Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy
Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy
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DOI：
10.1038/ng815
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发表时间：
2002-02-01
期刊：
影响因子：
30.8
通讯作者：
Thierfelder, L
中科院分区：
文献类型：
--
作者：
Gerull, B;Gramlich, M;Thierfelder, L
充血性心力衰竭 (CHF) 可由各种心输出量不足的疾病状态引起。扩张型心肌病 (DCM) 引起的 CHF 是一种家族性疾病，占 20-30% 的病例，与编码细胞骨架蛋白、收缩蛋白或内核膜蛋白的基因突变相关 (1)。我们发现编码巨肌丝肌联蛋白 (TTN) 的基因突变会导致与染色体 2q31 (CMD1G; MIM 604145) 相关的常染色体显性 DCM。肌联蛋白分子从肌节 Z 盘延伸至 M 线，为收缩机制提供可延伸的支架，对于肌原纤维的弹性和完整性至关重要 (2)。在一个大型 DCM 家族中，TTN 外显子 326 中的分离 2 bp 插入突变会导致移码，截断 A 带肌联蛋白。大约 2 mD 的截短蛋白在骨骼肌中表达，但使用表位特异性抗肌联蛋白抗体进行的蛋白质印迹研究表明，突变蛋白通过位点特异性切割被截短为 1.14 mD 亚片段。在另一个 DCM 与 CMD1G 连接的大家族中，TTN 错义突变 (Trp930Arg) 预计会破坏位于 Z-disc-1-带过渡区的免疫球蛋白折叠的高度保守的疏水核心序列。 CMD1G 个体 TTN 突变的鉴定应有助于进一步了解家族性 CHF 和肌原纤维肌联蛋白更新的发病机制。
Congestive heart failure (CHF) can result from various disease states with inadequate cardiac output. CHF due to dilated cardiomyopathy (DCM) is a familial disease in 20-30% of cases and is associated with mutations in genes encoding cytoskeletal, contractile or inner-nuclear membrane proteins(1). We show that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145). Titin molecules extend from sarcomeric Z-discs to M-lines, provide an extensible scaffold for the contractile machinery and are crucial for myofibrillar elasticity and integrity(2). in a large DCM kindred, a segregating 2-bp insertion mutation in TTN exon 326 causes a frameshift, truncating A-band titin. The truncated protein of approximately 2 mD is expressed in skeletal muscle, but western blot studies with epitope-specific anti-titin antibodies suggest that the mutant protein is truncated to a 1.14-mD subfragment by site-specific cleavage. In another large family with DCM linked to CMD1G, a TTN missense mutation (Trp930Arg) is predicted to disrupt a highly conserved hydrophobic core sequence of an immunoglobulin fold located in the Z-disc-1-band transition zone. The identification of TTN mutations in individuals with CMD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.