Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects

强直性肌营养不良1型（DM 1）是由位于3'非翻译区的CTG扩增突变引起的。 肌营养不良蛋白激酶基因的一部分。RNA结合的鉴定和表征 与扩展的CUG重复序列相互作用的蛋白质，以及发现类似的转录但 内含子中未翻译的CCTG扩增导致强直性肌营养不良2型（DM 2），发现了一种新的 一种微卫星扩增突变通过RNA获得导致疾病的机制， CUG和CCUG扩增转录物导致关键RNA结合调节异常的功能机制 蛋白质，包括肌盲蛋白（MbnH）和CUG结合蛋白（CUG-BP），这反过来又导致 特定基因组的下游失调，导致两者共同的多系统特征 疾病尽管CNS缺陷是DM最具临床意义的方面之一，但其分子生物学特征是： 这些变化背后的机制尚不清楚。只有DM 1会导致发育缺陷，包括 精神发育迟滞，但这两种形式的糖尿病导致退行性中枢神经系统的影响， 表征了该提案的重点是表征DM 1和DM 2突变对CNS的影响 通过影像学研究和神经心理学测试对患者进行研究，并将这些变化与 通过小鼠模型的生成和表征来研究潜在的分子缺陷。完成 以下项目和核心被提议作为我们整体计划的一部分，该计划名为： 营养不良：分子病理生理学和中枢神经系统影响。 项目1：DM 1和DM 2中的时间/空间RNA表达效应 项目2：强直性肌营养不良中RNA介导的CNS发病机制 项目3：1型肌强直性营养不良儿童的结构和功能CNS变化 核心A：神经病理学和光学成像核心 核心B：行政核心

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the 3' untranslated portion of the dystrophica myotonica protein kinase gene. The identification and characterization of RNAbinding proteins that interact with expanded CUG repeats and the discovery that a similar transcribed but untranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2), have uncovered a new type of mechanism in which microsatellite expansion mutations cause disease through an RNA gain of function mechanism in which CUG and CCUG expansion transcripts lead to the dysregulation of key RNAbinding proteins, including muscleblind (MbnH) and CUG-binding protein (CUG-BP), which in turn lead to the downstream dysregulation of specific set of genes that cause the multisystemic features common to both diseases. Although the CNS deficits are one of the most clinically significant aspects of DM, the molecular mechanisms underlying these changes are unclear. Only DM1 causes developmental defects, including mental retardation, but both forms of DM result in degenerative CNS effects that have not yet been well characterized. The focus of this proposal is to characterize the CNS effects of the DM1 and DM2 mutations in patients through imaging studies and neuropsychological testing and to relate these changes to the underlying molecular deficits through the generation and characterization of mouse models. To accomplish these goals the following Projects and Cores are proposed as part of our overall Program entitled: Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects. Project 1: Temporal/spatial RNA expression effects in DM1 and DM2 Project 2: Mechanisms of RNA-Mediated CNS Pathogenesis in Myotonic Dystrophy Project 3: Structural and Functional CNS Changes in Children with Myotonic Dystrophy Type 1 Core A: Neuropathology and Optical Imaging Core Core B: Administrative Core