Choi Gyutae, Lee Sanghyo, Yoo Seungjae, Do Jeung Tae
Department of Stem Cell and Regenerative Biotechnology, KU Institute of Technology, Konkuk University, Seoul 05029, Republic of Korea.
3D Tissue Culture Research Center, Konkuk University, Seoul 05029, Republic of Korea.
Int J Mol Sci. 2025 Aug 26;26(17):8277. doi: 10.3390/ijms26178277.
Rett syndrome is a severe neurodevelopmental disorder that occurs primarily in females and is caused by mutations in the methyl-CpG-binding protein 2 () gene located on the X chromosome. Though MECP2 acts as a representative transcriptional regulator and affects gene expression both directly and indirectly, a complete understanding of this disease and the treatment mechanism has not been established yet. MECP2 plays a particularly important role in synaptic development, neuronal maturation, and epigenetic regulation in the brain. In this study, we summarize the molecular structure of MECP2, mutation-specific pathogenesis, and the role of MECP2 in regulating chromatin remodeling, RNA splicing, and miRNA processing to provide a comprehensive understanding of Rett syndrome. Additionally, we describe abnormal phenotypes manifested in various brain regions and other tissues owing to MECP2 dysfunction. Finally, we discuss current and future therapeutic approaches, including AAV-based gene therapy, RNA editing, X chromosome reactivation, and pharmacological interventions. Understanding the diverse functions and pathological mechanisms of MECP2 provides an important foundation for developing targeted therapies for Rett syndrome.
雷特综合征是一种严重的神经发育障碍疾病，主要发生于女性，由位于X染色体上的甲基化CpG结合蛋白2（MECP2）基因突变所致。尽管MECP2作为一种典型的转录调节因子，直接或间接地影响基因表达，但目前尚未完全明确该疾病及其治疗机制。MECP2在大脑的突触发育、神经元成熟和表观遗传调控中发挥着尤为重要的作用。在本研究中，我们总结了MECP2的分子结构、突变特异性发病机制，以及MECP2在调节染色质重塑、RNA剪接和微小RNA（miRNA）加工中的作用，以期全面了解雷特综合征。此外，我们还描述了由于MECP2功能障碍在各个脑区和其他组织中表现出的异常表型。最后，我们讨论了当前及未来的治疗方法，包括基于腺相关病毒（AAV）的基因治疗、RNA编辑、X染色体重新激活和药物干预。了解MECP2的多种功能和病理机制为开发针对雷特综合征的靶向治疗提供了重要基础。
