A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies.
A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies.
复制标题
DOI：
10.3389/fcvm.2016.00021
复制
发表时间：
2016
影响因子：
3.6
通讯作者：
Mestroni L
中科院分区：
文献类型：
--
作者：
Gigli M;Begay RL;Morea G;Graw SL;Sinagra G;Taylor MR;Granzier H;Mestroni L
肌动蛋白(TTN)是已知的存在于心肌中的最大的肌瘤蛋白。由于TTN的选择性剪接，心脏表达两种主要的亚型(N2B和N2BA)，包括四个不同的区域，称为Z线、I带、A带和M线。下一代测序可以同时对大量基因进行测序，并为轻松分析TTN等巨型基因提供了机会。TTN基因的突变可导致心肌病，特别是扩张型心肌病(DCM)。扩张型心肌病是最常见的心肌病，以收缩功能障碍和左心室扩张为特征。TTN截短变异已被描述为DCM的最常见原因，而TTN错义变异在DCM发病机制中的真正影响仍不清楚。在最近的人群筛查研究中，基于生物信息过滤的可能致病的罕见错义变体仅占已发现的数百个罕见TTN错义变体的12.6%，这表明错义变体在TTN中非常常见，而且往往是良性的。本综述的目的是了解TTN突变在扩张型心肌病和其他心肌病中的临床作用。虽然TTN截短在扩张型心肌病中很常见，但有证据表明TTN截短在肥厚型心肌病(HCM)表型中很少见。此外，TTN基因突变还可引起致心律失常的右室心肌病(ARVC)，具有不同的临床特征和预后。最后，一个罕见的TTN错义变异与限制性心肌病(RCM)表型共分离的鉴定表明，TTN是该疾病的一个新的致病基因。临床诊断检测目前能够分析包括TTN在内的100多个心肌病基因；然而，TTN的大小和广泛遗传变异的存在给确定重大致病突变带来了临床挑战。这篇综述讨论了心肌病中TTN基因变异的现有知识，以及TTN致病突变诊断在临床环境中的影响。
Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting.