Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects

肌强直性营养不良1型（DM1）是由位于肌强直性营养不良蛋白激酶基因3'未翻译部分的CTG扩增突变引起的。与扩展的CUG重复序列相互作用的RNA结合蛋白的鉴定和表征，以及内含子中类似的转录但未翻译的CCTG扩增导致2型肌强直性营养不良（DM2）的发现，揭示了一种新型机制，其中微卫星扩增突变通过RNA获得功能机制导致疾病，其中CUG和CCUG扩增转录导致关键RNA结合蛋白的失调。包括肌肉盲（MbnH）和cug结合蛋白（CUG-BP），这反过来导致下游特定基因的失调，导致两种疾病共同的多系统特征。尽管中枢神经系统缺陷是糖尿病临床最重要的方面之一，但这些变化背后的分子机制尚不清楚。只有DM1会导致发育缺陷，包括智力迟钝，但两种形式的DM都会导致中枢神经系统退行性影响，目前尚未得到很好的表征。本提案的重点是通过影像学研究和神经心理学测试来表征患者DM1和DM2突变对中枢神经系统的影响，并通过小鼠模型的生成和表征将这些变化与潜在的分子缺陷联系起来。为了实现这些目标，我们提出了以下项目和核心，作为我们整体计划的一部分：肌强直性营养不良：分子病理生理学和中枢神经系统效应。

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 RNA-binding 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 RNA-binding 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