Pathophysiology of Rett Syndrome /MECP2 Mutations

x连锁神经发育障碍Rett综合征（RTT）是导致女性智力迟钝（MR）和自闭症的主要原因之一。80%患有RTT的女孩在编码甲基cpg结合蛋白2 （MeCP2）的基因上发生突变，MeCP2是一种结合甲基化胞嘧啶的转录抑制因子。MECP2突变的表型后果范围从随机X染色体失活（XCI）患者的经典RTT到XCI良好的女孩的轻度甚至无MR。我们假设MeCP2功能受损导致神经元发育关键基因的错误表达，这介导了RTT的发病机制和某些形式的自闭症和MR. Project 1 （Dr. Zoghbi）将为RTT的发病机制和治疗研究创建小鼠模型，使用微阵列技术评估RTT小鼠基因表达的改变，以及患有MR、自闭症或学习障碍的RTT女孩的散发性雌性和雌性亲属的基因型。项目2（博士）Glaze和Percy)将对项目1中研究的女孩进行临床表征，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的神经功能障碍。项目3 （Van den Veyver博士）将描述MECP2变异在发育中的大脑和RTT组织中的表达；将MECP2突变对人类细胞系、小鼠胚胎干细胞和非洲爪蟾基因表达的影响与小鼠模型的表达数据（项目1）相关联，并研究项目1和项目2中给予小鼠甲基供体的DNA甲基化变化。Core的形态学-神经病理学部分（Armstrong博士）将对小鼠模型进行系统的形态学分析（项目1），并对小鼠和人体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，我们希望在一部分患者中确定MR/LD或自闭症的原因，深入了解RTT的发病机制，并为这种及相关的晚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.