遗传性扩张型心肌病LMNA基因突变的致病机理研究
|
摘要
核纤层蛋白基因突变可以引起扩张型心肌病,其特点是以房室传导阻滞为首发症状,心脏扩张症状出现迟于电生理异常；患者猝死率高,死因常为恶性心律失常。其发病机制现在尚不清楚,本研究从分子电生理机制方面探讨传导阻滞首发的原因,为疾病表型的发生机理提供一个可能的假说。
第一部分遗传性扩张型心肌病LMNA基因突变体表达载体的构建
目的：构建遗传性扩张型心肌病LMNA基因E82K、R644C、N195K突变体表达载体。方法：利用快速PCR定点突变技术,设计一对引物(包含预定的突变),通过PCR扩增出含突变位点的质粒,然后转化到超级感受态细胞中,用碱裂解法抽提质粒,进行测序鉴定,得到构建遗传性扩张型心肌病LMNA E82K、R644C、N195K突变体HEK293细胞异源表达载体；通过测序验证突变的正确性。结果：测序验证我们成功构建了遗传性扩张型心肌病LMNA基因E82K、R644C、N195K突变体表达载体。结论：成功构建表达载体为下一步研究奠定基础。
第二部分致遗传性扩张型心肌病房室伴传导阻滞的核纤层蛋白基因突变下调钠电流密度
目的：传导阻滞和恶性心律失常常与钠通道障碍有关。因此,本部分研究核纤层蛋白基因突变对钠通道功能的影响。方法：采用聚合酶链反应法制备相关LMNA突变体：E82K、R644C和N195K。将突变和野生的LMNA突变体和SCN5A的cDNA共转到HEK293细胞,应用全细胞膜片钳技术记录通道电流；利用实时定量RT-PCR和Western blot分析SCN5A基因表达水平。结果：相比于野生型,LMNA E82K明显降低HEK293细胞钠电流密度LMNA(86.19±9.36pA／pF,n=30 vs.155.73±19.09pA／pF,n=47;p=0.001),而LMNA R644C和N195K对此无明显影响。LMNA突变体不影响SCN5A的转录水平,但是LMNA E82K会抑制SCN5A蛋白表达,幅度达到30%。其他两个突变对蛋白表达水平并无影响。结论：核纤层蛋白导致的钠电流密度减小可能是核纤层蛋白突变致心脏传导阻滞的机制之一,它通过抑制蛋白表达水平抑制电流,而不影响转录水平;但它并非是唯一机制,LMNA N195K可能通过其它机制引起临床上传导阻滞的疾病表型。
第三部分致遗传性扩张型心肌病伴房室传导阻滞的核纤层蛋白基因突变引起缝隙连接43重构
目的：核纤层蛋白基因突变引起的扩张型心肌病的特点是以房室传导阻滞为首发症状,心脏扩张症状出现较迟。这种疾病表型与缝隙链接蛋白异常引起的心脏疾病相似。本部分研究核纤层蛋白基因突变对缝隙链接蛋白的影响。方法：利用野生和突变(E82K和R644C)的核纤层蛋白基因转染乳鼠心肌细胞,通过共聚焦显微镜和蛋白印迹分析探索缝隙链接改变。结果：E82K突变使缝隙链接蛋白43的表达量减少40%,其定位也发生改变,由细胞连接处转移到细胞内；但该突变对缝隙链接蛋白40影响不显著。而R644C突变对缝隙链接蛋白43和40都无明显影响。结论：核纤层蛋白基因突变导致的缝隙链接蛋白表达和定位的改变可能是导致心脏传导阻滞表现的机制之一。
Mutations in the lamin A/C gene (LMNA) may cause familial dilated cardiomyopathy (DCM) characterized by early onset of atrioventricular block (AVB) before the manifestation of DCM. The molecular mechanisms underlying the disease have not been fully clarified. We suggest a hypothesis that it is due to abnormalities of SCN5A ion channel and gap junctions explored using molecular biology and patch clamping techniques.
Part 1 Construction of the Eukaryotic Expression Vector of the LMNA Gene Mutation E82K、R644C、N195K
Objective:To construct the eukaryotic expression vector of the HERG gene and express in HEK293 cell. Methods:Amino acid substitution of glutamic for aspartic at position 82、644 and 195(E82K、R644C、N195K)in LMNA was performed by polymerase chain reaction(PCR).Mutagenesis was performed by site-directed mutagenesis PCR. The primers contained the mutant site. The mutant plasmid was confirmed by sequence analysis. Results:The eukaryotic expression vector was constructed correctly. Conclusions:The constrauts was made successfully, it was the foundation for the further functional study.
Part 2 Familial dilated cardiomyopathy-related lamin A/C gene mutation E82K reduces sodium current density
Objective:The phenotype of LMNA-related DCM is very similar to the phenotype of SCN5A-related DCM. Therefore, we studied the effects of LMNA mutations on SCN5A channels. Methods and results:The sodium current densities were studied in HEK293 cell lines co-transfected with wild-type (WT) or mutant LMNA (E82K and R644C) and SCN5A cDNA using whole-cell patch-clamp recording techniques. The peak sodium current density was reduced significantly in the cells transfected with LMNA E82K compared to that in cells transfected with WT LMNA (86.19±9.36pA/pF, n=30 vs.155.73±19.09pA/pF, n=47; p=0.001). The reduction of sodium current densities in LMNA E82K mutant cells was due to repressed SCN5A gene translation. The level of sodium channel protein was 0.72±0.14 in LMNA E82K cells relative to control vs.1±0.13 in WT LMNA cells (p<0.05); however, transcription of the SCN5A gene was not altered. Conclusions:Our findings suggest that the LMNA E82K mutation down-regulates sodium channel function by inhibiting SCN5A translation rather than transcription, and provides new insights into the mechanisms of DCM in these patients. The exact mechanism of the effect of the LMNA E82K mutation on SCN5A translation remains to be elucidated.
Part 3 Connexin43 Remodeling induced by LMNA gene mutations in family Dilated Cardiomyopathy with atrial ventricular block
Object:Mutations in the lamin A/C gene (LMNA) may cause familial dilated cardiomyopathy (dilated cardiomyopathy) characterized by early onset atrio-ventricular block (A-V block) before the manifestation of dilated cardiomyopathy and high risk of sudden death due to ventricular arrhythmia, which is very similar to the phenotype of gap junction related heart disease. In this part, we studied the effect of LMNA mutations on connexins. Methods:The Cx43 and Cx40 expression in cultured neonatal myocytes transfected with wild-type (WT) or mutant LMNA (E82K and R644C) were studied using confocal imaging and western blot analysis. Results:Cx43 protein expression was reduced by 40% in cells transfected with LMNA E82K than that in cells transfected with WT LMNA cDNA. Confocal imaging showed that the Cx43 located inside of the cells. By contrast, LMNA E82K mutation had no effect on expression and localization of Cx40. LMNA R644C transfection did not show any significant effects on gap junctions at all. Conclusions--Our findings suggest that LMNA E82K significantly reduced the Cx43 expression and altered its localization which may be one of the pathological mechanisms underlie LMNA-related heart disease.
第一部分遗传性扩张型心肌病LMNA基因突变体表达载体的构建
目的：构建遗传性扩张型心肌病LMNA基因E82K、R644C、N195K突变体表达载体。方法：利用快速PCR定点突变技术,设计一对引物(包含预定的突变),通过PCR扩增出含突变位点的质粒,然后转化到超级感受态细胞中,用碱裂解法抽提质粒,进行测序鉴定,得到构建遗传性扩张型心肌病LMNA E82K、R644C、N195K突变体HEK293细胞异源表达载体；通过测序验证突变的正确性。结果：测序验证我们成功构建了遗传性扩张型心肌病LMNA基因E82K、R644C、N195K突变体表达载体。结论：成功构建表达载体为下一步研究奠定基础。
第二部分致遗传性扩张型心肌病房室伴传导阻滞的核纤层蛋白基因突变下调钠电流密度
目的：传导阻滞和恶性心律失常常与钠通道障碍有关。因此,本部分研究核纤层蛋白基因突变对钠通道功能的影响。方法：采用聚合酶链反应法制备相关LMNA突变体：E82K、R644C和N195K。将突变和野生的LMNA突变体和SCN5A的cDNA共转到HEK293细胞,应用全细胞膜片钳技术记录通道电流；利用实时定量RT-PCR和Western blot分析SCN5A基因表达水平。结果：相比于野生型,LMNA E82K明显降低HEK293细胞钠电流密度LMNA(86.19±9.36pA／pF,n=30 vs.155.73±19.09pA／pF,n=47;p=0.001),而LMNA R644C和N195K对此无明显影响。LMNA突变体不影响SCN5A的转录水平,但是LMNA E82K会抑制SCN5A蛋白表达,幅度达到30%。其他两个突变对蛋白表达水平并无影响。结论：核纤层蛋白导致的钠电流密度减小可能是核纤层蛋白突变致心脏传导阻滞的机制之一,它通过抑制蛋白表达水平抑制电流,而不影响转录水平;但它并非是唯一机制,LMNA N195K可能通过其它机制引起临床上传导阻滞的疾病表型。
第三部分致遗传性扩张型心肌病伴房室传导阻滞的核纤层蛋白基因突变引起缝隙连接43重构
目的：核纤层蛋白基因突变引起的扩张型心肌病的特点是以房室传导阻滞为首发症状,心脏扩张症状出现较迟。这种疾病表型与缝隙链接蛋白异常引起的心脏疾病相似。本部分研究核纤层蛋白基因突变对缝隙链接蛋白的影响。方法：利用野生和突变(E82K和R644C)的核纤层蛋白基因转染乳鼠心肌细胞,通过共聚焦显微镜和蛋白印迹分析探索缝隙链接改变。结果：E82K突变使缝隙链接蛋白43的表达量减少40%,其定位也发生改变,由细胞连接处转移到细胞内；但该突变对缝隙链接蛋白40影响不显著。而R644C突变对缝隙链接蛋白43和40都无明显影响。结论：核纤层蛋白基因突变导致的缝隙链接蛋白表达和定位的改变可能是导致心脏传导阻滞表现的机制之一。
Mutations in the lamin A/C gene (LMNA) may cause familial dilated cardiomyopathy (DCM) characterized by early onset of atrioventricular block (AVB) before the manifestation of DCM. The molecular mechanisms underlying the disease have not been fully clarified. We suggest a hypothesis that it is due to abnormalities of SCN5A ion channel and gap junctions explored using molecular biology and patch clamping techniques.
