PREVENTION OF DYSTROPHIC PATHOLOGY IN MDX MICE BY A TRUNCATED DYSTROPHIN ISOFORM
PREVENTION OF DYSTROPHIC PATHOLOGY IN MDX MICE BY A TRUNCATED DYSTROPHIN ISOFORM
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DOI：
10.1093/hmg/3.10.1725
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发表时间：
1994-10-01
影响因子：
3.5
通讯作者：
CHAMBERLAIN, JS
中科院分区：
文献类型：
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作者：
RAFAEL, JA;SUNADA, Y;CHAMBERLAIN, JS
Dystrophin的C-末端结构域被选择性地剪接，以产生各种组织和发育阶段特有的异构体。最近的研究表明，C末端结构域与肌肉中的Dstrophin相关糖蛋白复合体(DGC)结合，但对选择性剪接的功能意义或个别亚型在特定组织中可能发挥的作用知之甚少。大脑中主要的营养不良蛋白转录本缺乏外显子71-74，并编码一种在骨骼肌中未观察到的异构体。为了探索这种截短的异构体在肌肉中发挥功能的能力，我们产生了表达小鼠肌营养不良蛋白微型基因缺失外显子71-74的转基因小鼠。在突变的MDX小鼠背景上统一表达该结构可导致正常的肌肉形态和生理，并防止肌肉营养不良的发展。这些小鼠也表现出DGC的正常表达和定位，这表明骨骼肌中Dstrophin的功能不需要选择性剪接的外显子。对另一种具有镶嵌表达模式的小鼠进行了分析。这些小鼠表现出明显比MDX小鼠温和的表型，尽管肌萎缩蛋白只在一半的肌肉纤维中表达。这些结果表明，将dystrophin病毒传递到肌肉群中的简单大多数纤维将大大减少与Duchenne肌营养不良相关的营养不良病理。
The C-terminal domain of dystrophin is alternatively spliced to produce a variety of tissue and developmental stage-specific isoforms. Recent studies suggest that the C-terminal domain binds to the dystrophin-associated glycoprotein complex (DGC) in muscle, but little is known about the functional significance of the alternative splicing or what role individual isoforms may play in specific tissues. The major dystrophin transcript in brain lacks exons 71 - 74, and encodes an isoform not observed in skeletal muscle. To explore the capacity of this truncated isoform to function in muscle, we have generated transgenic mice expressing a murine dystrophin mini-gene missing exons 71 - 74. Uniform expression of this construct on a mutant mdx mouse background results in normal muscle morphology and physiology, and prevents the development of muscular dystrophy. These mice also display normal expression and localization of the DGC, suggesting that the alternatively spliced exons are not required for dystrophin function in skeletal muscle. An additional line of mice was analyzed that had a mosaic pattern of expression. These mice display a markedly milder phenotype than mdx mice, despite the expression of dystrophin in only half the muscle fibers. These results indicate that viral delivery of dystrophin to a simple majority of fibers in a muscle group would greatly reduce the dystrophic pathology associated with Duchenne muscular dystrophy.