Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects

描述（由申请人提供）：1型强直性肌营养不良（DM 1）由位于DMPK基因中的CTG扩增突变引起。与扩增的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CCTG扩增导致强直性肌营养不良2型（DM 2）的发现，为RNA功能获得效应在骨骼肌DM表现中发挥重要作用提供了强有力的支持。虽然中枢神经系统的缺陷是糖尿病的最重要的临床方面之一，这些变化的分子机制尚不清楚。在目前的资助期间取得的进展扩展了我们对疾病的CNS特征和微卫星扩增突变的分子机制的理解。项目3（PI：Day）已经确定DM导致白色物质完整性的显著弥漫性异常，其与儿童的认知缺陷和成人的执行功能缺陷相似。Project #2 (PI Swanson）通过证明MBNL基因家族的另一个成员MBNL 2是出生后大脑发育期间选择性剪接的关键调节剂，扩展了我们对RNA获得功能效应的作用的理解。项目1（PI：Ranum）意外地发现微卫星扩增突变可以表达没有典型的AUC起始密码子的均聚扩增蛋白，并且新的蛋白质在DM患者组织中积累。这些结果表明，新的扩展蛋白有助于DM。该提案的重点将是更好地了解DM 1和DM 2突变的临床后果，并将特定的临床表型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3个项目和2个核心：项目1：DM 1和DM 2中重复相关的非ATG翻译项目2：强直性肌营养不良中RNA介导的CNS发病机制项目3：强直性肌营养不良的临床和遗传特征核心A：神经病理学/功能成像核心B：行政核心。

DESCRIPTION (provided by applicant): Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the DMPK gene. The identification and characterization of RNA-binding proteins that interact with expanded CUG repeats and the discovery that a similar CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2), have provided strong support that RNA gain of function effects play an important role in DM manifestations in skeletal muscle. Although the CNS deficits are one of the most clinically significant aspects of DM, the molecular mechanisms underlying these changes have been unclear. Progress during the current funding period extends our understanding of the CNS features of the disease and molecular mechanisms of microsatellite expansion mutations. Project #3 (PI: Day) has established that DM results in a striking diffuse abnormality of white matter integrity that parallels the cognitive deficits in children, and executive function deficits in adults. Project #2 (PI: Swanson) has extended our understanding of the role of RNA gain of function effects by demonstrating that another member of the MBNL gene family, MBNL2, is a critical regulator of alternative splicing during postnatal brain development. Project #1 (PI: Ranum) has made the unexpected discovery that microsatellite expansion mutations can express homopolymeric expansion proteins without the canonical AUG-initiation codon and that novel proteins accumulate in DM patient tissue. These results suggest novel expansion proteins contribute to DM. The focus of this proposal will be to better understand the clinical consequences of the DM1 and DM2 mutations and to relate specific clinical phenotypes to underlying molecular deficits. To accomplish these goals we propose 3 Projects and 2 Cores: Project 1: Repeat-Associated Non-ATG Translation in DM1 and DM2 Project 2: Mechanisms of RNA-Mediated CNS Pathogenesis in Myotonic Dystrophy Project 3: Clinical and Genetic Characterization of Myotonic Dystrophy Core A: Neuropathology/Functional Imaging Core Core B: Administrative Core.