Activation of MAPK in hearts of EMD null mice:: similarities between mouse models of X-linked and autosomal dominant Emery-Dreifuss muscular dystrophy
Activation of MAPK in hearts of EMD null mice:: similarities between mouse models of X-linked and autosomal dominant Emery-Dreifuss muscular dystrophy
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DOI：
10.1093/hmg/ddm137
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Worman, Howard J.
中科院分区：
文献类型：
--
作者：
Muchir, Antoine;Pavlidis, Paul;Worman, Howard J.
Emery-Dreifuss肌营养不良症（EDMD）是一种遗传性疾病，其特征在于肱骨-腓骨分布中缓慢进行性骨骼肌无力、早期挛缩和伴有传导阻滞的明显心肌病。编码emerin的EMD和编码A型核纤层蛋白的LMNA的突变分别引起X连锁和常染色体显性EDMD。Emerin和A型核纤层蛋白是核膜内膜的蛋白质。虽然EDMD的遗传原因已经被描述，蛋白质也被很好地表征，但对核膜蛋白异常如何导致横纹肌疾病知之甚少。在这项研究中，我们分析了全基因组表达谱在心脏Emd基因敲除小鼠，一个模型的X-连锁EDMD，使用Affyssin基因芯片。该分析显示了与我们先前在Lmna H222 P基因敲入小鼠（常染色体显性EDMD模型）心脏中描述的分子特征相似的分子特征。在两种小鼠模型中，有丝分裂原活化蛋白激酶（MAPK）通路的ERK 1/2分支以及与心肌病发病机制有关的下游靶点的激活是共同的。MAPK信号的激活似乎是X连锁和常染色体显性EDMD中心脏病发展的基石。
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.