The molecular characteristic of NADPH Oxidase components.
1. Introduction
Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by impairment of intracellular microbicidal activity of phagocytes. Mutations in one of four known nicotinamide adenine dinucleotide phosphate (NADPH) -oxidase components preclude generation of superoxide and related antimicrobial oxidants, leading to the phenotype of CGD. Defects in gp91-phox, encoded by
2. Phenotype- genotype correlation in CGD
Identification of specific mutations in CGD patients may help to clarify some of the variability in clinical severity seen in this disorder and shows genotype-phenotype correlation. In general, X-CGD patients follow a more severe clinical course than patients with an AR-CGD and exhibit in the first years of life. AR-CGD patients follow a milder clinical course, especially p47-phox defect, and mostly seen in first and second decade of life. AR-CGD patients with missense mutations usually exhibit a mild clinical course, associated with a residual activity of p47-phox and also p22 and p67-phoxs. However, the level of superoxide generation does not always correlate with the clinical course. Some patients suffer from severe and recurrent infections despite having neutrophils with 10–20% of normal oxidase activity (1). Within our study with 40 AR-CGD families, we could not define a direct correlation between the molecular defect and the clinical course of the disease. Either truncations (nonsense and frameshift mutations) or missense mutations could have resulted in severe influence on phenotype.
3. CYBA (cytochrome b alfa chain)gene
Cytochrome
In about 5% of the CGD patients, the disease is caused by mutations in the cytochrome
P22-phox has a key role in the interaction of NADPH-oxidase subunits and any difference in amino acid pattern of this phox protein may change the globular conformation of this protein due to the difference in the electrophoretic characteristic of new amino acid, which prevents the complex formation with other subunits.
Missense mutation points may have an important role in the interaction with other subunits, so the amino acid change in that regions may change the property of interactions and prevents or decreases the complex formation, so the activity of NADPH oxidase was abolished.
Total numbers of alleles which have missense mutations are 65 of 173 mutated alleles in
4. NCF1 (Neutrophil Cytosolic Factor 1) gene
In about 25% of the CGD patients, the disease is caused by mutations in the neutrophil cytosolic factor 1 (
A very common mutation found in these patients is a GT deletion in a GTGTrepeat sequence at the beginning of exon 2 of NCF1 (c.75_76delGT) gene (5, 7).
Total numbers of alleles which have missense mutations are 6 of 63 (other than delta-GT mutation in exon 2, in more than 620 alleles) mutated alleles in
5. NCF2 (Neutrophil Cytosolic Factor 2) gene
The neutrophil cytosolic factor 2 (
Total numbers of mutated alleles leading AR-CGD in
6. NCF4 (Neutrophil Cytosolic Factor 2) gene
7. Conclusion
19 different alleles in
In p22-phox the first interaction with p67-phox occur in B part (domain) which is located between 81-91 amino acids in p22-phox. There are 4 different missense mutations (in 21 alleles of
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