Gerull Brenda, Atherton John, Geupel Anke, Sasse-Klaassen Sabine, Heuser Arnd, Frenneaux Michael, McNabb Mark, Granzier Henk, Labeit Siegfried, Thierfelder Ludwig
Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13092, Berlin-Buch, Germany.
J Mol Med (Berl). 2006 Jun;84(6):478-83. doi: 10.1007/s00109-006-0060-6. Epub 2006 May 6.
Dilated cardiomyopathy (DCM) is an etiologically heterogeneous cardiac disease characterized by left ventricular dilation and systolic dysfunction. Approximately 25-30% of DCM patients show a family history of mainly autosomal dominant inheritance. We and others have previously demonstrated that mutations in the giant muscle filament titin (TTN) can cause DCM. However, the prevalence of titin mutations in familial DCM is unknown. In this paper, we report a novel heterozygous 1-bp deletion mutation (c.62890delG) in TTN that cosegregates with DCM in a large Australian pedigree (A3). The TTN deletion mutation c.62890delG causes a frameshift, thereby generating a truncated A-band titin due to a premature stop codon (p.E20963KfsX10) and the addition of ten novel amino acid residues. The clinical phenotype of DCM in kindred A3 demonstrates incomplete penetrance and variable expressivity. Finally, protein analysis of a skeletal muscle biopsy sample from an affected member did not reveal the predicted truncated titin isoform although the aberrant mRNA was present, suggesting posttranslational modification and degradation of the truncated protein. The identification of a novel disease-causing mutation in the giant titin gene in a third large family with DCM indicates that mutations in titin may account for a significant portion of the genetic etiology in familial DCM.
扩张型心肌病（DCM）是一种病因异质性的心脏疾病，其特征为左心室扩张和收缩功能障碍。大约25%-30%的DCM患者有家族病史，主要为常染色体显性遗传。我们和其他人之前已经证明，巨大肌丝肌联蛋白（TTN）的突变可导致DCM。然而，家族性DCM中肌联蛋白突变的患病率尚不清楚。在本文中，我们报告了TTN基因中一个新的杂合1-bp缺失突变（c.62890delG），该突变在一个大型澳大利亚家系（A3）中与DCM共分离。TTN缺失突变c.62890delG导致移码，从而由于过早的终止密码子（p.E20963KfsX10）和添加十个新的氨基酸残基而产生截短的A带肌联蛋白。家系A3中DCM的临床表型表现为不完全外显率和可变表达性。最后，尽管存在异常mRNA，但对一名患病成员的骨骼肌活检样本进行蛋白质分析时，并未发现预测的截短肌联蛋白异构体，这表明截短蛋白存在翻译后修饰和降解。在第三个患有DCM的大型家系中鉴定出巨大肌联蛋白基因中的一种新的致病突变，这表明肌联蛋白突变可能在家族性DCM的遗传病因中占很大一部分。
