Systemic deletion of DMD exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking DMD exon 52

Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the dystrophin (DMD) gene, leading to the complete absence of DMD and progressive degeneration of skeletal and heart muscles. Expression of an internally shortened dystrophin in DMD subjects (DMDΔ52) can be achieved by skipping DMD exon 51 to reframe the transcript. To predict the best possible outcome of this therapeutic strategy, we generated transgenic pigs lacking DMD exon 51 and 52, additionally representing a new model for Becker muscular dystrophy (BMD). To inspect the proteome alterations caused by the different dystrophin mutations in an unbiased and comprehensive manner, we performed a label-free liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) of myocardial and skeletal muscle samples from wild-type (WT), DMDΔ52 and DMDΔ51-52 pigs.

杜氏肌营养不良症（Duchenne muscular dystrophy, DMD）是一种致命的X连锁疾病，由肌营养不良蛋白（dystrophin, DMD）基因突变引发，会导致肌营养不良蛋白完全缺失，并造成骨骼肌与心肌的进行性变性。通过跳过DMD外显子51以恢复转录本读码框，可在DMD患者体内表达内部截短型肌营养不良蛋白（即DMDΔ52型）。为预判该治疗策略的最优效果，我们构建了缺失DMD外显子51与52的转基因猪，该模型同时可作为贝克型肌营养不良症（Becker muscular dystrophy, BMD）的新型动物模型。为无偏且全面地探究不同肌营养不良蛋白突变引发的蛋白质组改变，我们对野生型（wild-type, WT）、DMDΔ52型及DMDΔ51-52型转基因猪的心肌和骨骼肌样本开展了无标记液相色谱-串联质谱分析（label-free liquid chromatography-tandem mass spectrometry, LC-MS/MS）。