A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice.
A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice.
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DOI：
10.1038/s41598-020-74800-8
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发表时间：
2020-10-27
影响因子：
4.6
通讯作者：
Kuroyanagi H
中科院分区：
文献类型：
--
作者：
Ihara K;Sasano T;Hiraoka Y;Togo-Ohno M;Soejima Y;Sawabe M;Tsuchiya M;Ogawa H;Furukawa T;Kuroyanagi H
扩张型心肌病是一种以左心室扩张和心功能不全为特征的致死性心脏病。最近对DCM的遗传学研究已经确定了60多个基因中的致病突变，包括RBM20，它编码心脏特异性剪接的调节因子。据报道，与其他基因突变的DCM患者相比，RBM20突变的DCM患者表现出更严重的心脏表型，包括心功能受损、房颤（AF）和室性心律失常，导致心脏性猝死。RBM20的RSRSP片段是在特发性DCM患者中发现的错义突变热点，其功能是其核定位信号的关键部分。然而，在RSRSP延伸和心脏表型的突变之间的关系从来没有在动物模型中进行评估。在这里，我们发现，Rbm20突变小鼠在RSRSP延伸中携带错义突变S637A，模仿DCM患者，表现出严重的心功能不全和自发性AF和室性心律失常，模仿患者的临床状态。相反，移码缺失的Rbm20突变小鼠表现出不太严重的表型，尽管Rbm20依赖性可变剪接的丧失是不可区分的。RBM20S637A蛋白不能定位于核斑点，但在心肌细胞中积聚于细胞质、核周颗粒样结构，这可能有助于更严重的心脏表型。
Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.
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DOI：
10.3791/56478
发表时间：
2018-02-22
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ihara K;Sugiyama K;Takahashi K;Yamazoe M;Sasano T;Furukawa T
通讯作者：
Furukawa T
影响因子：
5.5
作者：
Burashnikov, Elena;Pfeiffer, Ryan;Barajas-Martinez, Hector;Delpon, Eva;Hu, Dan;Desai, Mayurika;Borggrefe, Martin;Haeissaguerre, Michel;Kanter, Ronald;Pollevick, Guido D.;Guerchicoff, Alejandra;Laino, Ruben;Marieb, Mark;Nademanee, Koonlawee;Nam, Gi-Byoung;Robles, Roberto;Schimpf, Rainer;Stapleton, Dwight D.;Viskin, Sami;Winters, Stephen;Wolpert, Christian;Zimmern, Samuel;Veltmann, Christian;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
DOI：
10.1073/pnas.1600633113
发表时间：
2016-07-05
影响因子：
11.1
作者：
Chang, Audrey N.;Mahajan, Pravin;Stull, James T.
通讯作者：
Stull, James T.
影响因子：
25
作者：
Johnson, Janel O.;Pioro, Erik P.;Boehringer, Ashley;Chia, Ruth;Feit, Howard;Renton, Alan E.;Pliner, Hannah A.;Abramzon, Yevgeniya;Marangi, Giuseppe;Winborn, Brett J.;Gibbs, J. Raphael;Nalls, Michael A.;Morgan, Sarah;Shoai, Maryam;Hardy, John;Pittman, Alan;Orrell, Richard W.;Malaspina, Andrea;Sidle, Katie C.;Fratta, Pietro;Harms, Matthew B.;Baloh, Robert H.;Pestronk, Alan;Weihl, Conrad C.;Rogaeva, Ekaterina;Zinman, Lorne;Drory, Vivian E.;Borghero, Giuseppe;Mora, Gabriele;Calvo, Andrea;Rothstein, Jeffrey D.;Drepper, Carsten;Sendtner, Michael;Singleton, Andrew B.;Taylor, J. Paul;Cookson, Mark R.;Restagno, Gabriella;Sabatelli, Mario;Bowser, Robert;Chio, Adriano;Traynor, Bryan J.
通讯作者：
Traynor, Bryan J.
影响因子：
16.2
作者：
Gasset-Rosa, Fatima;Lu, Shan;Cleveland, Don W.
通讯作者：
Cleveland, Don W.