Part 1 Construction of the Eukaryotic Expression Vector of the LMNA Gene Mutation E82K、R644C、N195K
Objective:To construct the eukaryotic expression vector of the HERG gene and express in HEK293 cell. Methods:Amino acid substitution of glutamic for aspartic at position 82、644 and 195(E82K、R644C、N195K)in LMNA was performed by polymerase chain reaction(PCR).Mutagenesis was performed by site-directed mutagenesis PCR. The primers contained the mutant site. The mutant plasmid was confirmed by sequence analysis. Results:The eukaryotic expression vector was constructed correctly. Conclusions:The constrauts was made successfully, it was the foundation for the further functional study.
Part 2 Familial dilated cardiomyopathy-related lamin A/C gene mutation E82K reduces sodium current density
Objective:The phenotype of LMNA-related DCM is very similar to the phenotype of SCN5A-related DCM. Therefore, we studied the effects of LMNA mutations on SCN5A channels. Methods and results:The sodium current densities were studied in HEK293 cell lines co-transfected with wild-type (WT) or mutant LMNA (E82K and R644C) and SCN5A cDNA using whole-cell patch-clamp recording techniques. The peak sodium current density was reduced significantly in the cells transfected with LMNA E82K compared to that in cells transfected with WT LMNA (86.19±9.36pA/pF, n=30 vs.155.73±19.09pA/pF, n=47; p=0.001). The reduction of sodium current densities in LMNA E82K mutant cells was due to repressed SCN5A gene translation. The level of sodium channel protein was 0.72±0.14 in LMNA E82K cells relative to control vs.1±0.13 in WT LMNA cells (p<0.05); however, transcription of the SCN5A gene was not altered. Conclusions:Our findings suggest that the LMNA E82K mutation down-regulates sodium channel function by inhibiting SCN5A translation rather than transcription, and provides new insights into the mechanisms of DCM in these patients. The exact mechanism of the effect of the LMNA E82K mutation on SCN5A translation remains to be elucidated.
Part 3 Connexin43 Remodeling induced by LMNA gene mutations in family Dilated Cardiomyopathy with atrial ventricular block
Object:Mutations in the lamin A/C gene (LMNA) may cause familial dilated cardiomyopathy (dilated cardiomyopathy) characterized by early onset atrio-ventricular block (A-V block) before the manifestation of dilated cardiomyopathy and high risk of sudden death due to ventricular arrhythmia, which is very similar to the phenotype of gap junction related heart disease. In this part, we studied the effect of LMNA mutations on connexins. Methods:The Cx43 and Cx40 expression in cultured neonatal myocytes transfected with wild-type (WT) or mutant LMNA (E82K and R644C) were studied using confocal imaging and western blot analysis. Results:Cx43 protein expression was reduced by 40% in cells transfected with LMNA E82K than that in cells transfected with WT LMNA cDNA. Confocal imaging showed that the Cx43 located inside of the cells. By contrast, LMNA E82K mutation had no effect on expression and localization of Cx40. LMNA R644C transfection did not show any significant effects on gap junctions at all. Conclusions--Our findings suggest that LMNA E82K significantly reduced the Cx43 expression and altered its localization which may be one of the pathological mechanisms underlie LMNA-related heart disease.
引文
[1]C.A. Remme, A.A. Wilde, SCN5A overlap syndromes:no end to disease complexity?, Europace 10 (2008) 1253-1255.
[2]H. J. Worman, G. Bonne, "Laminopathies":a wide spectrum of human diseases, Exp Cell Res 313 (2007) 2121-2133.
[3]V. L. Verstraeten, J. L. Broers, F. C. Ramaekers, M. A. van Steensel, The nuclear envelope, a key structure in cellular integrity and gene expression, Curr Med Chem 14 (2007) 1231-1248.
[4]C. L. Stewart, S. Kozlov, L. G. Fong, S. G. Young, Mouse models of the laminopathies, Exp Cell Res 313 (2007) 2144-2156.
[5]N. Sylvius, F. Tesson, Lamin A/C and cardiac diseases, Curr Opin Cardiol 21 (2006) 159-165.
[6]J. Rankin, S. Ellard, The laminopathies:a clinical review, Clin Genet 70 (2006) 261-274.
[7]B.C. Capell, F.S. Collins, Human laminopathies:nuclei gone genetically awry, Nat Rev Genet 7 (2006) 940-952.
[8]R. Somech, S. Shaklai, N. Amariglio, G. Rechavi, A. J. Simon, Nuclear envelopathies--raising the nuclear veil, Pediatr Res 57 (2005) 8R-15R.
[9]R. Ben Yaou, A. Muchir, T. Arimura, C. Massart, L. Demay, P. Richard, G. Bonne, Genetics of laminopathies, Novartis Found Symp 264 (2005) 81-90; discussion 90-97,227-230.
[10]H. J. Worman, J.C. Courvalin, How do mutations in lamins A and C cause disease?, J Clin Invest 113 (2004) 349-351.
[11]Y. Gruenbaum, R. D. Goldman, R. Meyuhas, E. Mills, A. Margalit, A. Fridkin, Y. Dayani, M. Prokocimer, A. Enosh, The nuclear lamina and its functions in the nucleus, Int Rev Cytol 226 (2003) 1-62.
[12]C. J. Hutchison, Lamins:building blocks or regulators of gene expression?, Nat Rev Mol Cell Biol 3 (2002) 848-858.
[13]S. Dhe-Paganon, E.D. Werner, Y.I. Chi, S. E. Shoelson, Structure of the globular tail of nuclear lamin, J Biol Chem 277 (2002) 17381-17384.
[14]J. Genschel, H.H. Schmidt, Mutations in the LMNA gene encoding lamin A/C, Hum Mutat 16 (2000) 451-459.
[15]A. Perrot, S. Hussein, V. Ruppert, H.H. Schmidt, M.S. Wehnert, N. T. Duong, M. G. Posch, A. Panek, R. Dietz, I. Kindermann, M.
Bohm, A. Michalewska-Wludarczyk, A. Richter, B. Maisch, S. Pankuweit, C. Ozcelik, Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy, Basic Res Cardiol (2008).
[16]H. Wang, J. Wang, W. Zheng, X. Wang, S. Wang, L. Song, Y. Zou, Y. Yao, R. Hui, Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect, Biochem Biophys Res Commun 344 (2006) 17-24.
[17]D. Fatkin, C. MacRae, T. Sasaki, M. R. Wolff, M. Porcu, M. Frenneaux, J. Atherton, H. J. Vidaillet, Jr., S. Spudich, U. De Girolami, J. G. Seidman, C. Seidman, F. Muntoni, G. Muehle, W. Johnson, B. McDonough, Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease, N Engl J Med 341 (1999) 1715-1724.
[18]J. Rankin, M. Auer-Grumbach, W. Bagg, K. Colclough, T. D. Nguyen, J. Fenton-May, A. Hattersley, J. Hudson, P. Jardine, D. Josifova, C. Longman, R. McWilliam, K. Owen, M. Walker, M. Wehnert, S. Ellard, Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C, Am J Med Genet A 146A (2008) 1530-1542.
[19]J. Genschel, B. Bochow, S. Kuepferling, R. Ewert, R. Hetzer, H. Lochs, H. Schmidt, A R644C mutation within lamin A extends the mutations causing dilated cardiomyopathy, Hum Mutat 17 (2001) 154.
[1]H. J.Worman, G. Bonne, "Laminopathies":a wide spectrum of human diseases, Exp Cell Res 313 (2007) 2121-2133.
[2]C. L. Stewart, S. Kozlov, L. G. Fong, S. G. Young, Mouse models of the laminopathies, Exp Cell Res 313 (2007) 2144-2156.
[3]N. Sylvius,F. Tesson, Lamin A/C and cardiac diseases, Curr Opin Cardiol 21 (2006) 159-165.
[4]J.Rankin, S. Ellard, The laminopathies:a clinical review, Clin Genet 70 (2006) 261-274.
[5]B.C. Capell, F.S. Collins, Human laminopathies:nuclei gone genetically awry, Nat Rev Genet 7 (2006) 940-952.
[6]R. Somech, S. Shaklai, N. Amariglio, G. Rechavi, A. J. Simon, Nuclear envelopathies--raising the nuclear veil, Pediatr Res 57 (2005) 8R-15R.
[7]V. Decostre, R. Ben Yaou, G. Bonne, Laminopathies affecting skeletal and cardiac muscles:clinical and pathophysiological aspects, Acta Myol 24 (2005) 104-109.
[8]M.S. Zastrow, S. Vlcek, K. L. Wilson, Proteins that bind A-type lamins:integrating isolated clues, J Cell Sci 117 (2004) 979-987.
[9]H. J. Worman, J. C. Courvalin, How do mutations in lamins A and C cause disease?, J Clin Invest 113 (2004) 349-351.
[10]Y. Gruenbaum, R. D. Goldman, R. Meyuhas, E. Mills, A. Margalit, A. Fridkin, Y. Dayani, M. Prokocimer, A. Enosh, The nuclear lamina and its functions in the nucleus, Int Rev Cytol 226 (2003) 1-62.
[11]C. J. Hutchison, Lamins:building blocks or regulators of gene-expression?, Nat Rev Mol Cell Biol 3 (2002) 848-858.
[12]J. Genschel, H. H. Schmidt, Mutations in the LMNA gene encoding lamin A/C, Hum Mutat 16 (2000) 451-459.
[13]E. Arbustini, A. Pilotto, A. Repetto, M. Grasso, A. Negri, M. Diegoli, C. Campana, L. Scelsi, E. Baldini, A. Gavazzi, L. Tavazzi, Autosomal dominant dilated cardiomyopathy with atrioventricular block:a lamin A/C defect-related disease, J Am Coll Cardiol 39 (2002) 981-990.
[14]H. M. Becane, G. Bonne, S. Varnous, A. Muchir, V. Ortega, E.-H. Hammouda, J. A. Urtizberea, T. Lavergne, M. Fardeau, B. Eymard, S. Weber, K. Schwartz, D. Duboc, High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation, Pacing Clin Electrophysiol 23 (2000) 1661-1666.
