Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the 'closed' regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.

中文翻译：

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不同的机制驱动肥厚型和扩张型心肌病相关 TPM1 变体的不同表型。


肥厚型和扩张型心肌病（分别为 HCM 和 DCM）是遗传性疾病，可能由同一肌节蛋白突变引起，但临床表型完全不同。同一基因内的点突变导致表型多样性的确切机制尚不清楚。我们的目标是开发一种机制解释两种 TPM1 突变 E62Q （HCM） 和 E54K （DCM） 中不同的表型。利用文献中的数据和表达目标 TPM1 突变的干细胞衍生心肌细胞的实验，我们构建了计算模拟，为每种变体引起的不同肌肉收缩性提供了合理的解释。在 E62Q 中，钙敏感性和超收缩性的增加最准确地解释为原肌球蛋白有效分子刚度的降低及其与肌动蛋白细丝相互作用的改变，这有利于“关闭”调节状态。相比之下，E54K 突变似乎通过长程变构相互作用发挥作用，以增加 C 末端肌钙蛋白 I 移动结构域与原肌球蛋白/肌动蛋白的结合率。这些与突变相关的分子事件产生了基因表达的不同改变，可以在人类工程心脏组织中观察到。肌球蛋白活性的调节剂通过根据预测挽救正常的收缩行为来证实我们提出的机制。