Genetic analysis of Chronic Granulomatous Disease with cytosolic defect in Japan

慢性肉芽肿病(CGD)是一种罕见的遗传性疾病，吞噬细胞不能产生超氧阴离子，其特征是反复发生、威胁生命的过氧化氢酶阳性微生物感染。吞噬细胞中的超氧化物生成系统由膜结合的催化成分细胞色素b558(gp91-Phox和p22-Phox)和胞浆成分(p47-Phox和p67-Phox和Rac p21)组成。在这个项目中，我们鉴定了6例p47-Phox缺乏症患者(BBRC199：1372-1377,1994)和1例p67-Phox缺乏症患者(按下血)的分子缺陷。在对日本CGD患者的统计分析结果中，这种疾病的发病率不低于百万分之四。我们还分析了racp21蛋白到膜的易位机制(BBRC195：264-269,1993)和p47-Phox到p22-Phox的易位机制，以及农夫的src同源基因(SH3)与后者的Pro富集区(PNAS 91：5345-5349,1994)的相互作用。我们还发现，p22-Phox中与His-94相邻的区域参与了无细胞体系中超氧化物的产生，这表现为与该区域对应的合成肽的抑制(BBRC204：924-929,1994)。

Chronic granulomatous disease (CGD) is a rare inherited disorder where phagocytes can not generate superoxide anion and is characterized by recurrent, life-threatening infections with catalase positive-micro Organisms. The superoxide generating system in phagocytes consists of a membrane-bound catalytic component, cytochrome b558, (gp91-phox and p22-phox, ) and cytosolic components (p47-phox and p67-phox and rac p21). A functionally active enzyme complex is formed upon stimulation by assembly of the components on the plasma membrane.In this project, we identified molecular defects of six CGD patients with p47-phox deficiency (BBRC 199 : 1372-1377,1994) and one with p67-phox deficiency (Blood in press). In the result of a statistical analysis of CGD patients in Japan, the incidence of this disease was no less than 4 out of one million births. We also analyzed the translocation mechanisms of racp21 protein to membrane (BBRC 195 : 264-269,1993) and that of p47-phox to p22-phox with the interaction between src homology locus (SH3) of the farmer and the proline rich region of the latter (PNAS 91 : 5345-5349,1994). We also found the region adjacent to His-94 in p22-phox is involved in the superoxide production in a cell free system that was shown by the inhibition with synthetic peptides corresponding the region (BBRC 204 : 924-929,1994).