[15]J. H. van Berlo, W. G. de Voogt, A. J. van der Kooi, J. P. van Tintelen, G. Bonne, R. B. Yaou, D. Duboc, T. Rossenbacker, H. Heidbuchel, M. de Visser, H. J. Crijns, Y.M. Pinto, Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations:do lamin A/C mutations portend a high risk of sudden death?, J Mol Med 83 (2005) 79-83.
[16]Y. Ruan, N. Liu, S. G. Priori, Sodium channel mutations and arrhythmias, Nat Rev Cardiol 6 (2009) 337-348.
[17]C. A. Remme, A. A. Wilde, C. R. Bezzina, Cardiac sodium channel overlap syndromes:different faces of SCN5A mutations,Trends Cardiovasc Med 18 (2008) 78-87.
[18]C. A. Remme, A. A. Wilde, SCN5A overlap syndromes:no end to disease complexity?, Europace 10 (2008) 1253-1255.
[19]V. Haufe, C. Chamberland, R. Dumaine, The promiscuous nature of the cardiac sodium current, J Mol Cell Cardiol 42 (2007) 469-477.
[20]L. F. Santana, H. Nunez-Duran, K. W. Dilly, W. J. Lederer, Sodium current and arrhythmogenesis in heart failure, Heart Fail Cl'in 1 (2005) 193-205.
[21]A. L. George, Jr., Inherited disorders of voltage-gated sodium channels, J Clin Invest 115 (2005) 1990-1999.
[22]P. C. Viswanathan, J. R. Balser, Inherited sodium channelopathies:a continuum of channel dysfunction, Trends Cardiovasc Med 14 (2004) 28-35.
[23]J. K. Diss, S. P. Fraser, M. B. Djamgoz, Voltage-gated Na+ channels: multiplicity of expression, plasticity, functional implications and pathophysiological aspects, Eur Biophys J 33 (2004) 180-193.
[24]R. E. Hershberger, LMNA-Related Dilated Cardiomyopathy, Genes Dev (June 17,2008.).
[25]H. Wang, J.Wang, W. Zheng, X. Wang, S. Wang, L. Song, Y. Zou, Y. Yao, R. Hui, Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect, Biochem Biophys Res Commun 344 (2006) 17-24.
[26]赵.叶冬梅,扩张型心肌病各类心衰的心律失常特点,时珍国医国药17(2006)M0007-M0007.
[27]钟.霍丽蓉,A型核纤层蛋白——多种结合蛋白共同的“脚手架”,国际遗传学杂志29(2006)264-269.
[28]C. Ostlund, H.J. Worman, Nuclear envelope proteins and neuromuscular diseases, Muscle Nerve 27 (2003) 393-406.
[29]E. McNally,M. Allikian, M.T. Wheeler, J.M. Mislow, A. Heydemann, Cytoskeletal defects in cardiomyopathy, J Mol Cell Cardiol 35 (2003) 231-241.
[30]惠.审.王虎(综述),核纤层蛋白Lamins的结构、功能及相关疾病的研究,中国分子心脏病学杂志2(2002)57-62.
[31]S. Dhe-Paganon, E. D. Werner, Y.I. Chi, S. E. Shoelson,'Structure of the globular tail of nuclear lamin, J Biol Chem 277 (2002) 17381-17384.
[32]J. Lammerding, P.C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R. D. Kamm, C. L. Stewart, R. T. Lee, Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction, J Clin Invest 113 (2004) 370-378.
[33]宋.章.NanbertZHONG,核纤层蛋白病——一个基因,多种疾病,北京大学学报：医学版37(2005)96-99.
[34]G. L. Brodsky, F. Muntoni, S. Miocic, G. Sinagra, C. Sewry, L. Mestroni, Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement, Circulation 101 (2000) 473-476.
[35]M. Paul, S. Zumhagen, B. Stallmeyer, M. Koopmann, T. Spieker, E. Schulze-Bahr, Genes causing inherited forms of cardiomyopathies. A current compendium, Herz 34 (2009) 98-109.
[36]T. P. Nguyen, D. W. Wang, T. H. Rhodes, A. L. George, Jr., Divergent biophysical'defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia, Circ Res 102 (2008) 364-371.
[37]J. Ge, A. Sun, V. Paajanen, S. Wang, C. Su, Z. Yang, Y. Li, S. Wang, J. Jia, K. Wang, Y. Zou, L. Gao, K. Wang, Z. Fan, Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy, Circ Res 1 (2008) 83-92.
[38]K. K. Hwang, J. C. Eissenberg, H. J. Worman, Transcriptional repression of euchromatic genes by Drosophila heterochromatin protein 1 and histone modifiers, Proc Natl Acad Sci U S A 98 (2001) 11423-11427.
[39]H. Polioudaki, N. Kourmouli, V. Drosou, A. Bakou, P. A: Theodoropoulos, P.B. Singh, T. Giannakouros, S.D. Georgatos, Histones H3/H4 form a tight complex with the inner nuclear membrane protein LBR and heterochromatin protein 1, EMBO Rep-2 (2001) 920-925.
[40]E. Markiewicz, T. Dechat, R. Foisner, R. A. Quinlan, C. J. Hutchison, Lamin A/C binding protein LAP2alpha is required for nuclear anchorage of retinoblastoma protein, Mol Biol Cell 13 (2002) 4401-4413.
[41]J. M. Holaska, K. K. Lee, A. K. Kowalski, K. L. Wilson, Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro, J Biol Chem 278 (2003) 6969-6975.
[42]T. Tsukahara, S. Tsujino, K. Arahata, CDNA microarray analysis of gene expression in fibroblasts of patients with X-linked Emery-Dreifuss muscular dystrophy, Muscle Nerve 25 (2002) 898-901.
[43]A. Muchir, P. Pavlidis, V. Decostre, A. J. Herron, T. Arimura, G. Bonne, H.J. Worman, Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy, J Clin Invest 117 (2007) 1282-1293.
[44]S. Zicha, V. A. Maltsev, S. Nattel, H. N. Sabbah, A. I. Undrovinas, Post-transcriptional alterations in the expression of cardiac Na+ channel subunits in chronic heart failure, J Mol Cell Cardiol 37 (2004) 91-100.
[45]B. Gavillet, J. S. Rougier, A. A. Domenighetti, R. Behar, C. Boixel, P. Ruchat, H. A. Lehr, T. Pedrazzini, H. Abriel, Cardiac sodium channel Navl.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin, Circ Res 99 (2006)407-414.
[46]J. Rankin, M. Auer-Grumbach, W. Bagg, K. Colclough, T. D. Nguyen, J. Fenton-May, A. Hattersley, J. Hudson, P. Jardine,. D. Josifova, C. Longman, R. McWilliam, K. Owen, M. Walker, M. Wehnert, S. Ellard, Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C, Am J Med Genet A 146A (2008) 1530-1542.
[47]J.Genschel, B. Bochow, S. Kuepferling, R. Ewert, R. Hetzer, H. Lochs, H. Schmidt, A R644C mutation within lamin A extends the mutations causing dilated cardiomyopathy, Hum Mutat 17 (2001) 154.
[48]D.Fatkin, C. MacRae, T. Sasaki, M. R. Wolff, M. Porcu, M. Frenneaux, J. Atherton, H. J. Vidaillet, Jr., S. Spudich, U. De Girolami, J. G. Seidman, C. Seidman, F..Muntoni, G. Muehle, W. Johnson, B. McDonough, Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease, N Engl J Med 341 (1999) 1715-1724.
[49]D. Shao, K. Okuse, M.B. Djamgoz, Protein-protein interactions involving voltage-gated sodium channels:Post-translational regulation, intracellular trafficking and functional expression, Int J Biochem Cell Biol 41 (2009) 1471-1481.
[50]D. J. Schulz, S. Temporal, D. M. Barry, M. L. Garcia, Mechanisms of voltage-gated ion channel regulation:from gene expression to localization, Cell Mol Life Sci 65 (2008) 2215-2231.
[51]C. A. Ahern, J. F. Zhang, M. J. Wookalis, R. Horn, Modulation of the cardiac sodium channel NaVl.5 by Fyn, a Src family tyrosine kinase, Circ Res 96 (2005) 991-998.
[52]H. Abriel, R. S. Kass, Regulation of the voltage-gated cardiac sodium channel Navl.5 by interacting proteins, Trends Cardiovasc Med 15 (2005) 35-40.
[53]N. Ogata, Y. Ohishi, Molecular diversity of structure and function of the voltage-gated Na+ channels, Jpn J Pharmacol 88 (2002) 365-377.
[54]T. Lu, H. C. Lee, J. A. Kabat, E. F. Shibata, Modulation of rat cardiac sodium channel by the stimulatory G protein alpha subunit, J Physiol 518 (Pt 2) (1999) 371-384.
[55]A. Muchir, J. Shan, G. Bonne, S. E. Lehnart, H. J. Worman, Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy'caused by mutation in the gene encoding A-type lamins, Hum Mol Genet 18 (2009) 241-247.
[56]G. Jagatheesan, S. Thanumalayan, B. Muralikrishna, N. Rangaraj, A. A. Karande, V.K. Parnaik, Colocalization of intranuclear lamin foci with RNA splicing factors, J Cell Sci 112 (Pt 24) (1999) 4651-4661.
[57]E. Nili, G. S. Cojocaru, Y. Kalma; D. Ginsberg, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, R. Berger, S. Shaklai, N. Amariglio, F. Brok-Simoni, A. J. Simon, G. Rechavi, Nuclear membrane protein LAP2beta mediates transcriptional repression alone and together with its binding partner GCL (germ-cell-less), J Cell Sci 114 (2001) 3297-3307.
1. Capell BC, Collins FS. Human laminopathies:nuclei gone genetically awry. Nat Rev Genet 2006;7:940-52.
2. Worman HJ, Bonne G. "Laminopathies":a wide spectrum of human diseases. Exp Cell Res 2007:313:2121-33.
3. Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block:a lamin A/C defect-related disease. J Am Coll Cardiol 2002;39:981-90.
4. Becane HM, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000:23:1661-6.
5. Severs NJ, Bruce AF, Dupont E,. Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 2008:80:9-19.
6. Wang H, Wang J, Zheng W, et al. Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect. Biochem Biophys Res Commun 2006:344:17-24.
