NCF4 – Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is an inherited immunodeficiency marked by defective phagocyte NADPH oxidase activity, resulting in recurrent infections and granulomatous inflammation. The p40phox subunit, encoded by NCF4, binds phosphatidylinositol 3-phosphate via its PX domain and is essential for phagocytosis-induced superoxide production.

The first autosomal recessive CGD case due to NCF4 mutations was described in a boy with granulomatous colitis: compound heterozygosity for c.256del (p.Leu86fs) and c.314G>A (p.Arg105Gln) led to selective loss of intracellular superoxide production in neutrophils (1 proband) (PMID:19692703). Parents and one sibling were healthy heterozygous carriers, confirming segregation.

A larger series of 24 p40phox-deficient patients from 12 families demonstrated eight distinct in-frame or out-of-frame NCF4 variants, including the hypomorphic c.172C>T (p.Arg58Cys) allele, all resulting in biallelic loss-of-function or partial activity (PMID:29969437). These patients exhibited hyperinflammation and peripheral infections but lacked the invasive bacterial or fungal infections typical of classic CGD.

NCF4-related CGD follows autosomal recessive inheritance with biallelic pathogenic variants. In total 25 probands from 13 families support a strong gene–disease association through consistent segregation and allelic series.

Functional studies show that p40phox mutants fail to bind phosphatidylinositol 3-phosphate, abolish phagocytosis-induced NADPH oxidase activity in patient granulocytes, and are not rescued in reconstitution assays, aligning with the human phenotype.

Unlike classic CGD, patients with p40phox deficiency have normal or mildly impaired PMA-induced DHR oxidation and conserved killing of Candida albicans and Aspergillus fumigatus hyphae, indicating a distinct mechanistic and clinical profile.

Taken together, autosomal recessive NCF4 variants cause a unique CGD subtype characterized by selective intracellular oxidase defects, supporting diagnostic testing of NCF4 in patients with granulomatous colitis or atypical CGD presentations. Key take-home: NCF4 mutation screening refines CGD diagnosis and guides tailored management.

References

• Blood • 2009 • A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. PMID:19692703
• The Journal of Clinical Investigation • 2018 • Inherited p40phox deficiency differs from classic chronic granulomatous disease. PMID:29969437

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