Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel.
Max Delbrueck Center for Molecular Medicine, Berlin, Germany; Department of Cardiology, University of Tuebingen, Germany.
Int J Cardiol. 2014 Jan 15;171(1):24-30. doi: 10.1016/j.ijcard.2013.11.037. Epub 2013 Nov 25.
Familial restrictive cardiomyopathy (RCM) caused by a single gene mutation is the least common of the inherited cardiomyopathies. Only a few RCM-causing mutations have been described. Most mutations causing RCM are located in sarcomere protein genes which also cause hypertrophic cardiomyopathy (HCM). Other genes associated with RCM include the desmin and familial amyloidosis genes. In the present study we describe familial RCM with severe heart failure triggered by a de novo mutation in TTN, encoding the huge muscle filament protein titin.
Family members underwent physical examination, ECG and Doppler echocardiogram studies. The family comprised 6 affected individuals aged 12-35 years. Linkage to candidate loci was performed, followed by gene sequencing. Candidate loci/gene analysis excluded 18 candidate genes but showed segregation with a common haplotype surrounding the TTN locus. Sequence analysis identified a de novo mutation within exon 266 of the TTN gene, resulting in the replacement of tyrosine by cysteine. p.Y7621C affects a highly conserved region in the protein within a fibronectin-3 domain, belonging to the A/I junction region of titin. No other disease-causing mutation was identified in cardiomyopathy genes by whole exome sequencing.
Our study shows, for the first time, that mutations in TTN can cause restrictive cardiomyopathy. The giant filament titin is considered to be a determinant of a resting tension of the sarcomere and this report provides genetic evidence of its crucial role in diastolic function.
由单一基因突变引起的家族性限制性心肌病（RCM）是遗传性心肌病中最不常见的一种。只有少数 RCM 致病突变被描述过。大多数导致 RCM 的突变位于肌节蛋白基因中，这些基因也会导致肥厚型心肌病（HCM）。与 RCM 相关的其他基因包括结蛋白和家族性淀粉样变性基因。在本研究中，我们描述了一种家族性 RCM，其严重心力衰竭是由编码巨大肌丝蛋白titin 的 TTN 中的新生突变引起的。
对家族成员进行了体格检查、心电图和多普勒超声心动图检查。该家族由 6 名年龄在 12-35 岁的受影响个体组成。进行了候选基因座连锁分析，随后进行了基因测序。候选基因座/基因分析排除了 18 个候选基因，但显示与 TTN 基因座周围常见单倍型的分离。序列分析在 TTN 基因的外显子 266 内发现了一个新生突变，导致酪氨酸被半胱氨酸取代。p.Y7621C 影响蛋白中高度保守的纤维连接蛋白-3 结构域内的区域，属于 titin 的 A/I 连接区。通过全外显子组测序未在心肌病基因中发现其他致病突变。
我们的研究首次表明，TTN 突变可导致限制性心肌病。巨大的纤维丝 titin 被认为是肌节静息张力的决定因素，本报告提供了其在舒张功能中关键作用的遗传证据。
