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NCF1
neutrophil cytosolic factor 1
The NCF1 gene provides instructions for a protein critical to the immune system's defence against pathogens, particularly bacteria and fungi. The NCF1 gene codes for neutrophil cytosolic factor 1 (p47-phox), a key component of the NADPH oxidase (NOX) enzyme complex.
NCF1 is located on the long (q) arm of chromosome 7, at band 7q11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The NCF1 gene, or neutrophil cytosolic factor 1, is essential for the proper functioning of the immune system. It directs the production of a protein known as p47-phox, which is a subunit of the NADPH oxidase (NOX) enzyme complex. This complex is primarily active within immune cells, specifically phagocytes, where it plays a critical role in host defence mechanisms.
Phagocytes utilise the NOX enzyme to generate potent reactive oxygen species (ROS), which are used to destroy bacteria and fungi. A properly functioning NCF1 gene is therefore crucial for an effective immune response, preventing recurrent infections and managing inflammation.
What the gene does
The protein encoded by the NCF1 gene, p47-phox, is an integral part of the NADPH oxidase (NOX) enzyme complex. This enzyme system is predominantly found in phagocytes, a type of immune cell that engulfs and destroys foreign invaders like bacteria and fungi. Upon detection of pathogens, the NOX complex assembles, and p47-phox contributes to its activation.
Activated NOX then catalyses a chemical reaction that converts oxygen into superoxide. Superoxide is a precursor to other reactive oxygen species (ROS), such as hydrogen peroxide and hypochlorous acid. These highly reactive substances act as powerful antimicrobial agents, enabling phagocytes to effectively kill pathogens and prevent the spread of infection. Beyond direct pathogen killing, NOX also appears to regulate neutrophil activity, influencing inflammatory responses to promote healing and minimise tissue damage.
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Chromosome location
The NCF1 gene is situated on chromosome 7, specifically at location 7q11.23. This gene instructs the cell to produce a protein consisting of 390 amino acids.
Protein structure
The NCF1 protein (p47-phox) has a distinct domain organisation crucial for its function within the NADPH oxidase complex. It contains a PX domain spanning amino acids 4-125, which is typically involved in binding phosphoinositides. Following this are two SH3 domains: SH3 1 from amino acids 156-215 and SH3 2 from amino acids 226-285. SH3 domains often mediate protein-protein interactions. The C-terminal region, from amino acids 285-390, is characterised as a Disordered region, which can be important for flexible interactions and regulation.
Key variants
Genetic changes, often referred to as variants, within the NCF1 gene can impact its ability to produce a functional p47-phox protein. These variants can lead to a reduction or complete loss of the protein's activity, affecting the overall function of the NADPH oxidase complex. Such alterations can impair the immune system's ability to combat infections effectively.
Sample of pathogenic variants
4 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 |
|---|---|---|---|---|
GRCh37/hg19 7q11.23(chr7:74191613-74191693)x0 | - | Pathogenic | ★☆☆☆ | not provided |
GRCh37/hg19 7q11.23(chr7:74191613-74191693)x1 | - | Pathogenic | ★☆☆☆ | not provided |
GRCh37/hg19 7q11.23(chr7:74191613-74191693)x3 | - | Pathogenic | ★☆☆☆ | not provided |
GRCh37/hg19 7q11.23(chr7:74191613-74199645)x1 | - | Pathogenic | ★☆☆☆ | not provided |
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 NCF1 gene are primarily associated with an inherited condition called Chronic granulomatous disease. This condition is inherited in an autosomal recessive manner, meaning an individual must inherit two affected copies of the NCF1 gene, one from each parent, to develop the disorder. Individuals with Chronic granulomatous disease experience a significantly increased risk of recurrent and severe infections and inflammation due to their impaired immune response.
Inheritance pattern
Conditions caused by pathogenic NCF1 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 NCF1 gene is recognised within the NHS Genomic Medicine Service, indicating its clinical relevance in the UK. It is currently listed on several NHS PanelApp green-lighted panels, including "COVID-19 research", "Gastrointestinal epithelial barrier disorders", "Infantile enterocolitis & monogenic inflammatory bowel disease", and "Primary immunodeficiency or monogenic inflammatory bowel disease (R15)". This highlights its established role in various immune-related conditions and ongoing research.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the NCF1 gene?
The NCF1 gene provides instructions for creating a protein called p47-phox, which is a crucial component of the NADPH oxidase (NOX) enzyme complex. This complex is vital for the immune system, particularly in immune cells called phagocytes, to produce reactive oxygen species that kill pathogens.
What is Chronic granulomatous disease?
Chronic granulomatous disease is an inherited disorder caused by genetic variants, often in the NCF1 gene. It results in a weakened immune system, making individuals highly susceptible to recurrent bacterial and fungal infections, as well as inflammatory complications.
How is Chronic granulomatous disease inherited?
Chronic granulomatous disease caused by NCF1 variants is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the NCF1 gene, one from each parent, to be affected by the condition.
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
- Del Campo M, Antonell A, Magano LF. Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension. American journal of human genetics. 2006. PMID: 16532385
- Roos D, de Boer M, Köker MY. Chronic granulomatous disease caused by mutations other than the common GT deletion in NCF1, the gene encoding the p47phox component of the phagocyte NADPH oxidase. Human mutation. 2006. PMID: 16972229
- Jurkowska M, Bernatowska E, Bal J. Genetic and biochemical background of chronic granulomatous disease. Archivum immunologiae et therapiae experimentalis. 2004. PMID: 15179325
- Babior BM, Lambeth JD, Nauseef W. The neutrophil NADPH oxidase. Archives of biochemistry and biophysics. 2002. PMID: 11795892
- Vázquez N, Lehrnbecher T, Chen R. Mutational analysis of patients with p47-phox-deficient chronic granulomatous disease: The significance of recombination events between the p47-phox gene (NCF1) and its highly homologous pseudogenes. Experimental hematology. 2001. PMID: 11166463
- Roesler J, Curnutte JT, Rae J. Recombination events between the p47-phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease. Blood. 2000. PMID: 10706888
- Chanock SJ, Roesler J, Zhan S. Genomic structure of the human p47-phox (NCF1) gene. Blood cells, molecules & diseases. 2000. PMID: 10772875