期刊
BLOOD
卷 114, 期 15, 页码 3309-3315出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-07-231498
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- NCI NIH HHS [P30 CA082709] Funding Source: Medline
- NHLBI NIH HHS [R01 HL045635, R01HL45635] Funding Source: Medline
- NIAID NIH HHS [R01 AI070958, R01AI070958] Funding Source: Medline
- BLRD VA [I01 BX000513] Funding Source: Medline
Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91(phox) and p22(phox), which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47(phox) and p67(phox). A fifth subunit, p40(phox), plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3) P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40(phox), in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40(phox)R105Q lacked binding to PtdIns(3) P and failed to reconstitute phagocytosis-induced oxidase activity in p40(phox)-deficient granulocytes, with premature loss of p40(phox)R105Q from phagosomes. Thus, p40(phox) binding to PtdIns(3) P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease. (Blood. 2009; 114: 3309-3315)
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