Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype
Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype
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DOI：
10.1074/jbc.m412281200
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发表时间：
2005-08-05
影响因子：
4.8
通讯作者：
Watkins, H
中科院分区：
文献类型：
--
作者：
Mirza, M;Marston, S;Watkins, H
扩张型心肌病（DCM）是心力衰竭的主要原因，其特征是心脏扩张和收缩功能障碍。遗传性扩张型心肌病可由编码心肌肌钙蛋白T、肌钙蛋白C和α-原肌球蛋白的基因突变引起;相同基因的不同突变可引起肥厚型心肌病。为了了解某些突变如何特异性地导致DCM，我们通过比较野生型和突变重组蛋白来研究它们对收缩功能的影响。由于对两种肌钙蛋白T突变的初步研究产生了相互矛盾的结果，我们在一系列体外试验中分析了肌钙蛋白T、肌钙蛋白C和α-原肌球蛋白中所有8种已发表的DCM突变。细丝，重建与1：1的比例的突变体/野生型蛋白质（可能在体内的比例），都表现出降低的Ca 2+敏感性的激活在ATP酶和运动性测定，除了一个α-原肌球蛋白突变体表现出较低的最大Ca 2+激活。两种肌钙蛋白T突变体中的任何一种在皮肤化的心脏小梁中的掺入也降低了力产生的Ca 2+敏感性。结构/功能的考虑意味着不同的细丝DCM突变影响不同方面的调节功能，但以一致的方式改变收缩性。DCM突变抑制肌原纤维功能，这种作用与肥大性心肌病引起的细丝突变的作用基本相反，表明收缩力降低可能触发最终导致临床表型的途径。
Dilated cardiomyopathy ( DCM), characterized by cardiac dilatation and contractile dysfunction, is a major cause of heart failure. Inherited DCM can result from mutations in the genes encoding cardiac troponin T, troponin C, and alpha-tropomyosin; different mutations in the same genes cause hypertrophic cardiomyopathy. To understand how certain mutations lead specifically to DCM, we have investigated their effect on contractile function by comparing wild-type and mutant recombinant proteins. Because initial studies on two troponin T mutations have generated conflicting findings, we analyzed all eight published DCM mutations in troponin T, troponin C, and alpha-tropomyosin in a range of in vitro assays. Thin filaments, reconstituted with a 1: 1 ratio of mutant/wild-type proteins ( the likely in vivo ratio), all showed reduced Ca2+ sensitivity of activation in ATPase and motility assays, and except for one alpha-tropomyosin mutant showed lower maximum Ca2+ activation. Incorporation of either of two troponin T mutants in skinned cardiac trabeculae also decreased Ca2+ sensitivity of force generation. Structure/function considerations imply that the diverse thin filament DCM mutations affect different aspects of regulatory function yet change contractility in a consistent manner. The DCM mutations depress myofibrillar function, an effect fundamentally opposite to that of hypertrophic cardiomyopathy-causing thin filament mutations, suggesting that decreased contractility may trigger pathways that ultimately lead to the clinical phenotype.