Storbeck Christopher J, Drmanic Suzana, Daniel Kate, Waring James D, Jirik Frank R, Parry David J, Ahmed Nazim, Sabourin Luc A, Ikeda Joh-E, Korneluk Robert G
Solange-Gauthier-Karsh Molecular Genetics Laboartory, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
Hum Mol Genet. 2004 Mar 15;13(6):589-600. doi: 10.1093/hmg/ddh064. Epub 2004 Jan 20.
Myotonic dystrophy (DM1) is a multisystemic disorder caused by a CTG repeat expansion within the 3'-UTR of the DMPK gene. DM1 is characterized by delayed muscle development, muscle weakness and wasting, cardiac conduction abnormalities, cognitive defects and cataracts. Recent studies have demonstrated that the disease mechanism involves a dominant gain-of-function conferred upon mutant transcripts by expanded repeats. However, further attempts to model aspects of DM muscle pathology in cultured myoblasts suggest that 3'-UTR sequences flanking the CTG repeat tract are also required for full expression of the disease phenotype. Here, we report that overexpression of the DMPK 3'-UTR including either wild-type (11) or expanded (91) CTG repeats results in aberrant and delayed muscle development in fetal transgenic mice. In addition, transgenic animals with both expanded and wild-type CTG repeats display muscle atrophy at 3 months of age. Primary myoblast cultures from both 11 and 91 repeat mice display reduced fusion potential, but a greater reduction is observed in the 91 repeat cultures. Taken together, these data indicate that overexpression of the DMPK 3'-UTR interferes with normal muscle development in mice and that this is exacerbated by inclusion of a mutant repeat. This suggests that the delayed muscle development in DM1 involves an interplay between the expanded CTG repeat and adjacent 3'-UTR sequences.
强直性肌营养不良1型（DM1）是一种多系统疾病，由DMPK基因3'-非翻译区（UTR）内的CTG重复序列扩增引起。DM1的特征是肌肉发育延迟、肌肉无力和萎缩、心脏传导异常、认知缺陷和白内障。最近的研究表明，疾病机制涉及扩增重复序列赋予突变转录本的显性功能获得。然而，进一步尝试在培养的成肌细胞中模拟DM肌肉病理学的各个方面表明，CTG重复序列侧翼的3'-UTR序列对于疾病表型的完全表达也是必需的。在此，我们报告，包含野生型（11个）或扩增型（91个）CTG重复序列的DMPK 3'-UTR的过表达导致胎儿转基因小鼠出现异常和延迟的肌肉发育。此外，具有扩增型和野生型CTG重复序列的转基因动物在3个月大时出现肌肉萎缩。来自11个和91个重复序列小鼠的原代成肌细胞培养物显示融合潜能降低，但在91个重复序列培养物中观察到更大程度的降低。综上所述，这些数据表明DMPK 3'-UTR的过表达会干扰小鼠的正常肌肉发育，并且包含突变重复序列会加剧这种干扰。这表明DM1中延迟的肌肉发育涉及扩增的CTG重复序列与相邻3'-UTR序列之间的相互作用。
