Molecular analysis of hereditary progressive dystonia

遗传性进行性肌张力障碍（HPD）是由GTP环水解酶I （GCH）基因突变引起的。这种疾病的临床表现差异很大，许多病例似乎是散发的。我们之前提出，这种临床表型可能是由于突变体和正常GCH mRNA的差异表达，可能是在蛋白质水平上。为了支持这一建议，我们研究了几个新的日本HPD家族，其中一些成员是杂合的外显子跳跃或单碱基改变突变。这些突变产生截短的GCH和突变的GCH，其中一个氨基酸被替换。在COS-7细胞中，利用突变体与野生型GCH的共表达，进一步研究表明突变体GCH使正常酶失活。这些结果表明，突变体GCH对正常酶的显性负作用可能是决定HPD临床表型异质性的分子机制之一。

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.