7. Noorman M, van der Heyden MA, van Veen TA, et al. Cardiac cell-cell junctions in health and disease:Electrical versus mechanical coupling. J Mol Cell Cardiol 2009:47:23-31.
8. Mounkes LC, Kozlov SV, Rottman JN, Stewart CL. Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. Hum Mol Genet 2005;14:2167-80.
9. Rankin J, Auer-Grumbach M, Bagg W, et al. Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C. Am J Med Genet A 2008;146A:1530-42.
10. Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP, Hegele RA. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J Med Genet 2004:41:304-8.
11.Thomas SA, Schuessler RB, Berul CI, et al.Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction:evidence for chamber-specific molecular determinants of conduction. Circulation 1998:97:686-91.
12. Lerner DL, Yamada KA, Schuessler RB, Saffitz JE. Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 2000;101:547-52.
13. Gutstein DE,Morley GE, Tamaddon H, et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 2001;08:333-9.
14. Okruhlicova L, Tribulova N, Misejkova M, et al. Gap junction remodelling is involved in the susceptibility of diabetic rats to hypokalemia-induced ventricular fibrillation. Acta Histochem 2002;104:387-91.
15. Tribulova N,Manoach M, Varon D, Okruhlicova L, Zinman T, Shainberg A. Dispersion of cell-to-cell uncoupling precedes low K+-induced ventricular fibrillation. Physiol Res 2001:50:247-59.
16. Tribulova N, Okruhlicova L, Novakova S,et al. Hypertension-related intermyocyte junction remodelling is associated with a higher incidence of low-K(+)-induced lethal arrhythmias in isolated rat heart. Exp Physiol 2002;87:195-205.
17. Boukens BJ, Christoffels VM, Coronel R, Moorman AF. Developmental basis for electrophysiological heterogeneity in the ventricular and outflow tract myocardium as a substrate for life-threatening ventricular arrhythmias. Circ Res 2009;104:19-31.
18. Solan JL, Lampe PD. Connexin43 phosphorylation:structural changes and biological effects. Biochem J 2009;419:261-72.
19. Petrich BG, Eloff BC, Lerner DL, et al. Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J Biol Chem 2004;279:15330-8.
20. Petrich BG, Gong X, Lerner DL, et al. c-Jun N-terminal kinase activation mediates downregulation of connexin43 in cardiomyocytes. Circ Res 2002;91:640-7.
21. Cho JH, Cho SD, Hu H, et al. The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide. Carcinogenesis 2002;23:1163-9.
22. Muchir A, Pavlidis P, Decostre V, et al. Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J Clin Invest 2007;117:1282-93.
23. Muchir A, Shan J, Bonne G, Lehnart SE, Worman HJ. Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins. Hum Mol Genet 2009;18:241-7.
24. Kasahara H, Wakimoto H, Liu M, et al. Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein. J Clin Invest 2001;108:189-201.
25. Kasahara H, Ueyama T, Wakimoto H, et al. Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes. J Mol Cell Cardiol 2003;35:243-56.
26. Jagatheesan G, Thanumalayan S, Muralikrishna B, Rangaraj N, Karande AA, Parnaik VK. Colocalization of intranuclear lamin foci with RNA splicing factors. J Cell Sci 1999:112 (Pt 24):4651-61.
27. Melcon G, Kozlov S, Cutler DA, et al. Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum Mol Genet 2006;15:637-51.
28. Nili E, Cojocaru GS, Kalma Y, et al. Nuclear membrane protein LAP2beta mediates transcriptional repression alone and together with its binding partner GCL (germ-cell-less). J Cell Sci 2001:114:3297-307.
[1]S. Karkkainen, K. Peuhkurinen, Genetics of dilated cardiomyopathy, Ann Med 39 (2007) 91-107.
[2]C. Ostlund, H. J. Worman, Nuclear envelope proteins and neuromuscular diseases, Muscle Nerve 27 (2003) 393-406.
[3]A., Perrot, S. Hussein, V. Ruppert, H. H. Schmidt, M. S. Wehnert, N. T. Duong, M. G. Posch, A. Panek, R. Dietz, I. Kindermann, M. Bohm, A. Michalewska-Wludarczyk, A. Richter, B. Maisch, S. Pankuweit, C. Ozcelik, Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy, Basic Res Cardiol (2008).
[4]H.Wang, J.. Wang, W. Zheng, X. Wang, S. Wang, L. Song, Y. Zou, Y. Yao, R. Hui, Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect, Biochem Biophys Res Commun 344 (2006) 17-24.
[5]S. Karkkainen, T. Helio, R. Miettinen, P. Tuomainen, P. Peltola, J. Rummukainen, K. Ylitalo, M. Kaartinen, J. Kuusisto, L.Toivonen, M.S. Nieminen, M. Laakso, K. Peuhkurinen, A novel mutation, Ser143Pro, in the lamin A/C.gene is common in finnish patients with familial dilated cardiomyopathy, Eur Heart J 25 (2004) 885-893.
[6]M. R. Taylor, P. R. Fain, G. Sinagra, M. L. Robinson, A. D. Robertson, E. Carniel, A. Di Lenarda, T. J. Bohlmeyer,D. A. Ferguson, G. L. Brodsky, M. M. Boucek, J. Lascor, A. C. Moss, W. L. Li, G. L. Stetler, F. Muntoni, M.R. Bristow, L. Mestroni, Natural.history of dilated cardiomyopathy due to lamin A/C gene mutations, J Am Coll Cardiol 41 (2003) 771-780.
[7]H. M. Becane, G. Bonne, S. Varnous, A. Muchir, V. Ortega, E. H. Hammouda, J. A. Urtizberea, T. Lavergne, M. Fardeau, B. Eymard, S. Weber, K. Schwartz, D. Duboc, High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation, Pacing Clin Electrophysiol 23 (2000) 1661-1666.
[8]S. Karkkainen, E. Reissell, T. Helio, M. Kaartinen, P. Tuomainen, L. Toivonen, J. Kuusisto, M. Kupari, M.S. Nieminen, M. Laakso; K. Peuhkurinen; Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy, Heart 92 (2006) 524-526.
[9]J. H. van Berlo, W. G. de Voogt, A. J. van der Kooi, J. P. van Tintelen, G. Bonne, R. B. Yaou, D. Duboc, T. Rossenbacker, H. Heidbuchel, M. de Visser, H. J. Crijns, Y. M. Pinto, Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations:do lamin A/C mutations portend a high risk of sudden death?, J Mol Med 83 (2005) 79-83.
[10]M. Pasotti, C. Klersy, A. Pilotto, N. Marziliano, C. Rapezzi, A. Serio, S. Mannarino, F. Gambarin, V. Favalli, M. Grasso, M. Agozzino, C. Campana, A. Gavazzi,0. Febo, M. Marini, M. Landolina, A. Mortara, G. Piccolo, M. Vigano, L. Tavazzi, E. Arbustini, Long-term outcome and risk stratification in dilated cardiolaminopathies, J Am Coll Cardiol 52 (2008) 1250-1260.
[11]C. Meune, J. H. Van Berlo, F. Anselme, G. Bonne, Y. M. Pinto, D. Duboc, Primary prevention of sudden death in patients with lamin A/C gene mutations, N Engl J Med 354 (2006) 209-210.
[12]T. Sullivan, D. Escalante-Alcalde, H. Bhatt, M. Anver, N.Bhat,K. Nagashima, C.L. Stewart, B. Burke, Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy, J Cell Biol 147 (1999) 913-920.
[13]T. Arimura, A. Helbling-Leclerc, C. Massart, S. Varnous,F. Niel, E. Lacene, Y. Fromes, M. Toussaint, A.M. Mura, D.I. Keller, H. Amthor, R. Isnard, M. Malissen, K. Schwartz, G. Bonne, Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies,'Hum Mol Genet 14 (2005) 155-169.
[14]L. C. Mounkes, S. V. Kozlov, J. N. Rottman, C. L. Stewart, Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice, Hum Mol Genet 14 (2005) 2167-2180.
[15]Y. Wang, A. J. Herron, H.J. Worman, Pathology and nuclear abnormalities in hearts of transgenic mice expressing M371K lamin A encoded by an LMNA mutation causing Emery-Dreifuss muscular dystrophy, Hum Mol Genet 15 (2006) 2479-2489.
[16]C.M. Wolf, L. Wang, R. Alcalai, A. Pizard, P. G. Burgon, F. Ahmad, M. Sherwood, D. M. Branco, H. Wakimoto, G.I. Fishman, V. See, C. L. Stewart, D. A. Conner, C.I. Berul, C. E. Seidman, J. G. Seidman, Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease, J Mol Cell Cardiol 44 (2008) 293-303.
[17]C. Vigouroux, M. Auclair, E. Dubosclard, M. Pouchelet, J. Capeau, J. C. Courvalin, B. Buendia, Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene, J Cell Sci 114 (2001) 4459-4468.
[18]J. L. Broers, E. A. Peeters, H.J. Kuijpers, J. Endert, C. V. Bouten, C. W. Oomens, F. P. Baaijens, F. C. Ramaekers, Decreased mechanical stiffness in LMNA-/-cells is caused by defective nucleo-cytoskeletal integrity:implications for the development of laminopathies, Hum Mol Genet 13 (2004) 2567-2580.
[19]J., Lammerding, P. C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R. D. Kamm, C. L. Stewart, R. T. Lee, Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction, J Clin Invest 113 (2004) 370-378.
[20]J. Lammerding, J. Hsiao, P. C. Schulze, S. Kozlov, C. L. Stewart, R. T. Lee, Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells, J Cell Biol 170 (2005) 781-791.
[21]B.C. Capell, F. S. Collins, Human laminopathies:nuclei gone genetically awry, Nat Rev Genet 7 (2006) 940-952.
[22]M. Bakay, Z. Wang, G. Melcon, L. Schiltz, J. Xuan, P. Zhao, V. Sartorelli, J. Seo, E. Pegoraro, C. Angelini, B. Shneiderman, D. Escolar, Y. W. Chen, S. T. Winokur, L. M. Pachman, C. Fan, R. Mandler, Y. Nevo, E. Gordon, Y. Zhu, Y. Dong, Y. Wang, E. P. Hoffman, Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration, Brain 129 (2006) 996-1013.
