Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan.
Nat Commun. 2011;2:308. doi: 10.1038/ncomms1306.
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by a loss of the dystrophin protein. Control of dystrophin mRNA splicing to convert severe DMD to a milder phenotype is attracting much attention. Here we report a dystrophinopathy patient who has a point mutation in exon 31 of the dystrophin gene. Although the mutation generates a stop codon, a small amount of internally deleted, but functional, dystrophin protein is produced in the patient cells. An analysis of the mRNA reveals that the mutation promotes exon skipping and restores the open reading frame of dystrophin. Presumably, the mutation disrupts an exonic splicing enhancer and creates an exonic splicing silencer. Therefore, we searched for small chemicals that enhance exon skipping, and found that TG003 promotes the skipping of exon 31 in the endogenous dystrophin gene in a dose-dependent manner and increases the production of the dystrophin protein in the patient's cells.
杜氏肌营养不良症（DMD）是一种致命的肌肉萎缩疾病，由肌营养不良蛋白的缺失引起。控制肌营养不良蛋白 mRNA 的剪接，将严重的 DMD 转化为更温和的表型，这引起了广泛关注。本文报道了一名肌营养不良症患者，其肌营养不良蛋白基因第 31 外显子发生点突变。尽管该突变产生了一个终止密码子，但在患者细胞中仍会产生少量内部缺失但具有功能的肌营养不良蛋白。对 mRNA 的分析表明，该突变促进了外显子跳跃，并恢复了肌营养不良蛋白的开放阅读框。推测该突变破坏了外显子剪接增强子并创建了外显子剪接沉默子。因此，我们寻找了能促进外显子跳跃的小分子化合物，发现 TG003 能以剂量依赖的方式促进内源性肌营养不良蛋白基因第 31 外显子的跳跃，并增加患者细胞中肌营养不良蛋白的产生。
