote healing.
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Chromosome location
The NCF2 gene is located on chromosome 1 at position 1q25.3. This chromosomal location provides the physical address for the gene within the human genome.
Protein structure
The NCF2 protein is 526 amino acids long and features several distinct domains and regions. It includes three TPR (Tetratricopeptide Repeat) regions: TPR 1 (amino acids 37-70), TPR 2 (amino acids 71-104), and TPR 3 (amino acids 121-154). Additionally, there are two SH3 (Src homology 3) domains: SH3 1 (amino acids 240-299) and SH3 2 (amino acids 457-516). The protein also contains a PB1 (Phox and Bem1p) domain (amino acids 351-429) and two disordered regions (amino acids 303-346 and 433-458).
Key variants
Variations within the NCF2 gene can alter the function of the p67-phox protein, potentially affecting the immune system's ability to combat infections. Over 50 different changes in the NCF2 gene have been identified, with some leading to an increased susceptibility to certain conditions.
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.1099C>T | p.Gln367Ter | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.1120C>T | p.Gln374Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.1162G>T | p.Glu388Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.1180T>G | p.Tyr394Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.175-1G>A | - | Pathogenic | ★★☆☆ | NCF2-related disorder |
c.196C>T | p.Arg66Ter | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.229C>T | p.Arg77Ter | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.417del | p.Ala140fs | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.500G>A | p.Trp167Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
c.574C>T | p.Gln192Ter | Pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 |
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 the NCF2 gene are associated with chronic granulomatous disease, an inherited immune disorder. This condition typically results in recurrent severe infections and inflammation due to the immune system's reduced ability to produce reactive oxygen species that kill pathogens. NCF2 mutations account for less than 5% of all chronic granulomatous disease cases. Additionally, some normal genetic variations in NCF2 have been linked to an increased risk of systemic lupus erythematosus, an autoimmune condition where the immune system mistakenly attacks the body's own tissues.
Inheritance pattern
Conditions caused by pathogenic NCF2 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 NCF2 gene is included in several NHS Genomic Medicine Service national test panels. It is part of the COVID-19 research panel, the Infantile enterocolitis & monogenic inflammatory bowel disease panel, and the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), indicating its recognised clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the NCF2 gene responsible for?
The NCF2 gene provides instructions for making the p67-phox protein, a critical part of the NADPH oxidase enzyme. This enzyme is vital for immune cells to produce reactive oxygen species, which are used to destroy invading bacteria and fungi.
What health conditions are associated with NCF2 gene variants?
Variants in the NCF2 gene are primarily associated with chronic granulomatous disease, an inherited disorder characterised by severe, recurrent infections. Some common variations in the gene may also increase the risk of developing autoimmune conditions like systemic lupus erythematosus.
How common are NCF2 gene mutations in chronic granulomatous disease?
Mutations in the NCF2 gene are a less common cause of chronic granulomatous disease, accounting for under 5% of all diagnosed cases of the condition.
References
- Jacob CO, Eisenstein M, Dinauer MC. Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proceedings of the National Academy of Sciences of the United States of America. 2012. PMID: 22203994
- Cunninghame Graham DS, Morris DL, Bhangale TR. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS genetics. 2011. PMID: 22046141
- 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