[23]J.M. Holaska, K. K. Lee, A. K. Kowalski, K. L Wilson, Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro, J Biol Chem 278 (2003) 6969-6975.
[24]J. H.Van Berlo, J.W. Voncken, N. Kubben, J. L. Broers, R. Duisters, R. E. van Leeuwen, H. J. Crijns, F. C. Ramaekers, C. J. Hutchison, Y.M. Pinto, A-type lamins are essential for TGF-betal induced PP2A to dephosphorylate transcription factors, Hum Mol Genet 14 (2005) 2839-2849.
[25]G. Melcon, S. Kozlov, D.A. Cutler, T. Sullivan, L. Hernandez, P. Zhao, S. Mitchell, G. Nader, M. Bakay, J. N. Rottman, E. P. Hoffman, C. L. Stewart, Loss of emerin at the nuclear envelope disrupts the Rbl/E2F and MyoD pathways during muscle regeneration, Hum Mol Genet 15(2006) 637-651.
[26]J. M. Gonzalez, A. Navarro-Puche, B. Casar, P. Crespo, V. Andres, Fast regulation of AP-1 activity through interaction of lamin A/C, ERK1/2, and c-Fos at the nuclear envelope, J Cell Biol 183 (2008) 653-666.
[27]A. Muchir, P. Pavlidis, V. Decostre, A. J. Herron, T. Arimura,G. Bonne, H.J. Worman, Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy, J Clin Invest 117 (2007) 1282-1293.
[28]A. Muchir, J. Shan, G. Bonne, S. E. Lehnart, H. J. Worman, Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins, Hum Mol Genet 18 (2009) 241-247.
[1]L. J. Herfst, M. B. Rook, H. J. Jongsma, Trafficking and functional expression of cardiac Na+ channels, J Mol Cell Cardiol 36 (2004) 185-193.
[2]Y. Ruan, N. Liu, S. G. Priori, Sodium channel mutations and arrhythmias, Nat Rev Cardiol 6 (2009) 337-348.
[3]A. L. George, Jr., Inherited disorders of voltage-gated sodium channels, J Clin Invest 115 (2005) 1990-1999.
[4]A. A. M. W. Simona Casini, and Hanno L. Tan, Sodium Ion Channelopathies.
[5]s. casini, sodium ion channelopathies.
[6]T. M. Olson, M. T. Keating, Mapping a cardiomyopathy locus to chromosome 3p22-p25, J Clin Invest 97 (1996) 528-532.
[7]W. P. McNair, L. Ku, M. R. Taylor, P. R. Fain, D. Dao, E. Wolfel, L. Mestroni, SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia, Circulation 110(2004) 2163-2167.
[8]T.M. Olson, V.V. Michels, J. D. Ballew, S. P. Reyna, M. L. Karst, K. J. Herron, S.C. Horton, R. J. Rodehef fer, J. L. Anderson, Sodium channel mutations and susceptibility to heart failure and atrial fibrillation, Jama 293 (2005) 447-454.
[9]P. R.Greenlee, J. L. Anderson, J. R. Lutz, A. E. Lindsay, A. D. Hagan, Familial automaticity-conduction disorder with associated cardiomyopathy, West J Med 144 (1986).33-41.
[10]W. A. Groenewegen, M. Firouzi, C. R. Bezzina, S. Vliex, I.M. van Langen,. L. Sandkuijl, J. P. Smits, M. Hulsbeek, M.B. Rook, H. J. Jongsma, A.A. Wilde, A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill, Circ Res 92 (2003) 14-22.
[11]R. Shi, Y. Zhang, C. Yang, C. Huang, X. Zhou, H. Qiang, A. A. Grace, C. L. Huang, A. Ma, The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death, Europace 10 (2008) 1329-1335.
[12]J. Ge, A. Sun, V. Paajanen,S.Wang, C. Su, Z. Yang, Y. Li, S. Wang, J. Jia, K. Wang, Y. Zou, L. Gao, K. Wang, Z. Fan, Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy, Circ Res 1 (2008) 83-92.
[13]M. Hesse, C. S. Kondo, R. B. Clark, L. Su, F. L. Allen, C.T. Geary-Joo, S. Kunnathu, D. L. Severson, A. Nygren, W. R. Giles, J. C. Cross, Dilated cardiomyopathy is associated with reduced expression of the cardiac sodium channel Scn5a, Cardiovasc Res 75 (2007) 498-509.
[14]L. S. Maier, T. Zhang, L. Chen, J. DeSantiago, J. H. Brown, D. M. Bers, Transgenic CaMKIIdeltaC overexpression uniquely alters' cardiac myocyte Ca2+ handling:reduced SR Ca2+ load and'activated SR Ca2+ release, Circ Res 92 (2003) 904-911.
[15]C. R.'Bezzina, M. B. Rook, W. A. Groenewegen, L. J. Herfst; A. C.van der Wal, J. Lam, H. J. Jongsma, A. A. Wilde, M. M. Mannens, Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system, Circ Res 92 (2003) 159-168.
[16]D.W. Benson, D. W. Wang, M. Dyment, T. K. Knilans, F.A. Fish, M.J. Strieper, T. H.Rhodes,A. L. George, Jr., Congenital'sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A), J Clin Invest 112 (2003) 1019-1028.
[17]T. P. Nguyen, D.W. Wang, T. H. Rhodes, A. L. George, Jr., Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia, Circ Res 102 (2008) 364-371.
[18]A. Frustaci, S. G. Priori, M. Pieroni, C. Chimenti, C. Napolitano, I. Rivolta,T.Sanna, F. Bellocci, M. A. Russo, Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome, Circulation 112 (2005) 3680-3687.
[19]G. Frigo, A. Rampazzo, B. Bauce, K. Pilichou, G. Beffagna, G. A. Danieli, A. Nava, B. Martini, Homozygous SCN5A mutation in Brugada syndrome with monomorphic ventricular tachycardia and structural heart abnormalities, Europace 9 (2007) 391-397.
[20]T. A. van Veen, M. Stein, A. Royer, K. Le Quang, F. Charpentier, W. H. Colledge, C. L. Huang, R. Wilders, A. A. Grace, D. Escande, J. M. de Bakker, H. V. van Rijen, Impaired impulse propagation in Scn5a-knockout mice:combined contribution of excitability, connexin expression, and tissue architecture in relation to aging, Circulation 112 (2005) 1927-1935.
[21]B. Gavillet, J. S. Rougier, A. A. Domenighetti, R. Behar, C. Boixel, P. Ruchat, H. A. Lehr, T. Pedrazzini, H. Abriel, Cardiac sodium channel Navl.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin, Circ Res 99 (2006) 407-414.
[22]E. Murphy, D.A. Eisner, Regulation of intracellular and mitochondrial sodium in health and disease, Circ Res 104 (2009) 292-303.
[23]D. Shao, K. Okuse, M.B. Djamgoz, Protein-protein interactions involving voltage-gated sodium channels:Post-translational regulation, intracellular trafficking and functional expression, Int J Biochem Cell Biol 41 (2009) 1471-1481.
[2]H. J. Worman, G. Bonne, "Laminopathies":a wide spectrum of human diseases, Exp Cell Res 313 (2007) 2121-2133.
[3]V. L. Verstraeten, J. L. Broers, F. C. Ramaekers, M. A. van Steensel, The nuclear envelope, a key structure in cellular integrity and gene expression, Curr Med Chem 14 (2007) 1231-1248.
[4]C. L. Stewart, S. Kozlov, L. G. Fong, S. G. Young, Mouse models of the laminopathies, Exp Cell Res 313 (2007) 2144-2156.
[5]N. Sylvius, F. Tesson, Lamin A/C and cardiac diseases, Curr Opin Cardiol 21 (2006) 159-165.
[6]J. Rankin, S. Ellard, The laminopathies:a clinical review, Clin Genet 70 (2006) 261-274.
[7]B.C. Capell, F.S. Collins, Human laminopathies:nuclei gone genetically awry, Nat Rev Genet 7 (2006) 940-952.
[8]R. Somech, S. Shaklai, N. Amariglio, G. Rechavi, A. J. Simon, Nuclear envelopathies--raising the nuclear veil, Pediatr Res 57 (2005) 8R-15R.
[9]R. Ben Yaou, A. Muchir, T. Arimura, C. Massart, L. Demay, P. Richard, G. Bonne, Genetics of laminopathies, Novartis Found Symp 264 (2005) 81-90; discussion 90-97,227-230.
[10]H. J. Worman, J.C. Courvalin, How do mutations in lamins A and C cause disease?, J Clin Invest 113 (2004) 349-351.
[11]Y. Gruenbaum, R. D. Goldman, R. Meyuhas, E. Mills, A. Margalit, A. Fridkin, Y. Dayani, M. Prokocimer, A. Enosh, The nuclear lamina and its functions in the nucleus, Int Rev Cytol 226 (2003) 1-62.
[12]C. J. Hutchison, Lamins:building blocks or regulators of gene expression?, Nat Rev Mol Cell Biol 3 (2002) 848-858.
[13]S. Dhe-Paganon, E.D. Werner, Y.I. Chi, S. E. Shoelson, Structure of the globular tail of nuclear lamin, J Biol Chem 277 (2002) 17381-17384.
[14]J. Genschel, H.H. Schmidt, Mutations in the LMNA gene encoding lamin A/C, Hum Mutat 16 (2000) 451-459.
[15]A. Perrot, S. Hussein, V. Ruppert, H.H. Schmidt, M.S. Wehnert, N. T. Duong, M. G. Posch, A. Panek, R. Dietz, I. Kindermann, M.
Bohm, A. Michalewska-Wludarczyk, A. Richter, B. Maisch, S. Pankuweit, C. Ozcelik, Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy, Basic Res Cardiol (2008).
[16]H. Wang, J. Wang, W. Zheng, X. Wang, S. Wang, L. Song, Y. Zou, Y. Yao, R. Hui, Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect, Biochem Biophys Res Commun 344 (2006) 17-24.
[17]D. Fatkin, C. MacRae, T. Sasaki, M. R. Wolff, M. Porcu, M. Frenneaux, J. Atherton, H. J. Vidaillet, Jr., S. Spudich, U. De Girolami, J. G. Seidman, C. Seidman, F. Muntoni, G. Muehle, W. Johnson, B. McDonough, Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease, N Engl J Med 341 (1999) 1715-1724.
