van Tintelen J Peter, Tio Rene A, Kerstjens-Frederikse Wilhelmina S, van Berlo Jop H, Boven Ludolf G, Suurmeijer Albert J H, White Stefan J, den Dunnen Johan T, te Meerman Gerard J, Vos Yvonne J, van der Hout Annemarie H, Osinga Jan, van den Berg Maarten P, van Veldhuisen Dirk J, Buys Charles H C M, Hofstra Robert M W, Pinto Yigal M
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Am Coll Cardiol. 2007 Jun 26;49(25):2430-9. doi: 10.1016/j.jacc.2007.02.063. Epub 2007 Jun 11.
The goal of this study was to identify the underlying gene defect in a family with inherited myocardial fibrosis.
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.
Twenty-five family members were clinically evaluated, and 5 unaffected and 8 affected family members were included in a genome-wide linkage study.
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.
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.
本研究的目的是确定一个遗传性心肌纤维化家族潜在的基因缺陷。
对一个具有常染色体显性遗传形式的心肌纤维化且临床结局高度恶性的大家族进行了研究。由于心肌纤维化先于临床和超声心动图表现出现，我们认为该疾病是一种遗传性心脏纤维化形式。
对25名家族成员进行了临床评估，5名未受影响和8名受影响的家族成员被纳入全基因组连锁研究。
在核纤层蛋白A/C（LMNA）基因区域发现了最高的优势对数（LOD）分数（LOD = 2.6）。通过变性梯度凝胶电泳和测序进行的LMNA突变分析均未显示出突变。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探针扩增分析显示，包含起始密码子的外显子和相邻的非编码外显子缺失。体外研究表明，该缺失导致核纤层蛋白形成核聚集体，提示突变等位基因正在转录。
这种新发现的LMNA缺失导致一种独特的、高度恶性的心肌病，伴有早发性原发性心脏纤维化，可能是由于缩短的突变蛋白的作用，继而导致心律失常和终末期心力衰竭。
