RBM20心肌病是由剪接因子RBM20的突变引起的扩张型心肌病的心律失常形式。最近的一项研究发现,男性RBM20心肌病患者的表型比女性患者更严重。这里,我们旨在确定RBM20心肌病动物模型中的性别差异,并研究潜在的潜在机制.此外,我们的目的是确定一个新的RBM20心肌病患者队列中临床参数的性别和性别差异.我们表征了Rbm20基因敲除(KO)小鼠模型,并显示关键RBM20目标的拼接,心功能,和心律失常的易感性没有性别差异。接下来,我们对这些小鼠进行了深度表型分析,并显示雄性和雌性Rbm20-KO小鼠具有转录组和磷酸化蛋白质组差异。假设这些差异可能会影响心脏补偿压力的能力,我们将Rbm20-KO小鼠暴露于急性儿茶酚胺能刺激下,再次未发现功能差异.我们还在具有Rbm20-R636Q突变的小鼠模型中复制了功能差异的缺乏。最后,我们提出了一个由33例RBM20心肌病患者组成的患者队列,结果显示这些患者在疾病严重程度上没有性别和性别差异.目前RBM20心肌病小鼠模型显示,雄性小鼠心肌蛋白的基因表达和磷酸化发生了更明显的变化,但心脏形态和功能没有性别差异。此外,除了之前报道的之外,在来自德国和荷兰的患者队列中,男性RBM20心肌病患者的心功能并不较差.新的和注意的心脏病的最佳管理越来越个性化,部分原因是性别之间的结果差异。据报道,RBM20心肌病在男性患者中更为严重,这带来了男性患者比女性患者在诊所接受更多审查的风险。我们的发现不支持这一观察,并建议男性和女性RBM20心肌病患者的治疗不应有所不同。而是应该关注潜在的疾病机制。
RBM20 cardiomyopathy is an arrhythmogenic form of dilated cardiomyopathy caused by mutations in the splicing factor
RBM20. A recent study found a more severe phenotype in male patients with
RBM20 cardiomyopathy patients than in female patients. Here, we aim to determine sex differences in an animal model of
RBM20 cardiomyopathy and investigate potential underlying mechanisms. In addition, we aim to determine sex and gender differences in clinical parameters in a novel RBM20 cardiomyopathy patient cohort. We characterized an
Rbm20 knockout (KO) mouse model, and show that splicing of key
RBM20 targets, cardiac function, and arrhythmia susceptibility do not differ between sexes. Next, we performed deep phenotyping of these mice, and show that male and female Rbm20-KO mice possess transcriptomic and phosphoproteomic differences. Hypothesizing that these differences may influence the heart\'s ability to compensate for stress, we exposed Rbm20-KO mice to acute catecholaminergic stimulation and again found no functional differences. We also replicate the lack of functional differences in a mouse model with the Rbm20-R636Q mutation. Lastly, we present a patient cohort of 33 RBM20 cardiomyopathy patients and show that these patients do not possess sex and gender differences in disease severity. Current mouse models of RBM20 cardiomyopathy show more pronounced changes in gene expression and phosphorylation of cardiac proteins in male mice, but no sex differences in cardiac morphology and function. Moreover, other than reported before, male RBM20 cardiomyopathy patients do not present with worse cardiac function in a patient cohort from Germany and the Netherlands.NEW & NOTEWORTHY Optimal management of the cardiac disease is increasingly personalized, partly because of differences in outcomes between sexes. RBM20 cardiomyopathy has been described to be more severe in male patients, and this carries the risk that male patients are more scrutinized in the clinic than female patients. Our findings do not support this observation and suggest that treatment should not differ between male and female RBM20 cardiomyopathy patients, but instead should focus on the underlying disease mechanism.