| Project/Area Number |
09835007
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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 |
老化(加齢)
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| Research Institution | Ehime Uniersity |
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Principal Investigator |
MIKI Tetsuro Department of Geriatric Medicine School of Medicine, Ehime University Professor, 医学部, 教授 (00174003)
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| Co-Investigator(Kenkyū-buntansha) |
NAKURA Jun Department of Geriatric Medicine School of Medicine, Ehime University Assistant, 医学部, 助手 (70304607)
KOHARA Katsuhiko Department of Geriatric Medicine School of Medicine, Ehime University Associate, 医学部, 助教授 (30260384)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Werner Syndrome / Aging / Helicase / Mutation / Case-Control Study / Miocardinal Infarction / Transcription / Fibroblast / ウエルナ-症候群 / 早老症 / 遺伝子診断 |
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| Research Abstract |
We identified a total of 14 mutations in the gene responsible for Werner syndrome (WRN) in 53 Werner syndrome patients. These mutations are 4 nonsense mutations, 6 frame-shift mutations, 3 splicing mutations, and a genomic deletion. We found that all of the mutations cause truncation in the corresponding predicted protein products, resulting in lack of the nuclear localizing signal on the C-terminal of the proteins. Hence, we conclude that Werner syndrome arc caused by loss of function of the WRN protein resulted from failure of the mutated WRN proteins to translocate into the nucleus.
A case-control study revealed that homozygotes, but not heterozygotes, for a polymorphic missense variant at amino acid 1367 in the WRN protein have higher risk for myocardial infarction. This result could represent that the missense change itself affects some part of function of the WRN protein because the protein with certain imssense change could inhibit one of interactions of the protein with specific molecules, possibly causing part of WS phenotypes.
We studied transcriptional activation of a promoter by the WRN protein in a yeast assay system. The results showed that the WRN protein functions as a transcriptional activator in the system. Furthermore, we performed additional transcriptional assays using various parts of the WRN gene to define the critical region of the WRN protein for transcriptional activation in yeast. The results revealed the critical region for the activation most likely mapped to the region of 315 aa to 403 aa. The region of 404 aa to 1309 aa may also effect activation in the presence of the critical region. The two regions contain an acidic domain and the region of 404 aa to 1309 also contains a helicase domain.
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