Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.

中文翻译：

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DNA甲基-CpG结合蛋白MeCP2在瑞特综合征病理生物学和疾病机理中的作用

Rett综合征（RTT）是一种严重，罕见和进行性发展性疾病，患者表现出神经学退缩和自闭症谱特征。受影响的个体主要是年轻女性，超过95％的患者在甲基CpG结合蛋白2（MECP2）基因中带有从头突变。尽管大多数RTT患者具有MECP2突变（经典RTT），但一小部分患者（非典型RTT）可能在其他基因中带有遗传突变，例如细胞周期蛋白依赖性激酶样5（CDKL5）和FOXG1。由于RTT症状的神经学基础，MeCP2功能最初是在神经细胞（神经元）中研究的。但是，后来的研究强调了它在包括胶质细胞在内的其他脑细胞类型中的重要性。在这方面，科学家受益于使用许多不同的细胞系统和功能丧失或获得功能突变的转基因小鼠对疾病进行建模。此外，对人类死后脑组织的有限研究在RTT病理生物学和疾病机制方面提供了宝贵的发现。MeCP2在大脑中的表达受到严格调节，其表达的改变会导致大脑功能异常，在某些自闭症谱系障碍病例中牵涉MeCP2。在某些疾病条件下，MeCP2动态平衡控制受到损害，在啮齿动物中其调控涉及调控性microRNA（miR132）和脑源性神经营养因子（BDNF）。在这里，我们将概述RTT疾病的潜在机制以及MECP2基因相关的基因突变以及该疾病的病理生物学，两个研究最多的蛋白质变体（MeCP2E1和MeCP2E2同工型）的作用的最新进展。 ），以及控制大脑中MeCP2稳态网络的调节机制，包括BDNF和miR132。