Charlet-B Nicolas, Savkur Rajesh S, Singh Gopal, Philips Anne V, Grice Elizabeth A, Cooper Thomas A
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Cell. 2002 Jul;10(1):45-53. doi: 10.1016/s1097-2765(02)00572-5.
Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder caused by a CTG expansion in the 3' untranslated region of the DMPK gene. A predominant characteristic of DM1 is myotonia resulting from skeletal muscle membrane hyperexcitability. Here we demonstrate loss of the muscle-specific chloride channel (ClC-1) mRNA and protein in DM1 skeletal muscle tissue due to aberrant splicing of the ClC-1 pre-mRNA. The splicing regulator, CUG binding protein (CUG-BP), which is elevated in DM1 striated muscle, binds to the ClC-1 pre-mRNA, and overexpression of CUG-BP in normal cells reproduces the aberrant pattern of ClC-1 splicing observed in DM1 skeletal muscle. We propose that disruption of alternative splicing regulation causes a predominant pathological feature of DM1.
1型强直性肌营养不良症（DM1）是一种由DMPK基因3'非翻译区CTG重复扩增引起的显性多系统疾病。DM1的一个主要特征是骨骼肌膜兴奋性过高导致的肌强直。在此，我们证明，由于ClC-1前体mRNA的异常剪接，DM1骨骼肌组织中肌肉特异性氯离子通道（ClC-1）的mRNA和蛋白质缺失。剪接调节因子CUG结合蛋白（CUG-BP）在DM1横纹肌中表达升高，它与ClC-1前体mRNA结合，在正常细胞中过表达CUG-BP可重现DM1骨骼肌中观察到的ClC-1异常剪接模式。我们认为，可变剪接调控的破坏导致了DM1的一个主要病理特征。
