Genetic analysis of Chronic Granulomatous Disease with cytosolic defect in Japan

日本伴有细胞质缺陷的慢性肉芽肿病的遗传分析

• 批准号: 05670427
• 负责人: NUNOI Hiroyuki
• 金额: $ 1.34万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670427/
• 关键词: Chronic Granulomatous Disease; Neutrophile; Molecular analysis; Classification of the disease; Statistics of the disease; 病型分類と統計; 常染色体劣性遺伝; P47細胞質蛋白; p67細胞質蛋白

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).

慢性肉芽肿病（CGD）是一种罕见的遗传性疾病，其中吞噬细胞不能产生超氧阴离子，其特征是反复发作的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催化组分细胞色素b558（gp 91-phox和p22-phox）和胞质组分（p47-phox和p67-phox和rac p21）组成。在这个项目中，我们鉴定了6名CGD患者的p47-phox缺陷（BBRC 199：1372- 1377，1994）和1名p67-phox缺陷（Blood in press）的分子缺陷。对日本CGD患者的统计分析结果显示，该病的发病率不低于百万分之四。我们还分析了racp 21蛋白向膜的转位机制（BBRC 195：264- 269，1993）和p47-phox向p22-phox的转位机制（PNAS 91：5345- 5349，1994）。我们还发现p22-phox中与His-94相邻的区域参与无细胞系统中超氧化物的产生，这通过与该区域对应的合成肽的抑制作用来证明（BBRC 204：924- 929，1994）。

项目成果

山崎幸雄: "慢性肉芽腫症におけるインターフェロンg長期投与の感染抑制効果" 日本小児科学会雑誌. 98. 1048-1056 (1994)

Yukio Yamazaki：“长期施用干扰素 G 对慢性肉芽肿病的感染抑制作用”日本儿科学会杂志 98. 1048-1056 (1994)。

Tohru Sawai: "Combination of arachidonic acid and guanosine5'-O-(3-Thiotriphosphate)induce translocation of rac p21s to membrane and activation of NADPH oxidase in a cell-free system." Biochem. Biophys. Res. Comm.195. 264-269 (1993)

Tohru Sawai：“花生四烯酸和鸟苷 5-O-（3-硫代三磷酸）的组合可诱导 rac p21 易位至细胞膜，并在无细胞系统中激活 NADPH 氧化酶。”

K.Takeshige,H.Nunoi,other 6: "Superoxide production by neutrophils" Active oxygens,lipid peroxides,and antioxidants.83-95 (1993)

K.Takeshige，H.Nunoi，其他 6：“中性粒细胞产生超氧化物”活性氧、脂质过氧化物和抗氧化剂。83-95 (1993)

T.Sawai,M.Asada,H.Nunoi,other6: "Combination of arachidonic acid and guanosine 5'-O(3-Thiotriphosphate)induce translocation of rac p21s to membtane and activation of NADPH oxidase in a cell-free system." Biochem.Biophys.Res.Comm.195. 264-269 (1993)

T.Sawai、M.Asada、H.Nunoi 等6：“花生四烯酸和鸟苷 5-O（3-硫代三磷酸）的组合可诱导 rac p21 易位至膜，并在无细胞系统中激活 NADPH 氧化酶。”

Yu L,Takeshige K,Nunoi H,other 1: "Characterization of the GTP-dependent activation of the superoxide-producing NADPH oxidase in a cell-free system of pig neutrophils" Biochemi.Biophys.Acta. 117. 70-80 (1993)

Yu L，Takeshige K，Nunoi H，其他 1：“猪中性粒细胞无细胞系统中产生超氧化物的 NADPH 氧化酶的 GTP 依赖性激活的表征”Biochemi.Biophys.Acta。