https://scholars.lib.ntu.edu.tw/handle/123456789/194390
標題: | 帶有顯著日間差異的遺傳性進行性肌肉張力不全症之研究 | 作者: | 王本榮 | 關鍵字: | 帶有顯著日間差異的遺傳性進行性肌肉張力不全症;Segawa;GTP cyclohydrolase I;Hereditary progressive dystonia with marked diurnal fluctuation;HDP | 公開日期: | 1998 | 出版社: | 臺北市:國立臺灣大學醫學院小兒科 | 摘要: | 帶有顯著日間差異的遺傳性進行性肌肉張 力不全症(以下簡稱 HPD)是一個顯性遺傳 的臨床疾病。它具有明顯日間症狀變動, 兒童期發病,並且對L-dopa具有完全療效 之特徵。我們自從1988年陸續有6名HPD的 病例被診斷治療。最近,Ichinose等首先 發現了日本HPD病人肇因於GTP cyclohydrolase I(GTPCH)基因的突變,我 們在本研究中分析了患者的基因變化。 GTPCH 缺乏會引起tetrahydrobiopterine (BH4)不足,所以同時也是引 起苯酮尿症的原因之一。然而GTPCH 缺乏 所引起的苯酮尿症卻是隱性遺傳的。 在本研究中我們發現了一個病人有 R249S (747CàG)突變。病人血球經PHA 刺 激後可以測到很低的GTPCH 活性,但是 mRNA 的表現卻是正常的。突變株如果在大 腸菌中表現其活性正常,但是在細胞中表 現的活性及蛋白質卻是偏低的。所以R249S 致病的原因是因為其穩定度不足。本研究 指出突變的機轉才是決定疾病表現(HPD 或 苯酮尿症)的主要因子。疾病表現和遺傳型 式並沒有絕對的關係。 GTP cyclohydrolase I (GTPCH), which catalyzes the rate limiting step of tetrahydrobiopterin (BH4) biosynthesis, is associated with two clinically distinctive human diseases. Hyperphenylalaninemia is a severe disease induced by recessive GTPCH mutations, whereas dopa-responsive dystonia (DRD) is a benign disease in which only dominant mutations have been found. We found a homologous (recessive) GTPCH mutation (R249S, 747CàG) in a DRD patient who had low but measurable GTPCH activity in her PHA-stimulated mononuclear blood cells. Arginine 249 is located at the Cterminus of GTPCH, outside the enzyme catalytic site. The expression of GTPCH mRNA in the patient's mononuclear blood cells was normal. Enzyme specific activity and kinetics of R249S mutant protein expressed in E. coli and eukaryotic cells were also normal. However, the amount of R249S mutant protein expressed in transfected cells was lower than the wild-type protein. In pulse-chase experiment, the synthesis of mutant protein was normal, but its stability was decreased. This is the first destabilizing mutation found in the GTPCH gene. Our data raise the possibility that DRD could be either dominantly or recessively inherited. The phenotype of GTPCH deficiency seems to be determined by residual activity, while the inheritance is more likely determined by the mechanism of mutation. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/22823 | 其他識別: | 872314B002140 | Rights: | 國立臺灣大學醫學院小兒科 |
顯示於: | 醫學系 |
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872314B002140.pdf | 127.98 kB | Adobe PDF | 檢視/開啟 |
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