| Project/Area Number |
06670648
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Neurology
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
MITAJIMA Hiroaki Hamamatsu Unversity School of Medicine, Department of Medicine, Research associate, 医学部, 助手 (90221613)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMIZU Hideaki Hamamatsu University School of Medicine, Department of Medicine, Research associ, 医学部附属病院, 助手 (70270981)
米村 克彦 浜松医科大学, 医学部, 助手 (40252176)
清水 貴子 浜松医科大学, 医学部, 助手 (90206201)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1994: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | ceruloplasmin / iron / gene mutation / thiobarbituric acid-reactive substance / lipid peroxidation / チオバルビツール酸反応-陽性物質 / アポセルロプラスミン欠損症 / 鉄代謝 / チオバルビツール酸反応物質 |
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| Research Abstract |
Ceruloplasmin is a blue copper oxidase that carries more than 95% of the plasma copper content in vertebrates. It is carried by alpha_2-glycoprotein which is synthesized mainy in the liver. We report here on the identification of a genetic defect in the ceruloplasmin gene and incerased lipid peroxidation in patients previously noted to have the absence of circulating serum ceruloplasmin in association with late-onset retinal and basal ganglia degeneration, and diabetes mellitus. In patients T2-weighted MR imaging of the brain revealed basal ganglia densities consistent with iron deposition, and liver biopsy confirmed the presence of excess iron.
PCR amplification of 19 exons composing the human ceruloplasmin gene revealed a distinct size difference in exon 7. DNA sequence analysis of this exon revealed a 5-bp insertion at amino acid 410 (nucleotide 1287), resulting in a frame-shift mutation and a truncated open reading frame. The validity of this mutation was confirmed by analysis of DNA from the patients' daughters and sons, which revealed heterozygosity for this same 5-bp insertion. The presence of this mutation identifies aceruloplasminemia as an autosomal recessive disorder of iron metabolism.
Plasma lipid peroxidation was measured as thiobarbituric acid-reactive products (TBA products) in plasma samples from controls, heterozygotes, and affected patients. Basal levels of lipid peroxides were three times control values in patients with aceruloplasminemia. TBA products were significantly increased in these patients in the presence of copper ions and hydrogen peroxide. In each case these increases were suppressed by the addition of exogenous ceruloplasmin. These data suggest that increased susceptibility to lipid peroxidation may contribute to the unique neuropathology in patients with aceruloplasminemia.
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