Dominant negative effect of GTP cyclohydrolase I mutations in dopa‐responsive hereditary progressive dystonia
Dominant negative effect of GTP cyclohydrolase I mutations in dopa‐responsive hereditary progressive dystonia
复制标题
GTP 环水解酶 I 突变对多巴反应性遗传性进行性肌张力障碍的显着负面影响
作者：
M. Hirano;Takehiko Yanagihara;S. Ueno
遗传性进行性肌张力障碍（HPD）是由编码GTP环化水解酶I（GCH）的突变基因引起的。这种疾病的临床表现差异很大，许多病例似乎是散发的。我们以前提出，这种临床变化可能是由于突变和正常GCH mRNA的差异表达，大概在蛋白质水平。为了支持这一提议，我们研究了一个新的日本HPD家族，其中2名成员为外显子跳跃突变杂合子。该突变产生截短的GCH，其在正常酶（GCH 180）的氨基末端共享180个氨基酸残基。一个受影响的杂合子有一个较高的突变/正常mRNA的比例比一个未受影响的杂合子，与我们以前的发现在HPD家族与GCH 114一致。进一步的研究，使用突变体与野生型GCH在COS-7细胞中的共表达，表明三种突变GCH使正常酶失活。GCH 114是最有效的酶失活，其次是GCH 180和正常发生的突变体GCH 209。这些结果表明，突变GCH对正常酶的显性负效应可能是决定HPD临床表型异质性的分子机制之一。
Herediatary progressive dystonia (HPD) is caused by the mutant gene encoding GTP cyclohydrolase I (GCH). The clinical presentation of this disease varies considerably, and many cases appear to be sporadic. We have previously proposed that this clinical variation 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 a new Japanese family with HPD, in which 2 members were heterozygous for an exon‐skipping mutation. This mutation produced truncated GCH, which shared 180‐amino acid residues at the amino terminus of the normal enzyme (GCH180). An affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote, consistent with our previous finding in the HPD family with GCH114. A further study, using coexpression of the mutant with wild‐type GCH in COS‐7 cells, showed that three mutant GCHs inactivated the normal enzyme. GCH114 was most effective in enzyme inactivation, which was followed by GCH180 and a normally occurring mutant GCH209. 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.
通过差异剪接产生的转录激活子 mTFE3 的显性失活形式。
DOI：
10.1126/science.1840705
发表时间：
1991
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Roman,C;Cohn,L;Calame,K
通讯作者：
Calame,K