Genetic analysis of Chronic Granulomatous Disease with cytosolic defect in Japan

1994 Fiscal Year Final Research Report Summary

• Project/Area Number: 05670427
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: 内科学一般
• Research Institution: THE UNIVERSITY OF TOKYO
• Principal Investigator: NUNOI Hiroyuki The University of Tokyo, Insittute of Medical Scinece, Assistant prof., 医科学研究所, 助手 (50218260)
• Project Period (FY): 1993 – 1994
• Keywords: Chronic Granulomatous Disease / Neutrophile / Molecular analysis / Classification of the disease / Statistics of the disease

Research Abstract

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).

Research Products

• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Iwata M.: "Homologous dinucleotide (GT) deletion in Japanese patients with chronic granulomatous disease with p47-phox deficeincy." Biochim. Biophys. Res. Commun.199. 1372-1377 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Simadzu, M.: "Structural organization of the gene for CD-40 lignad:Molecular analysis for diagnosis of X-linked hyper-IgM syndrome." Biochim. Biophys. Acta. 1260. 67-72 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Park, M-Y: "Peptides corresponding to the region adjacent to His-94in the small subunit of cytochrome b558 inhibit superoxide generation in a cell-free system from human neutrophils." Biochem. Biophys. Res. Commun.204. 924-929 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sumimoto, H: "Role of Src homology 3 domains in assemble and activation of the phagocyte NADPH oxidase" Proc. Natl. Acad. Sci.91. 5345-5349 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nunoi, H: "AG dinucleotide insertion in a patient with chronic granulomatous disease lacking cytosolic 67-kDa protein." Blood. (in press). (1995)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Koichiro Takeshige: "Lipid Peroxides, and antioxidants. (Yagi K., ed)" Superoxide production by neutrophils., 83-95 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tohru Sawai, Makoto Asada, Hiroyuki Nunoi, Ichiro Matsuda, Stoshi Ando, Takuya Sasaki, Kozo Kaibuchi, Yoshimi Takai and Kouichi Katayama.: "Combination of arachidonic acid and guanosine 5'-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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Iwata, M., H.Nunoi, T.Nakano, H.Niwa, S.Tsuruta, S.Ohga, H.Yamazaki, S.Ohmi, S.Kanegasaki and I.Matsuda: "Homologous dinucleotide (GT) deletion in Japanese patients with chronic granulomatous disease with p47-phox deficeincy." Biochim.Biophys.Res.Commun.199. 1372-1377 (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Simadzu, M., H.Nunoi, H.Terasaki, R.Ninomiya, M.Iwata, S.Kanegasaki and I.Matsuda: "Structural organization of the gene for CD-40 lignad : Molecular analysis for diagnosis of X-linked hyper-IgM syndrome." Biochim.Biophys.Acta. 1260. 67-72 (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Park, M-Y., S.Imajoh-Ohmi, H.Nunoi and S.Kanegasaki: "Peptides corresponding to the region adjacent to His-94 in the small subunit of cytochrome b558 inhibit superoxide generation in a cell-free system from human neutrophils." Biochem.Biophys.Res.Commun.204. 924-929 (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sumimoto, H., Y.Kage, H.Nunoi, H.et al.: "Role of Src homology 3 domains in assemble and activation of the phagocyte NADPH oxidase." Proc.Natl.Acad.Sci.91. 5345-5349 (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nunoi, H., M.Iwata, S.Tatsuzawa, Y.Onoe, S.Shimizu, S.Kanegasaki and I.Matsuda: "AG dinucleotide insertion in a patient with chronic granulomatous disease lacking cytosolic 67-kDa protein." Blood. (in press). (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Koichiro Takeshige, Hiroyuki Nunoi, Kiyoshi Ishida, Masahiko Nozaki, Kunihiko Aoyagi, Takashi Mitsuyama, Lixin Yu, and Shigeki Minakami: Active Oxygens, Lipied Peroxides, and antioxidants. (Yagi K., ed) Superoxide production by neutrophils.Japan Sci.AOC.Press, Tokyo/CRC Press, Boca Raton, 83-95 (1993)
  • Description: 「研究成果報告書概要(欧文)」より