Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy
Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy
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DOI：
10.1152/ajpheart.00913.2013
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发表时间：
2014-03-01
影响因子：
4.8
通讯作者：
Sadayappan, Sakthivel
中科院分区：
文献类型：
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作者：
Barefield, David;Kumar, Mohit;Sadayappan, Sakthivel
肥厚型心肌病（HCM）的病因已被归因于编码肌节蛋白的基因突变。特别是，MYBPC 3（编码心肌肌球蛋白结合蛋白-C（cMyBP-C）的基因）的突变与超过三分之一的HCM病例有关。在这些突变中，预计70%会导致C '截短的蛋白产物，这在组织样品中是检测不到的。这些截短突变的杂合子携带者表现出不同的HCM发病率，症状往往发生在以后的生活中。我们假设MYBPC 3突变的杂合子携带者，虽然表面上无症状，但在明显的HCM发展之前有细微的功能障碍。本研究比较了杂合子（+/t）敲入MYBPC 3截短突变小鼠与野生型（+/+）同窝仔，以确定在肥大发生前是否在全心脏或单细胞水平发生功能改变。+/t小鼠显示MYBPC 3转录减少了40%，但cMyBP-C水平、磷酸化状态或心脏形态没有变化。尽管如此，+/t小鼠在肌节长度为1.9 μ m（+/t68.5 +/- 4.1 mN/mm（2）vs. +/+ 82.2 +/- 3.2）和2.3 μ m（+/t79.2 +/- 3.1 mN/mm（2）vs. +/+ 95.5 +/- 2.4）时显示出最大力发展显著降低。此外，杂合小鼠在体内显示早期/之后（E/A）（+/t1.74 +/-0.12 vs. +/+2.58 +/-0.43）和E '/A'（+/t1.18 +/-0.05 vs. +/+1.52 +/-0.15）比率的显著降低，表明舒张功能障碍。这些结果表明，看似无症状的杂合子MYBPC 3携带者确实遭受可能预示HCM发作的损伤。
The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C'-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show similar to 40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 mu m (+/t 68.5 +/- 4.1 mN/mm(2) vs. +/+ 82.2 +/- 3.2) and 2.3 mu m (+/t 79.2 +/- 3.1 mN/mm(2) vs. +/+ 95.5 +/- 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 +/- 0.12 vs. +/+ 2.58 +/- 0.43) and E'/A' (+/t 1.18 +/- 0.05 vs. +/+ 1.52 +/- 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM.