| Project/Area Number |
10670597
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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 |
Neurology
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| Research Institution | Nara Medical University |
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Principal Investigator |
UENO Satoshi Nara Medical University, Medicine, Associate Professor, 医学部, 助教授 (40184949)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | dystonia / GTP cyclohydrolase I / PCR / dominant negative effect / GTP cyclohydrolase / 変異 / ドーパ / GCH |
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| Research Abstract |
Hereditary progressive dystonia (HPD) is caused by the mutation in the GTP cyclohydrolase I (GCH) gene. The clinical presentation of this disease varies considerably, and many cases appear to be sporadic. We previously proposed that this clinical phenotype may be due to differential expression of the mutant and normal GCH mRNA, presumably at the protein level. To provide support for this proposal, we studied several new Japanese families with HPD, in which some members were heterozygous for an exon-skipping or single base change mutations. These mutations produced truncated GCH, and mutant GCH with a single amino acid replacement. A further study, using coexpression of the mutant with wildtype GCH in COS-7 cells, showed that mutant GCH inactivated the normal enzyme. These results suggested that the dominant negative effect of a mutant GCH on the normal enzyme might be one of the molecular mechanisms determining the heterogeneity of clinical phenotypes of HPD.
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