Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.
Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.
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DOI：
10.1016/j.cell.2015.10.049
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发表时间：
2015-11-19
期刊：
影响因子：
64.5
通讯作者：
Zatz M
中科院分区：
文献类型：
--
作者：
Vieira NM;Elvers I;Alexander MS;Moreira YB;Eran A;Gomes JP;Marshall JL;Karlsson EK;Verjovski-Almeida S;Lindblad-Toh K;Kunkel LM;Zatz M
杜氏肌营养不良症是由肌营养不良蛋白基因突变引起的，是肌营养不良症最常见的形式。DMD无法治愈，目前恢复肌营养不良蛋白表达的治疗方法仅部分有效。肌营养不良蛋白在肌肉中的缺乏导致信号传导途径的失调，这可能是疾病治疗和药物发现的靶点。以前，我们确定了两个特殊的金毛寻回犬肌营养不良症（GRMD）的狗是轻度影响，有功能的肌肉和正常的寿命，尽管完全没有抗肌萎缩蛋白。现在，我们对这些狗与严重受影响的GRMD和对照动物进行的连锁、全基因组测序和转录组分析的数据显示，Jagged1基因（Notch信号通路的已知调节因子）的表达增加是轻度表型的标志。功能分析表明，Jagged1过表达改善营养不良的表型，表明Jagged1可能代表一个目标，DMD治疗的肌营养不良蛋白的独立方式。
Duchenne muscular dystrophy, caused by mutations at the dystrophin gene, is the most common form of Muscular Dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways which could be targets for disease therapy and drug discovery. Previously we identified two exceptional Golden Retriever Muscular Dystrophy (GRMD) dogs that are mildly affected, have functional muscle and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole genome sequencing and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveal that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner.