Alt. symbols: p40phox | SH3PXD4

Approved name: neutrophil cytosolic factor 4
Alt. names: neutrophil cytosolic factor 4 (40kD), neutrophil cytosolic factor 4, 40kDa | neutrophil NADPH oxidase factor 4

Location: 22q12.3: 36860988 - 36878017 (+)
Gene type: protein_coding, 7 transcripts.

Scores: LoFtool: 0.855000 | pLI: 0.00000790 | LOEUF: 1.198

HGNC: 7662

NCBI: 4689, RefSeq: NG_023400.1

Ensembl: ENSG00000100365.16

LRG_159 | Status: public

OMIM: 601488

Expression | ProteinAtlas

The NADPH oxidase complex in phagocytes is important for both immune defense and clearance of potential auto-antigens. NCF4 encodes the p40-phox subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, an enzyme responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates. It is thought to be important for assembly and/or activation of the complex. During phagocytosis, upregulation of the membrane phospholipid phosphatidylinositol 3-phosphate and subsequent high-affinity binding to the p40-phox PX domain enhances NADPH oxidase activity (PMID: 29969437).

Biallelic splice site, deletion, insertion, nonsense and missense NCF4 mutations cause a form of autosomal recessive chronic granulomatous disease (CGD) [OMIM: 613960]. Of note, NCF4 mutations account for less than 1% of CGD cases overall and routine DHR testing of peripheral blood using PMA stimulation may not detect NCF4-related CGD (PMID: 29969437). In general, CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses, resulting in granul oma formation and other inflammatory disorders such as inflammatory bowel disease (IBD). However, NCF4-deficient patients have a distinct phenotype involving more hyperinflammation, particularly severe and difficult-to-control IBD, and peripheral infections, but without the invasive bacterial or fungal infections seen in other forms of CGD (PMID: 29969437). Moreover, patients may show incomplete clinical penetrance into adolescence. Mycobacterial disease has been reported in CGD, largely manifesting as regional and disseminated BCG infections and tuberculosis. CGD patients are less susceptible to nontuberculous infections than persons with defects in T-cell or IFN-gamma/IL-12 pathways. For example, the latter will likely develop disseminated disease from BCG infection, while the former are more likely to have severe localized disease such as draining skin lesions at sites of BCG vaccination (PMID: 18277931). Of note, one patient with NCF4 deficiency who developed local lymphadenitis (BCG-itis) and Mycobacterium avium intracellulare meningitis was also heterozygous for a dominant-negative STAT1 LOF mutation associated with MSMD (PMID: 28011069). [Load More]