Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, West Wing Level 6, Oxford, OX3 9DU, UK,
J Muscle Res Cell Motil. 2013 Aug;34(3-4):285-94. doi: 10.1007/s10974-013-9358-5. Epub 2013 Sep 5.
The inherited cardiac diseases hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be caused by missense mutations in the TPM1 gene which encodes the thin filament regulatory protein α-tropomyosin. Different mutations are responsible for either HCM or DCM, suggesting that distinct changes in tropomyosin structure and function can lead to the different diseases. Various biophysical and physiological approaches have been used to investigate the structure-function effects of the mutations, and animal models developed. The reported effects of the mutations include changes to the secondary structure of tropomyosin, its binding to actin and its position on the thin filament, and alterations to actin-myosin interactions and myofilament Ca(2+) sensitivity. The latter changes have been found to be particularly consistent, with HCM mutations increasing Ca(2+) sensitivity and DCM mutations in general decreasing this parameter and uncoupling the effect of troponin phosphorylation upon Ca(2+) responsiveness. As well as impacting on contractility, these changes are likely to alter intracellular Ca(2+) handling and signaling, and a combination of these alterations may provide the trigger for disease remodeling.
遗传性心脏病肥厚型心肌病（HCM）和扩张型心肌病（DCM）均可由编码细肌丝调节蛋白α-原肌球蛋白的 TPM1 基因突变引起。不同的突变分别导致 HCM 或 DCM，这表明原肌球蛋白结构和功能的不同变化可导致不同的疾病。已经使用了各种生物物理和生理方法来研究突变的结构-功能影响，并开发了动物模型。报道的突变效应包括原肌球蛋白二级结构的变化、与肌动蛋白的结合及其在细肌丝上的位置，以及肌动球蛋白相互作用和肌丝 Ca(2+)敏感性的改变。后一种变化尤其一致，HCM 突变增加 Ca(2+)敏感性，而 DCM 突变通常降低该参数，并使肌钙蛋白磷酸化对 Ca(2+)反应性的影响脱偶联。除了影响收缩性外，这些变化可能还会改变细胞内 Ca(2+)处理和信号转导，而这些改变的组合可能为疾病重塑提供触发因素。
