Samaco Rodney C, Nagarajan Raman P, Braunschweig Daniel, LaSalle Janine M
Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, University of California, Davis 95616, USA.
Hum Mol Genet. 2004 Mar 15;13(6):629-39. doi: 10.1093/hmg/ddh063. Epub 2004 Jan 20.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Although MECP2 is ubiquitously transcribed, MeCP2 expression is developmentally regulated and heterogeneous in neuronal subpopulations, defined as MeCP2(lo) and MeCP2(hi). To test the hypothesis that pathways affecting MeCP2 expression changes may be defective in RTT, autism and other neurodevelopmental disorders without MECP2 mutations, a high-throughput quantitation of MeCP2 expression was performed on a tissue microarray containing frontal cortex samples from 28 different patients with neurodevelopmental disorders and age-matched controls. Combined quantitative analyses of MeCP2 protein and alternatively polyadenylated transcript levels were performed by laser scanning cytometry and tested for significant differences from age-matched controls. Normal cerebral samples showed an increase in total MeCP2 expression and the percentage of MeCP2(hi) cells with age that could be explained by increased MECP2 transcription within the MeCP2(hi) population. A significant decrease in the relative usage of the long transcript in the MeCP2(lo) population was observed in postnatal compared to fetal brain, but alternate polyadenylation did not correlate with MeCP2 expression changes at the single cell level. Brain samples from several related neurodevelopmental disorders, including autism, pervasive developmental disorder, Prader-Willi and Angelman syndromes showed significant differences in MeCP2 expression from age-matched controls by apparently different transcriptional and post-transcriptional mechanisms. These results suggest that multiple pathways regulate the complex developmental expression of MeCP2 and are defective in autism-spectrum disorders in addition to RTT.
瑞特综合征（RTT）是一种由MECP2基因突变引起的神经发育障碍，MECP2编码甲基CpG结合蛋白2（MeCP2）。尽管MECP2在全身广泛转录，但MeCP2的表达在发育过程中受到调控，并且在神经元亚群中存在异质性，分为MeCP2(lo)和MeCP2(hi)。为了验证影响MeCP2表达变化的通路在RTT、自闭症和其他无MECP2突变的神经发育障碍中可能存在缺陷这一假设，对包含28名不同神经发育障碍患者和年龄匹配对照的额叶皮质样本的组织微阵列进行了MeCP2表达的高通量定量分析。通过激光扫描细胞术对MeCP2蛋白和可变聚腺苷酸化转录本水平进行联合定量分析，并测试与年龄匹配对照的显著差异。正常脑样本显示，总MeCP2表达以及MeCP2(hi)细胞百分比随年龄增加，这可以通过MeCP2(hi)群体中MECP2转录增加来解释。与胎儿脑相比，出生后MeCP2(lo)群体中长转录本的相对使用显著减少，但可变聚腺苷酸化与单细胞水平的MeCP2表达变化无关。来自几种相关神经发育障碍（包括自闭症、广泛性发育障碍、普拉德-威利综合征和安吉尔曼综合征）的脑样本显示，与年龄匹配对照相比，MeCP2表达存在显著差异，其机制明显不同，包括转录和转录后机制。这些结果表明，多种通路调节MeCP2复杂的发育表达，并且在除RTT之外的自闭症谱系障碍中存在缺陷。
