Mankodi Ami, Takahashi Masanori P, Jiang Hong, Beck Carol L, Bowers William J, Moxley Richard T, Cannon Stephen C, Thornton Charles A
Department of Neurology, School of Medicine and Dentistry, University of Rochester, Box 673, 601 Elmwood Avenue, New York 14642, USA.
Mol Cell. 2002 Jul;10(1):35-44. doi: 10.1016/s1097-2765(02)00563-4.
In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
在强直性肌营养不良（肌强直性营养不良，DM）中，含有扩展的CUG或CCUG重复序列的RNA的表达与骨骼肌的变性和重复动作电位（肌强直）有关。利用DM转基因小鼠模型的骨骼肌，我们发现扩展的CUG重复序列的表达将跨膜氯电导降低到远低于预期引起肌强直的水平。扩展的CUG重复序列触发肌肉中主要氯通道ClC-1的前体mRNA的异常剪接，导致表面膜上ClC-1蛋白的丢失。我们还在两种类型的人类DM中发现了ClC-1剪接和表达的类似缺陷。我们提出，突变RNA对RNA加工的反式显性效应导致DM中的氯通道病和膜兴奋性过高。
