NCF1 – p47phox-Deficient Chronic Granulomatous Disease

Autosomal recessive chronic granulomatous disease due to NCF1 deficiency presents in childhood with recurrent bacterial and fungal infections, notably lymph node and liver abscesses. Affected individuals lack p47phox protein in neutrophils on immunoblot and fail nitroblue tetrazolium and dihydrorhodamine assays, indicating absent superoxide production. Diagnosis is confirmed by biallelic loss-of-function mutations in NCF1, including recurrent c.579G>A (p.Trp193Ter) and GT dinucleotide deletions arising from pseudogene recombination. Segregation studies demonstrate carrier parents and siblings with intermediate oxidase activity, supporting autosomal recessive inheritance. NCF1 variants account for ~20% of autosomal recessive CGD globally, with founder effects in specific populations.

Genetic evidence spans single-patient case reports to large cohorts. Initial reports described a homozygous G–233→A (p.Gly78Glu) variant in one patient (PMID:8286749) and exon-skipping splice-site mutations in others. Subsequent analyses in 80 unrelated kindreds identified diverse NCF1 mutations, with GT deletion present in 25 of 25 alleles in p47phox-deficient families ([PMID:18546332]; [PMID:10706888]). A recurrent c.579G>A (p.Trp193Ter) mutation shows founder prevalence in Ashkenazi and Kavkazi Jews ([PMID:11920901]).

Variant spectrum is dominated by loss-of-function alleles: frameshifts (e.g., c.75_76del (p.Tyr26HisfsTer26)), nonsense (c.579G>A (p.Trp193Ter)), and splice-site mutations. Unequal crossover with pseudogenes yields recurrent GT deletions in exon 2. The common c.579G>A variant has been used for prenatal diagnosis and carrier screening, enabled by gene-scan and sequence-specific assays.

Functional assays confirm that NCF1 mutations abolish oxidase activity. Site-directed mutagenesis of cysteines in p47phox alters O₂⁻ production kinetics ([PMID:9466817]). Patient iPSCs corrected by targeted pseudogene editing restore superoxide generation, demonstrating causality and therapeutic potential ([PMID:29296942]).

No conflicting studies dispute the NCF1–CGD association; all data concordantly support a loss-of-function mechanism requiring biallelic disruption. Experimental concordance across biochemical, cellular, and genetic models solidifies clinical validity.

In conclusion, NCF1 mutations cause a definitive autosomal recessive CGD phenotype. Genetic testing for NCF1 variants, particularly c.579G>A (p.Trp193Ter) and GT deletions, is essential for diagnosis, family counseling, and management. Key take-home: absent p47phox and NADPH oxidase activity identify NCF1-deficient CGD and guide early intervention.

References

• Blood • 1994 • Autosomal recessive chronic granulomatous disease with absence of the 67-kD cytosolic NADPH oxidase component: identification of mutation and detection of carriers. PMID:8286749
• Blood • 2000 • Recombination events between the p47-phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease. PMID:10706888
• Prenatal diagnosis • 2002 • Prenatal diagnosis in two families with autosomal, p47(phox)-deficient chronic granulomatous disease due to a novel point mutation in NCF1. PMID:11920901
• Human mutation • 2008 • Molecular epidemiology of chronic granulomatous disease in a series of 80 kindreds: identification of 31 novel mutations. PMID:18546332
• Clinical immunology (Orlando, Fla.) • 2008 • Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients. PMID:18708296
• Archives of biochemistry and biophysics • 1998 • The leukocyte NADPH oxidase subunit p47PHOX: the role of the cysteine residues. PMID:9466817
• Blood advances • 2017 • Gene-edited pseudogene resurrection corrects p47phox-deficient chronic granulomatous disease. PMID:29296942

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