Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy.
J Biol Chem. 2021 Jul;297(1):100854. doi: 10.1016/j.jbc.2021.100854. Epub 2021 Jun 5.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.
肥厚型心肌病（HCM）是最常见的遗传性心脏病。编码心肌肌球蛋白结合蛋白 C（cMyBP-C）的 MYBPC3 基因中的变异是 HCM 的主要原因。然而，由于我们对 HCM 致病变异引发的病理机制了解不完整，患者中发现的数百种 MYBPC3 变异的致病性状态仍然未知。在这里，我们检查了根据连锁和群体遗传学标准分类为 HCM 相关或非致病性的 44 种非截断 MYBPC3 变体。我们发现，大约一半的 HCM 相关变体显示 RNA 剪接或蛋白质稳定性改变，这两者都可能导致 cMyBP-C 单倍不足。这些与 HCM 致病性相关的蛋白质单倍不足驱动因素的特异性分别为 100%和 94%。此外，我们发现 ClinVar 中目前分类为不确定意义的 11%的非截断 MYBPC3 变体可诱导其中一种分子表型。我们的策略可应用于其他由蛋白质功能丧失引起的疾病，支持 cMyBP-C 单倍不足是 HCM 的基本病理机制的观点。
