Suay-Corredera Carmen, Alegre-Cebollada Jorge
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
FEBS Lett. 2022 Mar;596(6):703-746. doi: 10.1002/1873-3468.14301. Epub 2022 Feb 28.
Hypertrophic cardiomyopathy (HCM), a disease characterized by cardiac muscle hypertrophy and hypercontractility, is the most frequently inherited disorder of the heart. HCM is mainly caused by variants in genes encoding proteins of the sarcomere, the basic contractile unit of cardiomyocytes. The most frequently mutated among them is MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), a key regulator of sarcomere contraction. In this review, we summarize clinical and genetic aspects of HCM and provide updated information on the function of the healthy and HCM sarcomere, as well as on emerging therapeutic options targeting sarcomere mechanical activity. Building on what is known about cMyBP-C activity, we examine different pathogenicity drivers by which MYBPC3 variants can cause disease, focussing on protein haploinsufficiency as a common pathomechanism also in nontruncating variants. Finally, we discuss recent evidence correlating altered cMyBP-C mechanical properties with HCM development.
肥厚型心肌病（HCM）是一种以心肌肥厚和收缩亢进为特征的疾病，是最常见的遗传性心脏疾病。HCM主要由编码肌节（心肌细胞的基本收缩单位）蛋白的基因变异引起。其中最常发生突变的是MYBPC3，它编码心肌肌球蛋白结合蛋白C（cMyBP-C），是肌节收缩的关键调节因子。在这篇综述中，我们总结了HCM的临床和遗传学方面，并提供了关于健康和HCM肌节功能的最新信息，以及针对肌节机械活性的新兴治疗选择。基于对cMyBP-C活性的已知认识，我们研究了MYBPC3变异导致疾病的不同致病驱动因素，重点关注蛋白质单倍剂量不足作为非截短变异中常见的发病机制。最后，我们讨论了将改变的cMyBP-C机械特性与HCM发展相关联的最新证据。
