Pathophysiology of Rett Syndrome /MECP2 Mutations

X连锁神经发育障碍雷特综合征(RTT)是女性精神发育迟滞(MR)和自闭症的主要原因之一。80%患有RTT的女孩有编码甲基CpG结合蛋白2(MeCP2)的基因突变，MeCP2是一种结合甲基化胞嘧啶的转录抑制因子。MECP2突变的表型后果从具有随机X染色体失活(XCI)的女孩中的经典RTT到具有良好XCI的女孩中的轻微甚至没有MR。我们假设MeCP2功能受损会导致神经元发育关键基因的错误表达，从而介导RTT的发病机制和某些形式的自闭症，项目1(Zoghbi博士)将为RTT创建小鼠模型，用于发病机制和治疗研究，使用微阵列技术评估RTT小鼠的基因表达变化，以及具有MR、自闭症或学习障碍的散发性RTT女孩的基因表达变化。项目2(Glaze和Percy博士)将对项目1中研究的女孩进行临床研究，并测试甲基供体(叶酸和甜菜碱)是否可以通过增强胞嘧啶甲基化来改善RTT中的神经功能障碍。项目3(Van den Veyver博士)将表征MECP2变体在发育中的大脑和RTT组织中的表达；MECP2突变对人类细胞系、小鼠胚胎干细胞和非洲爪哇基因表达的影响与小鼠模型(项目1)的表达数据相关联(项目1)，以及在项目1和项目2中研究甲基供体对小鼠DNA甲基化的变化。Core的形态-神经病理学部分(博士Armstrong)将对小鼠模型(项目1)进行系统的形态分析，并对小鼠和人类组织进行免疫组织化学研究(项目3)。通过这些多学科的研究，我们希望找出一部分患者中MR/LD或自闭症的原因，深入了解RTT的发病机制，并为这种疾病和相关的迟发性神经发育疾病制定治疗策略。

The X-linked neurodevelopmental disorder Rett syndrome (RTT) is one of the leading causes of mental retardation (MR) and autism in females. 80% of girls with RTT have mutations in the gene encoding methyl-CpG- binding protein 2 (MeCP2), a transcriptional repressor that binds methylated cytosines. The phenotypic consequences of MECP2 mutations range from classic RTT in those with random X chromosome inactivation (XCI) to mild or even no MR in girls with favorable XCI. We hypothesize that impaired MeCP2 function leads to misexpression of genes crucial for neuronal development, which mediates RTT pathogenesis and some forms of autism and MR. Project 1 (Dr. Zoghbi) will create mouse models for RTT for pathogenesis and therapeutic studies, use microarray technology to evaluate alterations in gene expression in the RTT mice, and genotypic sporadic females and female relatives of RTT girls with MR, autism, or learning disabilities. Project 2 (Drs. Glaze and Percy) will clinically characterize the girls studied in Project 1 and test whether methyl donors (folate and betaine) can ameliorate neurologic dysfunction in RTT by enhancing cytosine methylation. Project 3 (Dr. Van den Veyver) will characterize expression of MECP2 variants in developing brain and in RTT tissue; correlate effects of MECP2 mutations on gene expression in human cell lines, mouse embryonic stem cells and Xenopus with expression data from mouse models (Project 1) and study changes in DNA methylation by methyl donors administered to mice in Projects 1 and 2. The Morphology-Neuropathology portion of the Core (Dr. Armstrong) will do systematic morphological analyses on mouse models (Project 1) and conduct immunohistochemical studies on mouse and human tissues (Project 3). Through these multi-disciplinary studies we hope to identify the cause of MR/LD or autism in a subset of patients, to gain insight into the pathogenesis of RTT, and to develop therapeutic strategies for this and related late-onset neurodevelopmental diseases.