Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy
Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy
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DOI：
10.1172/jci29042
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发表时间：
2007-05-01
影响因子：
15.9
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.
编码核层蛋白A和C的LMNA的突变会导致影响包括心脏在内的各种器官的疾病。我们在常染色体显性emry - dreifuss肌营养不良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基因芯片对心脏全基因组表达谱的分析显示，在临床疾病发展初期，MAPK通路中基因的表达具有统计学意义。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的分子标志物。在心脏组织和分离的心肌细胞中，有MAPK级联和下游靶点的激活，先前涉及心肌病的发病机制。H222P Lamin A在培养细胞中的表达激活了MAPKs和下游靶基因。突变a型纤层蛋白激活MAPK信号可能是常染色体显性埃默里-德莱弗斯肌营养不良患者心脏病发展的基石。
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.