Disease modeling of hypertrophic cardiomyopathy: using the technology of induced pluripotent stem cells to investigate the genotype-phenotyp relation of MYBPC3-mutation in hypertrophic cardiomyopathy

肥厚性心肌病（HCM）是一种典型的进行性疾病，可通过心律失常或心力衰竭导致死亡。我们现在知道超过70%的HCM病例有遗传基础，主要涉及编码肌节蛋白的基因突变。遗传是典型的常染色体显性遗传，其机制被认为主要是由于在关键的细胞位置（如肌节）内掺入突变蛋白质。值得注意的是，心肌肌球蛋白结合蛋白C（MYBPC 3）的突变可能是这一规则的例外，因为有些人已经提出它们通过单倍不足而不是毒肽起作用。自从首次发现心肌病相关突变以来的二十年中，患者治疗方面几乎没有进展。心脏移植仍然是决定性的治疗方法，这是有限的器官可用性，需要终身免疫抑制，中位生存时间为12-16年，本研究的目的是使用两个突破性的干细胞技术，患者特异性诱导多能干细胞（iPSCs）的产生，并将其定向分化为心肌细胞，以了解心肌病的基因型-表型关系。在这项研究中，我们从MYBPC 3突变引起的肥厚性心肌病患者中产生了人道的iPSC系，并评估了MYBPC 3突变对未成熟和成熟心肌细胞的功能影响。此外，我们将通过iPSC的遗传修饰直接测试单倍不足假说。该计划将为心肌病领域带来急需的见解和新的实验工具。

Hypertrophic cardiomoypathy (HCM) is a typically progressive disease that cause death through arrhythmias or heart failure. We now know that over 70% of cases of HCM have a genetic basis, principally involving mutations in genes encoding sarcomeric proteins. Inheritance is typically autosomal dominant, and the mechanism is thought mostly to result from incorporation of mutant proteins within key cellular locations like the sarcomere. Notably, mutations in cardiac myosin-binding protein C (MYBPC3) may present an exception to this rule, as they have been proposed by some to act through haploinsufficiency rather than as poison peptides. In the two decades since the first discoveries of cardiomyopathy-related mutations, there has been little advancement in patient treatment. Heart transplantation remains the definitive therapy, and this is limited by organ availability, the need for lifetime immunosuppression, and median survival times of 12-16 years.The aim of this study is to use two breakthrough stem cell technologies, the generation of patientspecific induced pluripotent stem cells (iPSCs), and their directed differentiation into cardiomyocytes, to understand the genotype-phenotype relationship of cardiomyopathy. In this study we generate humane iPSC lines from patients with hypertrophyic cardiomyoapthy due to MYBPC3 mutations and assessing the functional impact of MYBPC3 mutations in immature and maturing cardiomyocytes. Further we will directly test haploinsufficiency hypothesis by genetic modifications of the iPSCs. This program will bring much needed insights and new experimental tools to the cardiomyopathy field.