[18]J. Rankin, M. Auer-Grumbach, W. Bagg, K. Colclough, T. D. Nguyen, J. Fenton-May, A. Hattersley, J. Hudson, P. Jardine, D. Josifova, C. Longman, R. McWilliam, K. Owen, M. Walker, M. Wehnert, S. Ellard, Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C, Am J Med Genet A 146A (2008) 1530-1542.
[19]J. Genschel, B. Bochow, S. Kuepferling, R. Ewert, R. Hetzer, H. Lochs, H. Schmidt, A R644C mutation within lamin A extends the mutations causing dilated cardiomyopathy, Hum Mutat 17 (2001) 154.
[1]H. J.Worman, G. Bonne, "Laminopathies":a wide spectrum of human diseases, Exp Cell Res 313 (2007) 2121-2133.
[2]C. L. Stewart, S. Kozlov, L. G. Fong, S. G. Young, Mouse models of the laminopathies, Exp Cell Res 313 (2007) 2144-2156.
[3]N. Sylvius,F. Tesson, Lamin A/C and cardiac diseases, Curr Opin Cardiol 21 (2006) 159-165.
[4]J.Rankin, S. Ellard, The laminopathies:a clinical review, Clin Genet 70 (2006) 261-274.
[5]B.C. Capell, F.S. Collins, Human laminopathies:nuclei gone genetically awry, Nat Rev Genet 7 (2006) 940-952.
[6]R. Somech, S. Shaklai, N. Amariglio, G. Rechavi, A. J. Simon, Nuclear envelopathies--raising the nuclear veil, Pediatr Res 57 (2005) 8R-15R.
[7]V. Decostre, R. Ben Yaou, G. Bonne, Laminopathies affecting skeletal and cardiac muscles:clinical and pathophysiological aspects, Acta Myol 24 (2005) 104-109.
[8]M.S. Zastrow, S. Vlcek, K. L. Wilson, Proteins that bind A-type lamins:integrating isolated clues, J Cell Sci 117 (2004) 979-987.
[9]H. J. Worman, J. C. Courvalin, How do mutations in lamins A and C cause disease?, J Clin Invest 113 (2004) 349-351.
[10]Y. Gruenbaum, R. D. Goldman, R. Meyuhas, E. Mills, A. Margalit, A. Fridkin, Y. Dayani, M. Prokocimer, A. Enosh, The nuclear lamina and its functions in the nucleus, Int Rev Cytol 226 (2003) 1-62.
[11]C. J. Hutchison, Lamins:building blocks or regulators of gene-expression?, Nat Rev Mol Cell Biol 3 (2002) 848-858.
[12]J. Genschel, H. H. Schmidt, Mutations in the LMNA gene encoding lamin A/C, Hum Mutat 16 (2000) 451-459.
[13]E. Arbustini, A. Pilotto, A. Repetto, M. Grasso, A. Negri, M. Diegoli, C. Campana, L. Scelsi, E. Baldini, A. Gavazzi, L. Tavazzi, Autosomal dominant dilated cardiomyopathy with atrioventricular block:a lamin A/C defect-related disease, J Am Coll Cardiol 39 (2002) 981-990.
[14]H. M. Becane, G. Bonne, S. Varnous, A. Muchir, V. Ortega, E.-H. Hammouda, J. A. Urtizberea, T. Lavergne, M. Fardeau, B. Eymard, S. Weber, K. Schwartz, D. Duboc, High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation, Pacing Clin Electrophysiol 23 (2000) 1661-1666.
[15]J. H. van Berlo, W. G. de Voogt, A. J. van der Kooi, J. P. van Tintelen, G. Bonne, R. B. Yaou, D. Duboc, T. Rossenbacker, H. Heidbuchel, M. de Visser, H. J. Crijns, Y.M. Pinto, Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations:do lamin A/C mutations portend a high risk of sudden death?, J Mol Med 83 (2005) 79-83.
[16]Y. Ruan, N. Liu, S. G. Priori, Sodium channel mutations and arrhythmias, Nat Rev Cardiol 6 (2009) 337-348.
[17]C. A. Remme, A. A. Wilde, C. R. Bezzina, Cardiac sodium channel overlap syndromes:different faces of SCN5A mutations,Trends Cardiovasc Med 18 (2008) 78-87.
[18]C. A. Remme, A. A. Wilde, SCN5A overlap syndromes:no end to disease complexity?, Europace 10 (2008) 1253-1255.
[19]V. Haufe, C. Chamberland, R. Dumaine, The promiscuous nature of the cardiac sodium current, J Mol Cell Cardiol 42 (2007) 469-477.
[20]L. F. Santana, H. Nunez-Duran, K. W. Dilly, W. J. Lederer, Sodium current and arrhythmogenesis in heart failure, Heart Fail Cl'in 1 (2005) 193-205.
[21]A. L. George, Jr., Inherited disorders of voltage-gated sodium channels, J Clin Invest 115 (2005) 1990-1999.
[22]P. C. Viswanathan, J. R. Balser, Inherited sodium channelopathies:a continuum of channel dysfunction, Trends Cardiovasc Med 14 (2004) 28-35.
[23]J. K. Diss, S. P. Fraser, M. B. Djamgoz, Voltage-gated Na+ channels: multiplicity of expression, plasticity, functional implications and pathophysiological aspects, Eur Biophys J 33 (2004) 180-193.
[24]R. E. Hershberger, LMNA-Related Dilated Cardiomyopathy, Genes Dev (June 17,2008.).
[25]H. Wang, J.Wang, W. Zheng, X. Wang, S. Wang, L. Song, Y. Zou, Y. Yao, R. Hui, Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect, Biochem Biophys Res Commun 344 (2006) 17-24.
[26]赵.叶冬梅,扩张型心肌病各类心衰的心律失常特点,时珍国医国药17(2006)M0007-M0007.
[27]钟.霍丽蓉,A型核纤层蛋白——多种结合蛋白共同的“脚手架”,国际遗传学杂志29(2006)264-269.
[28]C. Ostlund, H.J. Worman, Nuclear envelope proteins and neuromuscular diseases, Muscle Nerve 27 (2003) 393-406.
[29]E. McNally,M. Allikian, M.T. Wheeler, J.M. Mislow, A. Heydemann, Cytoskeletal defects in cardiomyopathy, J Mol Cell Cardiol 35 (2003) 231-241.
[30]惠.审.王虎(综述),核纤层蛋白Lamins的结构、功能及相关疾病的研究,中国分子心脏病学杂志2(2002)57-62.
[31]S. Dhe-Paganon, E. D. Werner, Y.I. Chi, S. E. Shoelson,'Structure of the globular tail of nuclear lamin, J Biol Chem 277 (2002) 17381-17384.
[32]J. Lammerding, P.C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R. D. Kamm, C. L. Stewart, R. T. Lee, Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction, J Clin Invest 113 (2004) 370-378.
[33]宋.章.NanbertZHONG,核纤层蛋白病——一个基因,多种疾病,北京大学学报：医学版37(2005)96-99.
[34]G. L. Brodsky, F. Muntoni, S. Miocic, G. Sinagra, C. Sewry, L. Mestroni, Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement, Circulation 101 (2000) 473-476.
[35]M. Paul, S. Zumhagen, B. Stallmeyer, M. Koopmann, T. Spieker, E. Schulze-Bahr, Genes causing inherited forms of cardiomyopathies. A current compendium, Herz 34 (2009) 98-109.
[36]T. P. Nguyen, D. W. Wang, T. H. Rhodes, A. L. George, Jr., Divergent biophysical'defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia, Circ Res 102 (2008) 364-371.
[37]J. Ge, A. Sun, V. Paajanen, S. Wang, C. Su, Z. Yang, Y. Li, S. Wang, J. Jia, K. Wang, Y. Zou, L. Gao, K. Wang, Z. Fan, Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy, Circ Res 1 (2008) 83-92.
[38]K. K. Hwang, J. C. Eissenberg, H. J. Worman, Transcriptional repression of euchromatic genes by Drosophila heterochromatin protein 1 and histone modifiers, Proc Natl Acad Sci U S A 98 (2001) 11423-11427.
[39]H. Polioudaki, N. Kourmouli, V. Drosou, A. Bakou, P. A: Theodoropoulos, P.B. Singh, T. Giannakouros, S.D. Georgatos, Histones H3/H4 form a tight complex with the inner nuclear membrane protein LBR and heterochromatin protein 1, EMBO Rep-2 (2001) 920-925.
[40]E. Markiewicz, T. Dechat, R. Foisner, R. A. Quinlan, C. J. Hutchison, Lamin A/C binding protein LAP2alpha is required for nuclear anchorage of retinoblastoma protein, Mol Biol Cell 13 (2002) 4401-4413.
[41]J. M. Holaska, K. K. Lee, A. K. Kowalski, K. L. Wilson, Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro, J Biol Chem 278 (2003) 6969-6975.
[42]T. Tsukahara, S. Tsujino, K. Arahata, CDNA microarray analysis of gene expression in fibroblasts of patients with X-linked Emery-Dreifuss muscular dystrophy, Muscle Nerve 25 (2002) 898-901.
[43]A. Muchir, P. Pavlidis, V. Decostre, A. J. Herron, T. Arimura, G. Bonne, H.J. Worman, Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy, J Clin Invest 117 (2007) 1282-1293.
[44]S. Zicha, V. A. Maltsev, S. Nattel, H. N. Sabbah, A. I. Undrovinas, Post-transcriptional alterations in the expression of cardiac Na+ channel subunits in chronic heart failure, J Mol Cell Cardiol 37 (2004) 91-100.
[45]B. Gavillet, J. S. Rougier, A. A. Domenighetti, R. Behar, C. Boixel, P. Ruchat, H. A. Lehr, T. Pedrazzini, H. Abriel, Cardiac sodium channel Navl.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin, Circ Res 99 (2006)407-414.
[46]J. Rankin, M. Auer-Grumbach, W. Bagg, K. Colclough, T. D. Nguyen, J. Fenton-May, A. Hattersley, J. Hudson, P. Jardine,. D. Josifova, C. Longman, R. McWilliam, K. Owen, M. Walker, M. Wehnert, S. Ellard, Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C, Am J Med Genet A 146A (2008) 1530-1542.
