Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I.
Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I.
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titin I波段中的单核苷酸多态性触发的病理机制的探索：心肌病连接的突变T2580i。
DOI：
10.1098/rsob.160114
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发表时间：
2016-09
期刊：
影响因子：
5.8
通讯作者：
Mayans O
中科院分区：
文献类型：
--
作者：
Bogomolovas J;Fleming JR;Anderson BR;Williams R;Lange S;Simon B;Khan MM;Rudolf R;Franke B;Bullard B;Rigden DJ;Granzier H;Labeit S;Mayans O
肌联蛋白错义单核苷酸多态性（mSNPs）是心力衰竭的主要致病因素。然而，区分良性和致病mSNP是一个巨大的挑战。在这里，我们研究的问题是否一个单一的mSNP在一个通用域的肌联蛋白可以影响心脏功能作为一个整体，如果是这样，如何。为此，我们研究了mSNP T2850I，似乎与致瘤性右心室心肌病（ARVC）有关。我们使用结构生物学，计算机模拟和转基因肌肉在体内的方法来跟踪从分子到生物体水平的突变的影响。数据表明，T2850 I交换是兼容的域的三维folds.Further，它强烈地使其不稳定，它诱导的肌联蛋白链的构象动力学的变化，改变其反应性，导致形成异常的相互作用的肌节。基因敲入小鼠的超声心动图显示心肌硬度增加引起轻度舒张功能障碍。总之，我们的数据提供的证据表明，肌联蛋白的I带中的单个mSNPs可以改变整体肌肉行为。我们认为疾病的机制是非天然肌节相互作用和肌联蛋白不稳定性的发展，导致I带顺应性降低。然而，理解T2850 I诱导的ARVC病理机制仍然是一个复杂的问题，需要更深入地了解肌联蛋白区域的肌节背景。
Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.
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影响因子：
2.4
作者：
Bruning, Marc;Barsukov, Igor;Mayans, Olga
通讯作者：
Mayans, Olga
影响因子：
2.9
作者：
Madan, Bharat;Seo, Sung Yong;Lee, Sun-Gu
通讯作者：
Lee, Sun-Gu
影响因子：
5.6
作者：
Nordstrand, K;Sandström, A;Berndt, KD
通讯作者：
Berndt, KD
影响因子：
37.8
作者：
LITTLE, WC;OHNO, M;CHENG, CP
通讯作者：
CHENG, CP
DOI：
10.1126/science.1217283
发表时间：
2012-05-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Keinan A;Clark AG
通讯作者：
Clark AG