Elucidation of the pathology in ARVC caused by Japanese-specific DSG2 mutations using knock-in mice models: searching for the therapeutic targets

我们培育了转基因敲入小鼠，其中含有蛋白粘连蛋白2突变297 R>C和499 D>A，与人类心律失常性右室心肌病患者中最常发现的变异（蛋白粘连蛋白2 292 R>C, 494 D>A）相对应。这些小鼠的表型与人类疾病的临床表现有显著的相似性。原粘粒2 297 r> C部分自8周龄起突然死亡。这些小鼠和老年小鼠的心脏形态学显示纤维化积聚，在某些情况下是戏剧性的，心室壁的部分完全被胶原蛋白取代。随着年龄的增长，小鼠的左心室超声显示逐渐出现心功能障碍，右心室功能增大和恶化。遥测实验发现纯合子桥粒蛋白2 297 R>C小鼠在14-16周龄时出现室性早搏和更严重的室性心动过速的电生理异常。杂合子和纯合子297 R>C和499 D>A的共聚焦显微镜，染色进行胶原检测，证实了上述实验技术的发现，心肌细胞形态异常，细胞缺失。所有这些发现证实了致心律失常性右室心肌病小鼠模型的成功建立，并将进一步研究所观察到的表型背后的分子和细胞机制。

We generated transgenic knock-in mice harbouring desmoglein 2 mutations 297 R>C and 499 D>A, corresponding to the most often found variants in human patients suffering Arrhythmogenic Right Ventricular Cardiomyopathy (Desmoglein 2 292 R>C, 494 D>A) . The phenotype of these mice shows significant similarity to human clinical presentation of the disease. Some of desmoglein 2 297 R>C died suddenly starting from the age of 8 week-old. Morphology of investigated hearts of those mice and the mice that are older shows fibrotic accumulation, in some cases dramatic, with complete replacement of the segments of ventricular wall by collagen. With aging, mice developed gradually cardiac dysfunction as measured by cardiac echography of left ventricle and enlargement and deterioration of right ventricular function. Telemetry experiment exposed electrophysiological abnormalities in homozygous desmoglein 2 297 R>C mice in the form of ventricular premature beats and in more severe cases ventricular tachycardia at the age of 14-16 week-old. Confocal microscopy of heterozygous and homozygous 297 R>C and 499 D>A, stained for collagen detection, confirmed the findings of the above experimental techniques showing cardiomyocytes with abnormal morphology and areas with missing cells. All these findings confirmed successful generation of mice model of Arrhythmogenic Right Ventricular Cardiomyopathy and further investigation will target molecular and cellular mechanisms underlying the observed phenotype.