[47]J.Genschel, B. Bochow, S. Kuepferling, R. Ewert, R. Hetzer, H. Lochs, H. Schmidt, A R644C mutation within lamin A extends the mutations causing dilated cardiomyopathy, Hum Mutat 17 (2001) 154.
[48]D.Fatkin, C. MacRae, T. Sasaki, M. R. Wolff, M. Porcu, M. Frenneaux, J. Atherton, H. J. Vidaillet, Jr., S. Spudich, U. De Girolami, J. G. Seidman, C. Seidman, F..Muntoni, G. Muehle, W. Johnson, B. McDonough, Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease, N Engl J Med 341 (1999) 1715-1724.
[49]D. Shao, K. Okuse, M.B. Djamgoz, Protein-protein interactions involving voltage-gated sodium channels:Post-translational regulation, intracellular trafficking and functional expression, Int J Biochem Cell Biol 41 (2009) 1471-1481.
[50]D. J. Schulz, S. Temporal, D. M. Barry, M. L. Garcia, Mechanisms of voltage-gated ion channel regulation:from gene expression to localization, Cell Mol Life Sci 65 (2008) 2215-2231.
[51]C. A. Ahern, J. F. Zhang, M. J. Wookalis, R. Horn, Modulation of the cardiac sodium channel NaVl.5 by Fyn, a Src family tyrosine kinase, Circ Res 96 (2005) 991-998.
[52]H. Abriel, R. S. Kass, Regulation of the voltage-gated cardiac sodium channel Navl.5 by interacting proteins, Trends Cardiovasc Med 15 (2005) 35-40.
[53]N. Ogata, Y. Ohishi, Molecular diversity of structure and function of the voltage-gated Na+ channels, Jpn J Pharmacol 88 (2002) 365-377.
[54]T. Lu, H. C. Lee, J. A. Kabat, E. F. Shibata, Modulation of rat cardiac sodium channel by the stimulatory G protein alpha subunit, J Physiol 518 (Pt 2) (1999) 371-384.
[55]A. Muchir, J. Shan, G. Bonne, S. E. Lehnart, H. J. Worman, Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy'caused by mutation in the gene encoding A-type lamins, Hum Mol Genet 18 (2009) 241-247.
[56]G. Jagatheesan, S. Thanumalayan, B. Muralikrishna, N. Rangaraj, A. A. Karande, V.K. Parnaik, Colocalization of intranuclear lamin foci with RNA splicing factors, J Cell Sci 112 (Pt 24) (1999) 4651-4661.
[57]E. Nili, G. S. Cojocaru, Y. Kalma; D. Ginsberg, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, R. Berger, S. Shaklai, N. Amariglio, F. Brok-Simoni, A. J. Simon, G. Rechavi, Nuclear membrane protein LAP2beta mediates transcriptional repression alone and together with its binding partner GCL (germ-cell-less), J Cell Sci 114 (2001) 3297-3307.
1. Capell BC, Collins FS. Human laminopathies:nuclei gone genetically awry. Nat Rev Genet 2006;7:940-52.
2. Worman HJ, Bonne G. "Laminopathies":a wide spectrum of human diseases. Exp Cell Res 2007:313:2121-33.
3. Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block:a lamin A/C defect-related disease. J Am Coll Cardiol 2002;39:981-90.
4. Becane HM, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000:23:1661-6.
5. Severs NJ, Bruce AF, Dupont E,. Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 2008:80:9-19.
6. Wang H, Wang J, Zheng W, et al. Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect. Biochem Biophys Res Commun 2006:344:17-24.
7. Noorman M, van der Heyden MA, van Veen TA, et al. Cardiac cell-cell junctions in health and disease:Electrical versus mechanical coupling. J Mol Cell Cardiol 2009:47:23-31.
8. Mounkes LC, Kozlov SV, Rottman JN, Stewart CL. Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. Hum Mol Genet 2005;14:2167-80.
9. Rankin J, Auer-Grumbach M, Bagg W, et al. Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C. Am J Med Genet A 2008;146A:1530-42.
10. Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP, Hegele RA. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J Med Genet 2004:41:304-8.
11.Thomas SA, Schuessler RB, Berul CI, et al.Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction:evidence for chamber-specific molecular determinants of conduction. Circulation 1998:97:686-91.
12. Lerner DL, Yamada KA, Schuessler RB, Saffitz JE. Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 2000;101:547-52.
13. Gutstein DE,Morley GE, Tamaddon H, et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 2001;08:333-9.
14. Okruhlicova L, Tribulova N, Misejkova M, et al. Gap junction remodelling is involved in the susceptibility of diabetic rats to hypokalemia-induced ventricular fibrillation. Acta Histochem 2002;104:387-91.
15. Tribulova N,Manoach M, Varon D, Okruhlicova L, Zinman T, Shainberg A. Dispersion of cell-to-cell uncoupling precedes low K+-induced ventricular fibrillation. Physiol Res 2001:50:247-59.
16. Tribulova N, Okruhlicova L, Novakova S,et al. Hypertension-related intermyocyte junction remodelling is associated with a higher incidence of low-K(+)-induced lethal arrhythmias in isolated rat heart. Exp Physiol 2002;87:195-205.
17. Boukens BJ, Christoffels VM, Coronel R, Moorman AF. Developmental basis for electrophysiological heterogeneity in the ventricular and outflow tract myocardium as a substrate for life-threatening ventricular arrhythmias. Circ Res 2009;104:19-31.
18. Solan JL, Lampe PD. Connexin43 phosphorylation:structural changes and biological effects. Biochem J 2009;419:261-72.
19. Petrich BG, Eloff BC, Lerner DL, et al. Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J Biol Chem 2004;279:15330-8.
20. Petrich BG, Gong X, Lerner DL, et al. c-Jun N-terminal kinase activation mediates downregulation of connexin43 in cardiomyocytes. Circ Res 2002;91:640-7.
21. Cho JH, Cho SD, Hu H, et al. The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide. Carcinogenesis 2002;23:1163-9.
22. Muchir A, Pavlidis P, Decostre V, et al. Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J Clin Invest 2007;117:1282-93.
23. Muchir A, Shan J, Bonne G, Lehnart SE, Worman HJ. Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins. Hum Mol Genet 2009;18:241-7.
24. Kasahara H, Wakimoto H, Liu M, et al. Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein. J Clin Invest 2001;108:189-201.
25. Kasahara H, Ueyama T, Wakimoto H, et al. Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes. J Mol Cell Cardiol 2003;35:243-56.
26. Jagatheesan G, Thanumalayan S, Muralikrishna B, Rangaraj N, Karande AA, Parnaik VK. Colocalization of intranuclear lamin foci with RNA splicing factors. J Cell Sci 1999:112 (Pt 24):4651-61.
27. Melcon G, Kozlov S, Cutler DA, et al. Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum Mol Genet 2006;15:637-51.
28. Nili E, Cojocaru GS, Kalma Y, et al. Nuclear membrane protein LAP2beta mediates transcriptional repression alone and together with its binding partner GCL (germ-cell-less). J Cell Sci 2001:114:3297-307.
[1]S. Karkkainen, K. Peuhkurinen, Genetics of dilated cardiomyopathy, Ann Med 39 (2007) 91-107.
[2]C. Ostlund, H. J. Worman, Nuclear envelope proteins and neuromuscular diseases, Muscle Nerve 27 (2003) 393-406.
[3]A., Perrot, S. Hussein, V. Ruppert, H. H. Schmidt, M. S. Wehnert, N. T. Duong, M. G. Posch, A. Panek, R. Dietz, I. Kindermann, M. Bohm, A. Michalewska-Wludarczyk, A. Richter, B. Maisch, S. Pankuweit, C. Ozcelik, Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy, Basic Res Cardiol (2008).
[4]H.Wang, J.. Wang, W. Zheng, X. Wang, S. Wang, L. Song, Y. Zou, Y. Yao, R. Hui, Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect, Biochem Biophys Res Commun 344 (2006) 17-24.
[5]S. Karkkainen, T. Helio, R. Miettinen, P. Tuomainen, P. Peltola, J. Rummukainen, K. Ylitalo, M. Kaartinen, J. Kuusisto, L.Toivonen, M.S. Nieminen, M. Laakso, K. Peuhkurinen, A novel mutation, Ser143Pro, in the lamin A/C.gene is common in finnish patients with familial dilated cardiomyopathy, Eur Heart J 25 (2004) 885-893.
[6]M. R. Taylor, P. R. Fain, G. Sinagra, M. L. Robinson, A. D. Robertson, E. Carniel, A. Di Lenarda, T. J. Bohlmeyer,D. A. Ferguson, G. L. Brodsky, M. M. Boucek, J. Lascor, A. C. Moss, W. L. Li, G. L. Stetler, F. Muntoni, M.R. Bristow, L. Mestroni, Natural.history of dilated cardiomyopathy due to lamin A/C gene mutations, J Am Coll Cardiol 41 (2003) 771-780.
[7]H. M. Becane, G. Bonne, S. Varnous, A. Muchir, V. Ortega, E. H. Hammouda, J. A. Urtizberea, T. Lavergne, M. Fardeau, B. Eymard, S. Weber, K. Schwartz, D. Duboc, High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation, Pacing Clin Electrophysiol 23 (2000) 1661-1666.
[8]S. Karkkainen, E. Reissell, T. Helio, M. Kaartinen, P. Tuomainen, L. Toivonen, J. Kuusisto, M. Kupari, M.S. Nieminen, M. Laakso; K. Peuhkurinen; Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy, Heart 92 (2006) 524-526.
[9]J. H. van Berlo, W. G. de Voogt, A. J. van der Kooi, J. P. van Tintelen, G. Bonne, R. B. Yaou, D. Duboc, T. Rossenbacker, H. Heidbuchel, M. de Visser, H. J. Crijns, Y. M. Pinto, Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations:do lamin A/C mutations portend a high risk of sudden death?, J Mol Med 83 (2005) 79-83.
[10]M. Pasotti, C. Klersy, A. Pilotto, N. Marziliano, C. Rapezzi, A. Serio, S. Mannarino, F. Gambarin, V. Favalli, M. Grasso, M. Agozzino, C. Campana, A. Gavazzi,0. Febo, M. Marini, M. Landolina, A. Mortara, G. Piccolo, M. Vigano, L. Tavazzi, E. Arbustini, Long-term outcome and risk stratification in dilated cardiolaminopathies, J Am Coll Cardiol 52 (2008) 1250-1260.
