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NCF4
neutrophil cytosolic factor 4
The NCF4 gene provides instructions for producing a protein called neutrophil cytosolic factor 4 (p40-phox), which is an important part of the NADPH oxidase enzyme complex, vital for immune system function. NCF4 plays a critical role in the body's immune response by contributing to the NADPH oxidase enzyme, particularly in phagocytes that defend against foreign invaders like bacteria and fungi.
NCF4 is located on the long (q) arm of chromosome 22, at band 22q12.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The NCF4 gene encodes neutrophil cytosolic factor 4, also known as p40-phox, a protein essential for the proper functioning of the immune system. This protein is a subunit of the NADPH oxidase enzyme complex, primarily active in immune cells called phagocytes. Phagocytes are specialised cells that engulf and destroy harmful microorganisms, forming a key part of the body's defence mechanism.
Dysfunction of the NCF4 protein can lead to impaired immune responses, making individuals more susceptible to certain infections and inflammatory conditions. Understanding the role of NCF4 helps in comprehending the molecular basis of specific immune disorders.
What the gene does
The NCF4 gene provides instructions for synthesising neutrophil cytosolic factor 4, or p40-phox, a component of the NADPH oxidase enzyme system. This enzyme is crucial for the immune system, particularly within phagocytes, which are immune cells responsible for identifying and eliminating foreign pathogens such as bacteria and fungi. The NADPH oxidase enzyme complex generates reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hypochlorous acid.
These reactive oxygen species act as potent antimicrobial agents, allowing phagocytes to kill invading microorganisms effectively. The presence of foreign invaders triggers the assembly of the NADPH oxidase complex, leading to a burst of ROS production. Additionally, the NCF4 protein is thought to modulate the activity of neutrophils, another type of immune cell involved in managing inflammatory responses to promote healing and minimise tissue damage.
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Chromosome location
The NCF4 gene is situated on chromosome 22 at position 22q12.3. Chromosome 22 is one of the 23 pairs of chromosomes in humans, containing hundreds of genes that provide instructions for various cellular functions.
Protein structure
The NCF4 protein, also known as p40-phox, consists of 339 amino acids. It features several distinct domains that facilitate its role within the NADPH oxidase complex. These include a PX domain, located from amino acids 19-140, a SH3 domain spanning amino acids 170-229, and a PB1 domain found from amino acids 237-329. These domains are crucial for protein-protein interactions and the proper assembly and function of the enzyme complex.
Key variants
Variants within the NCF4 gene can alter the structure or function of the neutrophil cytosolic factor 4 protein. Such changes may compromise the efficiency of the NADPH oxidase enzyme, leading to a weakened immune response. Most NCF4-related conditions follow an autosomal recessive inheritance pattern, meaning an individual must inherit two altered copies of the gene, one from each parent, to be affected.
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.529-2A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.614_615del | p.Lys205fs | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.758+50C>T | R270* | Pathogenic/Likely pathogenic | ★★☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.759-40C>T | Q322* | Pathogenic | ★★☆☆ | Chronic granulomatous disease |
c.456del | p.Arg153fs | Pathogenic | ★☆☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.758+28_758+29insA | P263fs | Pathogenic | ★☆☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.758+36_758+81del | F265fs | Pathogenic | ★☆☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.759-19C>T | Q329* | Pathogenic | ★☆☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.759-24T>G | L327* | Pathogenic | ★☆☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
c.771G>A | p.Val257= | Pathogenic | ★☆☆☆ | Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 |
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 NCF4 gene are associated with chronic granulomatous disease, a rare inherited disorder characterised by a weakened immune system. Individuals with this condition experience recurrent and severe infections and inflammation. NCF4 variants are considered a rare cause of chronic granulomatous disease, resulting in a deficiency of functional NADPH oxidase. This deficiency impairs the body's ability to produce reactive oxygen species needed to kill certain bacteria and fungi.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NCF4 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 NCF4 gene is included in several UK NHS national genomic testing panels. It is part of the COVID-19 research panel, indicating its relevance in studies related to immune responses. Furthermore, NCF4 is listed on the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), reflecting its established role in conditions affecting immune function.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the NCF4 gene?
The NCF4 gene provides instructions for making neutrophil cytosolic factor 4 (p40-phox), a protein that is a critical part of the NADPH oxidase enzyme complex. This complex is vital for the immune system, particularly in immune cells called phagocytes.
How does NCF4 affect the immune system?
NCF4 helps the immune system by contributing to the NADPH oxidase enzyme, which generates reactive oxygen species. These molecules are essential for phagocytes to kill foreign invaders like bacteria and fungi, thereby protecting the body from illness.
What condition is associated with NCF4 gene variants?
Variants in the NCF4 gene are a rare cause of chronic granulomatous disease. This condition leads to a weakened immune system, making affected individuals highly susceptible to recurrent infections and inflammation due to an impaired ability to fight off certain pathogens.
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
- Matute JD, Arias AA, Wright NA. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009. PMID: 19692703
- Sumimoto H. Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. The FEBS journal. 2008. PMID: 18513324