Muchir Antoine, Pavlidis Paul, Decostre Valérie, Herron Alan J, Arimura Takuro, Bonne Gisèle, Worman Howard J
Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street. New York, NY 10032, USA.
J Clin Invest. 2007 May;117(5):1282-93. doi: 10.1172/JCI29042. Epub 2007 Apr 19.
Mutations in LMNA, which encodes nuclear Lamins A and C cause diseases affecting various organs, including the heart. We have determined the effects of an Lmna H222P mutation on signaling pathways involved in the development of cardiomyopathy in a knockin mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy. Analysis of genome-wide expression profiles in hearts using Affymetrix GeneChips showed statistically significant differences in expression of genes in the MAPK pathways at the incipience of the development of clinical disease. Using real-time PCR, we showed that activation of MAPK pathways preceded clinical signs or detectable molecular markers of cardiomyopathy. In heart tissue and isolated cardiomyocytes, there was activation of MAPK cascades and downstream targets, implicated previously in the pathogenesis of cardiomyopathy. Expression of H222P Lamin A in cultured cells activated MAPKs and downstream target genes. Activation of MAPK signaling by mutant A-type lamins could be a cornerstone in the development of heart disease in autosomal dominant Emery-Dreifuss muscular dystrophy.
编码核纤层蛋白A和C的LMNA基因突变会引发影响包括心脏在内的多个器官的疾病。我们已经在常染色体显性遗传型埃默里-德赖富斯肌营养不良症的基因敲入小鼠模型中，确定了Lmna H222P突变对参与心肌病发展的信号通路的影响。使用Affymetrix基因芯片对心脏进行全基因组表达谱分析，结果显示在临床疾病发展初期，MAPK通路中的基因表达存在统计学上的显著差异。通过实时PCR，我们发现MAPK通路的激活先于心肌病的临床症状或可检测到的分子标志物出现。在心脏组织和分离出的心肌细胞中，MAPK级联反应及其下游靶点被激活，这些靶点先前被认为与心肌病的发病机制有关。在培养细胞中表达H222P核纤层蛋白A会激活MAPK及其下游靶基因。突变A型核纤层蛋白激活MAPK信号可能是常染色体显性遗传型埃默里-德赖富斯肌营养不良症中心脏病发展的一个基石。
