Myotonic dystrophy (DM) is caused by expanded CTG/CCTG repeats, causing symptoms in skeletal muscle, heart, and central nervous system (CNS). CNS issues are debilitating and include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Here, we generate RNA-seq transcriptomes from DM and unaffected frontal cortex and identify 130 high-confidence splicing changes, most occurring only in cortex, not skeletal muscle or heart. Mis-spliced exons occur in neurotransmitter receptors, ion channels, and synaptic scaffolds, and GRIP1 mis-splicing modulates kinesin association. Optical mapping of expanded CTG repeats reveals extreme mosaicism, with some alleles showing >1,000 CTGs. Mis-splicing severity correlates with CTG repeat length across individuals. Upregulated genes tend to be microglial and endothelial, suggesting neuroinflammation, and downregulated genes tend to be neuronal. Many gene expression changes strongly correlate with mis-splicing, suggesting candidate biomarkers of disease. These findings provide a framework for mechanistic and therapeutic studies of the DM CNS.

强直性营养不良 (DM) 是由 CTG/CCTG 重复扩增引起的，导致骨骼肌、心脏和中枢神经系统 (CNS) 出现症状。中枢神经系统问题使人衰弱，包括嗜睡、执行功能障碍、白质萎缩和神经原纤维缠结。在这里，我们从 DM 和未受影响的额叶皮层生成 RNA-seq 转录组，并确定了 130 个高置信度剪接变化，大多数只发生在皮层，而不是骨骼肌或心脏。错误剪接的外显子发生在神经递质受体、离子通道和突触支架中，而 GRIP1 错误剪接可调节驱动蛋白的结合。扩展 CTG 重复序列的光学图谱显示极端镶嵌现象，一些等位基因显示 > 1,000 个 CTG。错接严重程度与个体间的 CTG 重复长度相关。上调的基因往往是小胶质细胞和内皮细胞，提示神经炎症，而下调的基因往往是神经元的。许多基因表达变化与错误剪接密切相关，表明疾病的候选生物标志物。这些发现为 DM CNS 的机制和治疗研究提供了框架。