In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament.
In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament.
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DOI：
10.1161/circresaha.110.231670
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发表时间：
2011-03-18
影响因子：
20.1
通讯作者：
Bezold KL
中科院分区：
文献类型：
--
作者：
Harris SP;Lyons RG;Bezold KL
自发现家族性肥厚型心肌病（HCM）的第一个突变以来的20年中，已经描述了影响许多肌节蛋白的惊人数量的突变。其中最普遍的是影响粗丝结合蛋白的突变，包括肌球蛋白必需和调节轻链和心肌肌球蛋白结合蛋白-C（cMyBP-C）。然而，尽管肌球蛋白结合蛋白，特别是cMyBP-C，与遗传性心肌病的频率，这些蛋白质的突变的功能后果和它们引起疾病的机制仍然只有部分理解。这篇综述的目的是总结已知的致病突变，影响主要的粗丝结合蛋白，并将这些突变与蛋白质功能。结论强调了HCM引起突变的发现对促进对粗丝蛋白的基础生物学的深入了解的影响，并加强了肌球蛋白结合蛋白是粗丝激活状态的动态调节剂的想法，这有助于肌球蛋白驱动肌肉收缩的速度和力量。仍需要进一步的工作来确定个别突变诱导肥大表型的机制。
In the 20 yrs since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM) an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins including the myosin essential and regulatory light chains and cardiac myosin binding protein-C (cMyBP-C). However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.