Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA missplicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.

中文翻译：

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强直性肌营养不良的短串联重复小鼠敲入模型中 RNA 选择性剪接的细胞类型特异性失调。

短串联重复序列 (STR) 容易发生扩增突变，从而导致多种遗传性神经和神经肌肉疾病。为了使用概括了 STR 扩增基因的组织特异性和发育时间的小鼠模型研究病理机制，我们使用滚环扩增和 CRISPR/Cas9 介导的基因组编辑来生成 1 型强直性肌营养不良（DM1）的 Dmpk CTG 扩增（CTGexp）敲入模型). 我们证明骨骼肌成肌细胞和脑脉络丛上皮细胞特别容易受到 Dmpk CTGexp 突变和 RNA 错误剪接的影响。我们的结果表明肌肉再生和脑脊液稳态失调是 DM1 的早期致病事件。