Autosomal dominant dilated cardiomyopathy with atrioventricular block: A lamin A/C defect-related disease
Autosomal dominant dilated cardiomyopathy with atrioventricular block: A lamin A/C defect-related disease
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DOI：
10.1016/s0735-1097(02)01724-2
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发表时间：
2002-03-20
影响因子：
24
通讯作者：
Tavazzi, L
中科院分区：
文献类型：
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作者：
Arbustini, E;Pilotto, A;Tavazzi, L
目的探讨层蛋白A/C(lamin A/C，LMNA)基因缺陷在家族性和散发性扩张型心肌病(DCM)伴房室传导阻滞(AVB)或血清肌酸磷酸酶(SCPK)升高中的发生率，以及相应的心肌和蛋白表达的变化。背景已有研究表明，家族性DCM伴发传导障碍或各种肌病与LMNA基因缺陷有关。结果在5例伴有AVB的家族性常染色体显性遗传性扩张型心肌病患者中发现了5个新的LMNA突变(K97E、E111X、R190W、E317K和1,713处的4个碱基插入)。心肌细胞核LMNA表达减少或缺失。对三个不同突变的心脏进行蛋白质印迹分析，显示出额外的30 kDa条带，表明突变对野生型蛋白有降解作用。心肌细胞核膜的电子显微镜观察到局灶性破坏、小泡形成和核孔聚集。结论LMNA基因突变占DCMS合并AVB的33%，均为家族性常染色体显性遗传。无AVB的扩张型心肌病患者sCPK升高不是LMNA突变的有用预测指标。(J Am Coll心脏ol 2002；39：981-90)(C)2002，由美国心脏病学会基金会主办。
OBJECTIVES We investigated the prevalence of lamin A/C (LMNA) gene defects in familial and sporadic dilated cardiomyopathies (DCM) associated with atrioventricular block (AVB) or increased serum creatine-phosphokinase (sCPK), and the corresponding changes in myocardial and protein expression.BACKGROUND It has been reported that familial DCM, associated with conduction disturbances or variable myopathies, is causally linked to LMNA gene defects.METHODS The LMNA gene and myocardial ultrastructural and immunochemical changes were analyzed in 73 cases of DCM (49 pure, 15 with AVB [seven familial, eight sporadic], 9 with increased sCPK), four cases of familial AVB and 19 non-DCM heart diseases. The normal controls included eight heart donor biopsies for tissue studies and 107 subjects for LMNA gene studies.RESULTS Five novel LMNA mutations (K97E, E111X, R190W, E317K, four base pair insertion at 1,713 cDNA) were identified in five cases of familial autosomal dominant DCM with AVB (5115: 33%). The LMNA expression of the myocyte nuclei was reduced or absent. Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein. Focal disruptions, bleb formation and nuclear pore clustering were documented by electron microscopy of the myocyte nuclear membranes. None of these changes and no mutations were found in the nine patients with DCM and increased sCPK or in the disease and normal controls.CONCLUSIONS The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant. Increased sCPK in patients with DCM without AVB is not a useful predictor of LMNA mutation. (J Am Coll Cardiol 2002;39:981-90) (C) 2002 by the American College of Cardiology Foundation.