| Project/Area Number |
12670535
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Kurume University school of Medicine |
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Principal Investigator |
HARADA Masaru Kurume University school of Medicine, Assistance, 医学部, 助手 (00241175)
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| Co-Investigator(Kenkyū-buntansha) |
KOGA Hironori Kurume University school of Medicine, Assistance, 医学部, 助手 (90268855)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | ATP7B / bile / copper / hepatocytes / Wilson disease / ウイルソン病 |
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| Research Abstract |
Wilson disease is a genetic disorder characterized by the accumulation of copper in the body due to a defect of biliary copper excretion from hepatocytes. The intracellular localization of Wilson disease gene product, ATP7B, was investigated by expressing ATP7B tagged with green fluorescent protein (GFP)(GFP-ATP7B) in cultured cells. Intracellular organelles were visualized by fluorescence microscopy. GFP-ATP7B colocalized with the late endosome markers, but not with markers for the Golgi apparatus and lysosomes. Various mutations have been documented in patients with Wilson disease. The clinical manifestations vary greatly among the patients, however, there is little information on the genotype-phenotype correlation. We investigated the distribution of a common ATP7B mutant His 1069Gl and a mutant Asp l270Ser by expressing the mutants tagged with GFP. While Asp l270Ser mutant localized in the late endosomes, His 1069Gln mutant did not locate in the late endosomes and was degraded by the proteasomes in the cytoplasm. Furthermore, His 1069Gl formed aggresomes composed of the degradates and intermediate filamentsat the microtubule-organizing center. These aggresomes were similar to Mallory bodies on electron microscopy. ATP7B localized in the late endosomes in both copper-depleting and copper-loaded conditions. ATP7B seems to translocate copper from the cytosol into the late endosomes, and copper may be excreted to bile via lysosomes. The disturbed incorporation of copper into the late endosomes caused by mutated ATP7B must be the main defect in Wilson disease. The different protein properties of ATP7B mutants may in part explain the variety of clinical spectrums in patients with Wilson disease.
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