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

我们产生了携带桥粒芯糖蛋白2突变297 R>C和499 D>A的转基因敲入小鼠，对应于患有致心律失常性右心室心肌病的人类患者中最常见的变体（桥粒芯糖蛋白2 292 R>C，494 D>A）。这些小鼠的表型显示出与人类疾病临床表现的显著相似性。桥粒芯糖蛋白2297 R>C部分在8周龄时突然死亡。这些小鼠和年龄较大的小鼠的研究心脏的形态显示纤维化积聚，在某些情况下是戏剧性的，心室壁的节段被胶原蛋白完全取代。随着年龄的增长，小鼠逐渐出现心功能不全，左心室回声和右心室功能逐渐增大和恶化。遥测实验暴露了纯合桥粒芯糖蛋白2 297 R>C小鼠在14-16周龄时以室性早搏和更严重的室性心动过速形式的电生理异常。对杂合和纯合的297 R>C和499 D>A进行共聚焦显微镜检查，染色用于胶原蛋白检测，证实了上述实验技术的发现，显示了具有异常形态的心肌细胞和具有缺失细胞的区域。所有这些发现证实了致心律失常性右心室心肌病小鼠模型的成功产生，进一步的研究将针对所观察到的表型的分子和细胞机制。

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.