Department of Biology, Centro de Estudios Científicos, Valdivia, Chile.
Eur J Hum Genet. 2012 Jan;20(1):69-76. doi: 10.1038/ejhg.2011.145. Epub 2011 Aug 10.
Rett syndrome (RTT) is a disorder that affects patients' ability to communicate, move and behave. RTT patients are characterized by impaired language, stereotypic behaviors, frequent seizures, ataxia and sleep disturbances, with the onset of symptoms occurring after a period of seemingly normal development. RTT is caused by mutations in methyl-CpG binding protein 2 (MECP2), an X-chromosome gene encoding for MeCP2, a protein that regulates gene expression. MECP2 generates two alternative splice variants encoding two protein isoforms that differ only in the N-terminus. Although no functional differences have been identified for these splice variants, it has been suggested that the RTT phenotype may occur in the presence of a functional MeCP2-e2 protein. This suggests that the two isoforms might be functionally distinct. Supporting this notion, the two variants show regional and age-related differences in transcript abundance. Here, we show that transgenic expression of either the MeCP2-e1 or MeCP2-e2 splice variant results in prevention of development of RTT-like phenotypic manifestations in a mouse model lacking Mecp2. Our results indicate that the two MeCP2 splice variants can substitute for each other and fulfill the basic functions of MeCP2 in the mouse brain.
雷特综合征（RTT）是一种影响患者沟通、运动和行为能力的疾病。RTT 患者的特征是语言障碍、刻板行为、频繁发作、共济失调和睡眠障碍，症状发作发生在看似正常发育的一段时间之后。RTT 是由甲基-CpG 结合蛋白 2（MECP2）基因突变引起的，MECP2 是一个编码 MeCP2 的 X 染色体基因，是一种调节基因表达的蛋白质。MECP2 产生两种替代剪接变体，编码两种仅在 N 末端不同的蛋白异构体。尽管这些剪接变体没有发现功能差异，但有人提出 RTT 表型可能在存在功能性 MeCP2-e2 蛋白的情况下发生。这表明这两种异构体可能具有不同的功能。支持这一观点，两种变体在转录本丰度上表现出区域和年龄相关的差异。在这里，我们表明，在缺乏 Mecp2 的小鼠模型中，转基因表达 MeCP2-e1 或 MeCP2-e2 剪接变体均可预防 RTT 样表型表现的发展。我们的结果表明，两种 MeCP2 剪接变体可以相互替代，并在小鼠大脑中履行 MeCP2 的基本功能。
