Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice
Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice
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DOI：
10.1172/jci7377
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发表时间：
1999-11-01
影响因子：
15.9
通讯作者：
Seidman, JG
中科院分区：
文献类型：
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作者：
McConnell, BK;Jones, KA;Seidman, JG
为了阐明心肌肌球蛋白结合蛋白-C (MyBP-C) 在心肌结构和功能中的作用，我们培育了表达这种肌节蛋白改变形式的小鼠。工程突变编码 MyBP-C 的截短形式，其中心肌肌球蛋白重链结合域和肌联蛋白结合域已被新的氨基酸残基取代。人类中类似的杂合缺陷会导致肥厚性心肌病。 MyBP-C 突变等位基因纯合的小鼠在正常肌节的 M 带中表达不到 10% 的截短蛋白。携带 MyBP-C 等位基因突变的纯合子小鼠可以存活，但在新生儿期表现出进行性扩张型心肌病，具有显着的组织病理学特征：肌细胞肥大、肌原纤维紊乱、纤维化和营养不良性钙化。纯合突变小鼠的超声心动图显示出生时左心室扩张和收缩功能降低；随着动物的成熟，心肌肥厚增加。成年纯合突变小鼠的左心室压力-容积分析表明收缩期收缩力下降并伴有舒张功能障碍。这些数据修正了我们对 MyBP-C 在心脏发育过程中肌原纤维形成中所起作用的理解，并表明该蛋白对于长期肌节功能和正常心脏形态的重要性。我们还提出，携带纯合家族肥厚型心肌病致病突变的小鼠可能为预测这些突变在人类中引起的疾病的严重程度提供有用的工具。
To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles express less than 10% of truncated protein in M-bands of otherwise normal sarcomeres. Homozygous mice bearing mutated MyBP-C alleles are viable but exhibit neonatal onset of a progressive dilated cardiomyopathy with prominent histopathology of myocyte hypertrophy, myofibrillar disarray, fibrosis, and dystrophic calcification. Echocardiography of homozygous mutant mice showed left ventricular dilation and reduced contractile function at birth; myocardial hypertrophy increased as the animals matured. Left-ventricular pressure-volume analyses in adult homozygous mutant mice demonstrated depressed systolic contractility with diastolic dysfunction. These data revise our understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac development and indicate the importance of this protein for long-term sarcomere function and normal cardiac morphology. We also propose that mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in humans.