Mild overexpression of MeCP2 causes a progressive neurological disorder in mice
Mild overexpression of MeCP2 causes a progressive neurological disorder in mice
复制标题
DOI：
10.1093/hmg/ddh282
复制
发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Zoghbi, HY
中科院分区：
文献类型：
--
作者：
Collins, AL;Levenson, JM;Zoghbi, HY
编码转录抑制因子的X连锁甲基CpG结合蛋白2（MECP2）的突变可导致Rett综合征和各种相关的神经发育障碍。与人类疾病相关的绝大多数突变是功能丧失型突变，但MeCP2功能的哪个方面对这些表型负责仍不清楚。我们在转基因小鼠中过表达野生型人类蛋白质，使用含有整个人类MECP2基因座的大基因组克隆。在转基因系MeCP2（Tg1）中进行的详细的神经行为和电生理研究表明，在10周龄左右开始出现表型，该转基因系表达的MeCP2水平与野生型相似。令人惊讶的是，这些小鼠显示出增强的运动和上下文学习以及海马体中增强的突触可塑性。然而，在20周龄后，这些小鼠出现癫痫发作，变得活动减退，其中30%的小鼠在1岁时死亡。这些数据表明，MeCP2水平必须在体内受到严格调控，即使这种蛋白质的轻度过表达也是有害的。此外，这些结果支持MECP2中的重复或功能获得性突变可能是某些X连锁迟发型神经行为障碍病例的基础。
Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at similar to2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and similar to30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.