G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model
G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model
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DOI：
10.1016/j.bbrep.2019.100711
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发表时间：
2019-11
影响因子：
2.7
通讯作者：
Y. Hamada;Takeshi Yamamoto;Y. Nakamura;Yoko Sufu-Shimizu;Takuma Nanno;Masakazu Fukuda;M. Ono;T. Oda;S. Okuda;T. Ueyama;Shigeki Kobayashi;M. Yano
中科院分区：
文献类型：
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作者：
Y. Hamada;Takeshi Yamamoto;Y. Nakamura;Yoko Sufu-Shimizu;Takuma Nanno;Masakazu Fukuda;M. Ono;T. Oda;S. Okuda;T. Ueyama;Shigeki Kobayashi;M. Yano
背景：心律失常性右室心肌病（ARVC）是一种遗传性心脏病，可导致心力衰竭和/或心源性猝死。一些桥粒基因（DSC2、PKG、PKP2、DSP和RyR2）被认为是ARVC的致病基因。其中，DSC2突变占ARVC遗传异常的2%。本研究旨在阐明DSC2中G790del突变对小鼠模型心律失常发生机制和心功能的影响。结果杂合子+/G790del和纯合子G790del/G790del小鼠均未出现右心室结构和功能缺陷或致死性心律失常。纯合子G790del/G790del 6月龄小鼠轻度左心室功能障碍。在纯合子G790del/G790del小鼠分离的心肌细胞中，细胞缩短随着细胞内Ca2+瞬态的延长而减少，并且在异丙肾上腺素的反应中经常观察到自发的Ca2+瞬态。结论DSC2中G790del突变与ARVC的发病机制无关，但在左室表现出轻微的收缩功能障碍和Ca2+失调。
Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease that causes heart failure and/or sudden cardiac death. Several desmosomal genes (DSC2, PKG, PKP2, DSP, and RyR2) are thought to be the causative gene involved in ARVC. Out of them, DSC2 mutations account for 2% of ARVC genetic abnormalities. This study aimed to clarify the effect of G790del mutation in DSC2 on the arrhythmogenic mechanism and cardiac function in a mouse model. Result Neither the heterozygous +/G790del nor homozygous G790del/G790del mice showed structural and functional defects in the right ventricle (RV) or lethal arrhythmia. The homozygous G790del/G790del 6-month-old mice slightly showed left ventricular (LV) dysfunction. Cell shortening decreased with prolongation of intracellular Ca2+ transient in cardiomyocytes isolated from the homozygous G790del/G790del mice, and spontaneous Ca2+ transients were frequently observed in response to isoproterenol. Conclusions G790del mutation in DSC2 was not relevant to the pathogenesis of ARVC, but showed a slight contractile dysfunction and Ca2+ dysregulation in the LV.