CNS DEGENERATION IN MYOTONIC DYSTROPHY TYPES 1 AND 2

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。为了更好地定义肌强直性营养不良（DM）的病理生理基础，我们将阐明中枢神经系统（CNS）参与DM1（19号染色体）和DM2（3号染色体）的异同，我们成功地利用这一方法阐明了RNA在这种多系统疾病的许多其他特征中的作用。利用明尼苏达大学独特的患者群体，我们将研究40名真正的成人发病DM1受试者，40名DM2成人，40名对照组和40名先天性DM1成人，比较神经心理学和体积MRI，弥散张量成像和分数各向异性用于确定灰质和白质病理。这将使我们能够确定这两种疾病中不寻常的病理相似性，这可能是由RNA效应引起的。在所有这些受试者中，以及在DM1和DM2受试者中，我们将确定相关基因（胰岛素受体、氯通道、肌小管蛋白）的剪接变化程度是否与DM1位点的重复长度或甲基化相关。这些结果将有助于确定糖尿病对中枢神经系统的病理生理作用，以及RNA重复扩增和甲基化在产生疾病这些特征中的作用

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To better define the pathophysiological basis of myotonic dystrophy (DM), we will clarify the differences and similarities of central nervous system (CNS) involvement in DM1 (chromosome 19) and DM2 (chromosome 3), an approach we successfully used to clarify the role of RNA in many other features of this multisystemic disease. Using the unique patient populations at the University of Minnesota, we will study 40 true adult-onset DM1 subjects, 40 DM2 adults, 40 controls, and 40 adults with congenital DM1, comparing neuropsychological and volumetric MRI, with diffusion tensor imaging and fractional anisotropy used to determine gray and white matter pathology. This will allow us to identify unusual pathological similarities in the two diseases, which are likely to be caused by the RNA effect. In all of these subjects, as well as in a larger group of DM1 and DM2 subjects we will determine whether the degree of splicing change in relevant genes (insulin receptor, chloride channel, myotubularin) correlates with repeat length or methylation of DM1 locus. These results will help determine the pathyophysiological effects of DM on the CNS and the role of RNA repeat expansions and methylation in creating those features of the disease