Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene
Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene
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DOI：
10.1016/j.jacc.2007.02.063
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发表时间：
2007-06-26
影响因子：
24
通讯作者：
Pinto, Yigal M.
中科院分区：
文献类型：
--
作者：
van Tintelen, J. Peter;Tio, Rene A.;Pinto, Yigal M.
目的本研究的目的是确定潜在的基因缺陷在一个家庭与遗传性心肌fibrosis.Background一个大的家庭与常染色体显性遗传形式的心肌纤维化的高度恶性的临床结果进行了调查。由于心肌纤维化之前的临床和超声心动图的迹象，我们认为这种疾病是一种遗传形式的心脏fibrosis.Methods的25个家庭成员进行了临床评估，5个未受影响的和8个受影响的家庭成员被列入一个全基因组的连锁study.Results的最高对数的优势（LOD）得分（LOD = 2.6）被发现在该地区的核纤层蛋白AC（LMNA）基因。通过变性梯度凝胶电泳和测序进行的LMNA突变分析均未显示突变。然而，随后的Southern印迹，互补脱氧核糖核酸测序，和多重连接依赖性探针扩增分析，发现缺失的起始密码子包含外显子和相邻的非编码外显子。体外研究表明，删除的结果形成核聚集体的核纤层蛋白，这表明突变的等位基因被transcribed.Conclusions这种新的LMNA缺失导致一个独特的，高度恶性的心肌病与早发性原发性心脏纤维化可能是由于缩短的突变蛋白的影响，这继发性导致心律失常和终末期心力衰竭。（J Am科尔心脏病学杂志2007;49：2430-9）（c）美国心脏病学会基金会2007年。
Objectives The goal of this study was to identify the underlying gene defect in a family with inherited myocardial fibrosis.Background A large family with an autosomal dominantly inherited form of myocardial fibrosis with a highly malignant clinical outcome has been investigated. Because myocardial fibrosis preceded the clinical and echocardiographic signs, we consider the disease to be a hereditary form of cardiac fibrosis.Methods Twenty-five family members were clinically evaluated, and 5 unaffected and 8 affected family members were included in a genome-wide linkage study.Results The highest logarithm of the odds (LOD) score (LOD = 2.6) was found in the region of the lamin AC (LMNA) gene. The LMNA mutation analysis, both by denaturing gradient gel electrophoresis and sequencing, failed to show a mutation. Subsequent Southern blotting, complementary deoxyribonucleic acid sequencing, and multiplex ligation-dependent probe amplification analysis, however, revealed a deletion of the start codon-containing exon and an adjacent noncoding exon. In vitro studies demonstrated that the deletion results in the formation of nuclear aggregates of lamin, suggesting that the mutant allele is being transcribed.Conclusions This novel LMNA deletion causes a distinct, highly malignant cardiomyopathy with early-onset primary cardiac fibrosis likely due to an effect of the shortened mutant protein, which secondarily leads to arrhythmias and end-stage cardiac failure. (J Am Coll Cardiol 2007;49:2430-9) (c) 2007 by the American College of Cardiology Foundation.