Muchir Antoine, Pavlidis Paul, Bonne Gisèle, Hayashi Yukiko K, Worman Howard J
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
Hum Mol Genet. 2007 Aug 1;16(15):1884-95. doi: 10.1093/hmg/ddm137. Epub 2007 Jun 13.
Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by slowly progressive skeletal muscle weakness in a humero-peroneal distribution, early contractures and prominent cardiomyopathy with conduction block. Mutations in EMD, encoding emerin, and LMNA, encoding A-type lamins, respectively, cause X-linked and autosomal dominant EDMD. Emerin and A-type lamins are proteins of the inner membrane of the nuclear envelope. Whereas the genetic cause of EDMD has been described and the proteins well characterized, little is known on how abnormalities in nuclear envelope proteins cause striated muscle disease. In this study, we analyzed genome-wide expression profiles in hearts from Emd knockout mice, a model of X-linked EDMD, using Affymetrix GeneChips. This analysis showed a molecular signature similar to that we previously described in hearts from Lmna H222P knock-in mice, a model of autosomal dominant EDMD. There was a common activation of the ERK1/2 branch of the mitogen-activated protein kinase (MAPK) pathway in both murine models, as well as activation of downstream targets implicated in the pathogenesis of cardiomyopathy. Activation of MAPK signaling appears to be a cornerstone in the development of heart disease in both X-linked and autosomal dominant EDMD.
埃默里-德赖富斯肌营养不良症（EDMD）是一种遗传性疾病，其特征为肱腓型分布的骨骼肌进行性缓慢无力、早期挛缩以及伴有传导阻滞的显著心肌病。分别编码emerin的EMD基因和编码A型核纤层蛋白的LMNA基因突变会导致X连锁型和常染色体显性EDMD。Emerin和A型核纤层蛋白是核被膜内膜的蛋白质。尽管EDMD的遗传病因已被描述，且相关蛋白质也已得到充分表征，但对于核被膜蛋白异常如何导致横纹肌疾病却知之甚少。在本研究中，我们使用Affymetrix基因芯片分析了X连锁型EDMD模型Emd基因敲除小鼠心脏的全基因组表达谱。该分析显示出一种与我们之前在常染色体显性EDMD模型Lmna H222P基因敲入小鼠心脏中所描述的分子特征相似的特征。在这两种小鼠模型中，丝裂原活化蛋白激酶（MAPK）途径的ERK1/2分支均有共同激活，以及与心肌病发病机制相关的下游靶点的激活。MAPK信号通路的激活似乎是X连锁型和常染色体显性EDMD心脏疾病发展中的一个基石。
