A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity
A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity
复制标题
DOI：
10.1182/blood-2009-07-231498
复制
发表时间：
2009-10-08
期刊：
影响因子：
20.3
通讯作者：
Dinauer, Mary C.
中科院分区：
文献类型：
--
作者：
Matute, Juan D.;Arias, Andres A.;Dinauer, Mary C.
慢性肉芽肿病（CGD）是一种免疫缺陷病，伴有复发性化脓性感染和肉芽肿性炎症，由吞噬细胞NADPH氧化酶亚基4个基因中任何一个的隐性突变导致吞噬细胞超氧化物产生丧失。这些包括形成膜整合的黄细胞色素B的gp 91（phox）和p22（phox），以及胞质亚基p47（phox）和p67（phox）。第五个亚基p40（phox）通过与磷脂酰肌醇3-磷酸（PtdIns（3）P）结合的phox同源（PX）结构域在吞噬诱导的超氧化物产生中起重要作用。我们报告的第一例常染色体隐性突变NCF 4，基因编码p40（phox），在一个男孩谁提出了肉芽肿性结肠炎。他的中性粒细胞在吞噬过程中表现出细胞内超氧化物产生的实质性缺陷，而细胞外释放的超氧化物引起的佛波酯或甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLF）不受影响。NCF 4的遗传分析表明，复合杂合性的移码突变与提前终止密码子和错义突变预测的PX结构域中的R105 Q取代。父母和一个兄弟姐妹是健康的杂合子携带者。p40（phox）R105 Q缺乏与PtdIns（3）P的结合，不能重建p40（phox）缺陷粒细胞中吞噬诱导的氧化酶活性，p40（phox）R105 Q从吞噬体中过早丢失。因此，p40（phox）与PtdIns（3）P的结合对于人类中性粒细胞中吞噬诱导的氧化剂产生是必不可少的，其缺乏可能与疾病有关。（血。2009; 114：3309-3315）
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)