强直性肌营养不良中的RNA毒性诱导NKX2 - 5表达。 - Suppr

RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression.

作者信息

Yadava Ramesh S, Frenzel-McCardell Carla D, Yu Qing, Srinivasan Varadamurthy, Tucker Amy L, Puymirat Jack, Thornton Charles A, Prall Owen W, Harvey Richard P, Mahadevan Mani S

机构信息

Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA.

出版信息

Nat Genet. 2008 Jan;40(1):61-8. doi: 10.1038/ng.2007.28. Epub 2007 Dec 16.

Myotonic muscular dystrophy (DM1) is the most common inherited neuromuscular disorder in adults and is considered the first example of a disease caused by RNA toxicity. Using a reversible transgenic mouse model of RNA toxicity in DM1, we provide evidence that DM1 is associated with induced NKX2-5 expression. Transgene expression resulted in cardiac conduction defects, increased expression of the cardiac-specific transcription factor NKX2-5 and profound disturbances in connexin 40 and connexin 43. Notably, overexpression of the DMPK 3' UTR mRNA in mouse skeletal muscle also induced transcriptional activation of Nkx2-5 and its targets. In human muscles, these changes were specific to DM1 and were not present in other muscular dystrophies. The effects on NKX2-5 and its downstream targets were reversed by silencing toxic RNA expression. Furthermore, using Nkx2-5+/- mice, we show that NKX2-5 is the first genetic modifier of DM1-associated RNA toxicity in the heart.

强直性肌营养不良（DM1）是成人中最常见的遗传性神经肌肉疾病，被认为是由RNA毒性引起的疾病的首个实例。利用DM1中RNA毒性的可逆转基因小鼠模型，我们提供证据表明DM1与诱导的NKX2 - 5表达相关。转基因表达导致心脏传导缺陷、心脏特异性转录因子NKX2 - 5表达增加以及连接蛋白40和连接蛋白43的严重紊乱。值得注意的是，DMPK 3' UTR mRNA在小鼠骨骼肌中的过表达也诱导了Nkx2 - 5及其靶标的转录激活。在人类肌肉中，这些变化是DM1特有的，在其他肌肉营养不良症中不存在。通过沉默毒性RNA表达，对NKX2 - 5及其下游靶标的影响得以逆转。此外，使用Nkx2 - 5+/-小鼠，我们表明NKX2 - 5是心脏中DM1相关RNA毒性的首个遗传修饰因子。