Perrot Andreas, Hussein Shwan, Ruppert Volker, Schmidt Hartmut H J, Wehnert Manfred S, Duong Nguyen Thuy, Posch Maximilian G, Panek Anna, Dietz Rainer, Kindermann Ingrid, Böhm Michael, Michalewska-Wludarczyk Aleksandra, Richter Anette, Maisch Bernhard, Pankuweit Sabine, Ozcelik Cemil
Charité-Universitätsmedizin Berlin, Kardiologie am Campus Buch und Virchow-Klinikum, Experimental and Clinical Research Center (ECRC) am Max-Delbrück-Centrum für Molekulare Medizin, Lindenberger Weg 80, Berlin, Germany.
Basic Res Cardiol. 2009 Jan;104(1):90-9. doi: 10.1007/s00395-008-0748-6. Epub 2008 Sep 15.
The familial form of dilated cardiomyopathy (DCM) occurs in about 20%-50% of DCM cases. It is a heterogeneous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most important disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.
家族性扩张型心肌病（DCM）约占DCM病例的20%-50%。它是一种异质性遗传病：已证实20多种不同基因的突变可导致家族性DCM。编码核膜蛋白核纤层蛋白A/C的LMNA基因是该疾病最重要的致病基因之一。因此，我们对73例家族性DCM患者的大样本队列进行了LMNA基因分析。临床检查（心电图、超声心动图和心导管检查）之后，通过直接测序对LMNA进行基因特征分析。我们在五个不同的家族中检测到五个杂合错义突变（发生率7%），这些家族的特征为严重DCM和伴有传导系统疾病的心力衰竭，需要植入起搏器和进行心脏移植。其中四个变异聚集在蛋白结构域卷曲1B中，该结构域对核纤层蛋白B相互作用和核纤层蛋白A/C二聚化很重要。虽然我们除了发现三个已知突变（E161K、R190Q、R644C）外还鉴定出两个新突变（E203V、K219T），但值得注意的是，四个突变代表了LMNA热点。正如我们在研究中所证实的，携带LMNA突变的DCM患者表现出明显一致的严重表型。在这类家族中检测LMNA似乎是推荐的，因为个体的基因型信息对临床医生肯定有用。
