NCF2 – Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent bacterial and fungal infections due to defective phagocyte NADPH oxidase activity. NCF2 encodes the cytosolic p67^(phox) subunit essential for assembly and activation of the oxidase complex. Biallelic loss-of-function variants in NCF2 underlie an autosomal recessive form of CGD with absent or severely reduced reactive oxygen species production (DHR/NBT assays).

Genetic evidence for NCF2 in CGD includes multiple unrelated probands with homozygous or compound heterozygous variants. Early genomic mapping identified the 16-exon structure of p67^(phox) and described homozygous RFLP segregation in a family with a 9-year-old proband and unaffected parents, consistent with recessive inheritance (PMID:7903171). Alu-mediated exon 5 deletions were found in five patients from four consanguineous families, demonstrating loss of function and accelerated protein degradation (PMID:19953534). A founder splice-site mutation c.257+2T>C was identified in 11 Tunisian patients from six families with absence of p67^(phox) and no residual ROI, supporting segregation and founder effect (PMID:27220316).

Case series describe diverse NCF2 variants and clinical presentations. A homozygous deletion c.835_836del (p.Thr279fsTer294) was reported in three unrelated families presenting with early colitis and juvenile arthritis, confirming pathogenicity by absent NADPH oxidase activity (PMID:28035544). Novel splice mutations c.1000+2T>G led to in-frame exon 11–12 skipping with residual oxidase activity, explaining late adult presentation (PMID:22514628).

Functional assays corroborate the loss-of-function mechanism. Splice-junction variant c.45+2>G in intron 3 eliminated p67^(phox) mRNA and protein in one patient, with rescue in cell-free oxidase assays only upon addition of wild-type p67^(phox) (PMID:7803798). Hypomorphic missense mutations such as p.Ala202Val decrease p67^(phox) translocation and reduce reactive oxygen species to 20–70% of normal, consistent with milder phenotypes (PMID:25937994).

No conflicting evidence or alternative disease associations for NCF2 and CGD have been reported. The consolidated genetic and experimental data meet ClinGen criteria for a Strong gene–disease relationship.

Key Take-home: Biallelic NCF2 variants result in autosomal recessive CGD via p67^(phox) deficiency, underpinning diagnostic genetic testing and informing management with prophylaxis and stem cell transplantation.

References

• Blood • 1993 • Characterization of the p67phox gene: genomic organization and restriction fragment length polymorphism analysis for prenatal diagnosis in chronic granulomatous disease. PMID:7903171
• Human Mutation • 2010 • Alu-repeat-induced deletions within the NCF2 gene causing p67-phox-deficient chronic granulomatous disease (CGD). PMID:19953534
• Journal of Clinical Immunology • 2016 • A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients. PMID:27220316
• Journal of Clinical Immunology • 2017 • Chronic Granulomatous Disease Due to Neutrophil Cytosolic Factor (NCF2) Gene Mutations in Three Unrelated Families. PMID:28035544
• PLoS One • 2012 • P67-phox (NCF2) lacking exons 11 and 12 is functionally active and leads to an extremely late diagnosis of chronic granulomatous disease (CGD). PMID:22514628
• Blood • 1995 • A mutation located at the 5' splice junction sequence of intron 3 in the p67phox gene causes the lack of p67phox mRNA in a patient with chronic granulomatous disease. PMID:7803798
• Journal of Clinical & Cellular Immunology • 2014 • Two CGD Families with a Hypomorphic Mutation in the Activation Domain of p67phox. PMID:25937994

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