[11]C. Meune, J. H. Van Berlo, F. Anselme, G. Bonne, Y. M. Pinto, D. Duboc, Primary prevention of sudden death in patients with lamin A/C gene mutations, N Engl J Med 354 (2006) 209-210.
[12]T. Sullivan, D. Escalante-Alcalde, H. Bhatt, M. Anver, N.Bhat,K. Nagashima, C.L. Stewart, B. Burke, Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy, J Cell Biol 147 (1999) 913-920.
[13]T. Arimura, A. Helbling-Leclerc, C. Massart, S. Varnous,F. Niel, E. Lacene, Y. Fromes, M. Toussaint, A.M. Mura, D.I. Keller, H. Amthor, R. Isnard, M. Malissen, K. Schwartz, G. Bonne, Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies,'Hum Mol Genet 14 (2005) 155-169.
[14]L. C. Mounkes, S. V. Kozlov, J. N. Rottman, C. L. Stewart, Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice, Hum Mol Genet 14 (2005) 2167-2180.
[15]Y. Wang, A. J. Herron, H.J. Worman, Pathology and nuclear abnormalities in hearts of transgenic mice expressing M371K lamin A encoded by an LMNA mutation causing Emery-Dreifuss muscular dystrophy, Hum Mol Genet 15 (2006) 2479-2489.
[16]C.M. Wolf, L. Wang, R. Alcalai, A. Pizard, P. G. Burgon, F. Ahmad, M. Sherwood, D. M. Branco, H. Wakimoto, G.I. Fishman, V. See, C. L. Stewart, D. A. Conner, C.I. Berul, C. E. Seidman, J. G. Seidman, Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease, J Mol Cell Cardiol 44 (2008) 293-303.
[17]C. Vigouroux, M. Auclair, E. Dubosclard, M. Pouchelet, J. Capeau, J. C. Courvalin, B. Buendia, Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene, J Cell Sci 114 (2001) 4459-4468.
[18]J. L. Broers, E. A. Peeters, H.J. Kuijpers, J. Endert, C. V. Bouten, C. W. Oomens, F. P. Baaijens, F. C. Ramaekers, Decreased mechanical stiffness in LMNA-/-cells is caused by defective nucleo-cytoskeletal integrity:implications for the development of laminopathies, Hum Mol Genet 13 (2004) 2567-2580.
[19]J., Lammerding, P. C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R. D. Kamm, C. L. Stewart, R. T. Lee, Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction, J Clin Invest 113 (2004) 370-378.
[20]J. Lammerding, J. Hsiao, P. C. Schulze, S. Kozlov, C. L. Stewart, R. T. Lee, Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells, J Cell Biol 170 (2005) 781-791.
[21]B.C. Capell, F. S. Collins, Human laminopathies:nuclei gone genetically awry, Nat Rev Genet 7 (2006) 940-952.
[22]M. Bakay, Z. Wang, G. Melcon, L. Schiltz, J. Xuan, P. Zhao, V. Sartorelli, J. Seo, E. Pegoraro, C. Angelini, B. Shneiderman, D. Escolar, Y. W. Chen, S. T. Winokur, L. M. Pachman, C. Fan, R. Mandler, Y. Nevo, E. Gordon, Y. Zhu, Y. Dong, Y. Wang, E. P. Hoffman, Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration, Brain 129 (2006) 996-1013.
[23]J.M. Holaska, K. K. Lee, A. K. Kowalski, K. L Wilson, Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro, J Biol Chem 278 (2003) 6969-6975.
[24]J. H.Van Berlo, J.W. Voncken, N. Kubben, J. L. Broers, R. Duisters, R. E. van Leeuwen, H. J. Crijns, F. C. Ramaekers, C. J. Hutchison, Y.M. Pinto, A-type lamins are essential for TGF-betal induced PP2A to dephosphorylate transcription factors, Hum Mol Genet 14 (2005) 2839-2849.
[25]G. Melcon, S. Kozlov, D.A. Cutler, T. Sullivan, L. Hernandez, P. Zhao, S. Mitchell, G. Nader, M. Bakay, J. N. Rottman, E. P. Hoffman, C. L. Stewart, Loss of emerin at the nuclear envelope disrupts the Rbl/E2F and MyoD pathways during muscle regeneration, Hum Mol Genet 15(2006) 637-651.
[26]J. M. Gonzalez, A. Navarro-Puche, B. Casar, P. Crespo, V. Andres, Fast regulation of AP-1 activity through interaction of lamin A/C, ERK1/2, and c-Fos at the nuclear envelope, J Cell Biol 183 (2008) 653-666.
[27]A. Muchir, P. Pavlidis, V. Decostre, A. J. Herron, T. Arimura,G. Bonne, H.J. Worman, Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy, J Clin Invest 117 (2007) 1282-1293.
[28]A. Muchir, J. Shan, G. Bonne, S. E. Lehnart, H. J. Worman, Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins, Hum Mol Genet 18 (2009) 241-247.
[1]L. J. Herfst, M. B. Rook, H. J. Jongsma, Trafficking and functional expression of cardiac Na+ channels, J Mol Cell Cardiol 36 (2004) 185-193.
[2]Y. Ruan, N. Liu, S. G. Priori, Sodium channel mutations and arrhythmias, Nat Rev Cardiol 6 (2009) 337-348.
[3]A. L. George, Jr., Inherited disorders of voltage-gated sodium channels, J Clin Invest 115 (2005) 1990-1999.
[4]A. A. M. W. Simona Casini, and Hanno L. Tan, Sodium Ion Channelopathies.
[5]s. casini, sodium ion channelopathies.
[6]T. M. Olson, M. T. Keating, Mapping a cardiomyopathy locus to chromosome 3p22-p25, J Clin Invest 97 (1996) 528-532.
[7]W. P. McNair, L. Ku, M. R. Taylor, P. R. Fain, D. Dao, E. Wolfel, L. Mestroni, SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia, Circulation 110(2004) 2163-2167.
[8]T.M. Olson, V.V. Michels, J. D. Ballew, S. P. Reyna, M. L. Karst, K. J. Herron, S.C. Horton, R. J. Rodehef fer, J. L. Anderson, Sodium channel mutations and susceptibility to heart failure and atrial fibrillation, Jama 293 (2005) 447-454.
[9]P. R.Greenlee, J. L. Anderson, J. R. Lutz, A. E. Lindsay, A. D. Hagan, Familial automaticity-conduction disorder with associated cardiomyopathy, West J Med 144 (1986).33-41.
[10]W. A. Groenewegen, M. Firouzi, C. R. Bezzina, S. Vliex, I.M. van Langen,. L. Sandkuijl, J. P. Smits, M. Hulsbeek, M.B. Rook, H. J. Jongsma, A.A. Wilde, A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill, Circ Res 92 (2003) 14-22.
[11]R. Shi, Y. Zhang, C. Yang, C. Huang, X. Zhou, H. Qiang, A. A. Grace, C. L. Huang, A. Ma, The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death, Europace 10 (2008) 1329-1335.
[12]J. Ge, A. Sun, V. Paajanen,S.Wang, C. Su, Z. Yang, Y. Li, S. Wang, J. Jia, K. Wang, Y. Zou, L. Gao, K. Wang, Z. Fan, Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy, Circ Res 1 (2008) 83-92.
[13]M. Hesse, C. S. Kondo, R. B. Clark, L. Su, F. L. Allen, C.T. Geary-Joo, S. Kunnathu, D. L. Severson, A. Nygren, W. R. Giles, J. C. Cross, Dilated cardiomyopathy is associated with reduced expression of the cardiac sodium channel Scn5a, Cardiovasc Res 75 (2007) 498-509.
[14]L. S. Maier, T. Zhang, L. Chen, J. DeSantiago, J. H. Brown, D. M. Bers, Transgenic CaMKIIdeltaC overexpression uniquely alters' cardiac myocyte Ca2+ handling:reduced SR Ca2+ load and'activated SR Ca2+ release, Circ Res 92 (2003) 904-911.
[15]C. R.'Bezzina, M. B. Rook, W. A. Groenewegen, L. J. Herfst; A. C.van der Wal, J. Lam, H. J. Jongsma, A. A. Wilde, M. M. Mannens, Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system, Circ Res 92 (2003) 159-168.
[16]D.W. Benson, D. W. Wang, M. Dyment, T. K. Knilans, F.A. Fish, M.J. Strieper, T. H.Rhodes,A. L. George, Jr., Congenital'sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A), J Clin Invest 112 (2003) 1019-1028.
[17]T. P. Nguyen, D.W. Wang, T. H. Rhodes, A. L. George, Jr., Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia, Circ Res 102 (2008) 364-371.
[18]A. Frustaci, S. G. Priori, M. Pieroni, C. Chimenti, C. Napolitano, I. Rivolta,T.Sanna, F. Bellocci, M. A. Russo, Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome, Circulation 112 (2005) 3680-3687.
[19]G. Frigo, A. Rampazzo, B. Bauce, K. Pilichou, G. Beffagna, G. A. Danieli, A. Nava, B. Martini, Homozygous SCN5A mutation in Brugada syndrome with monomorphic ventricular tachycardia and structural heart abnormalities, Europace 9 (2007) 391-397.
[20]T. A. van Veen, M. Stein, A. Royer, K. Le Quang, F. Charpentier, W. H. Colledge, C. L. Huang, R. Wilders, A. A. Grace, D. Escande, J. M. de Bakker, H. V. van Rijen, Impaired impulse propagation in Scn5a-knockout mice:combined contribution of excitability, connexin expression, and tissue architecture in relation to aging, Circulation 112 (2005) 1927-1935.
[21]B. Gavillet, J. S. Rougier, A. A. Domenighetti, R. Behar, C. Boixel, P. Ruchat, H. A. Lehr, T. Pedrazzini, H. Abriel, Cardiac sodium channel Navl.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin, Circ Res 99 (2006) 407-414.
[22]E. Murphy, D.A. Eisner, Regulation of intracellular and mitochondrial sodium in health and disease, Circ Res 104 (2009) 292-303.
[23]D. Shao, K. Okuse, M.B. Djamgoz, Protein-protein interactions involving voltage-gated sodium channels:Post-translational regulation, intracellular trafficking and functional expression, Int J Biochem Cell Biol 41 (2009) 1471-1481.