Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats
Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats
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肌球蛋白轻链 4 (MYL4) 功能障碍导致具有电、收缩和结构成分的遗传性心房心肌病：来自基因工程大鼠的证据
DOI：
10.1161/jaha.117.007030
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发表时间：
2017-11-01
影响因子：
5.4
通讯作者：
Xu, Yawei
中科院分区：
文献类型：
--
作者：
Peng, Wenhui;Li, Miaoxin;Xu, Yawei
背景：人们对心房心肌病的概念越来越感兴趣，但其潜在的分子和机制决定因素仍不明确。我们确定了一个遗传性心房心肌病家族，表现为进行性心房选择性机电功能障碍，快速性心律失常和需要植入起搏器的慢性心律失常。肌球蛋白轻链4 （MYL4）编码心房选择性必需肌球蛋白轻链，被确定为候选基因。我们使用转基因大鼠模型来研究MYL4在心房心肌病中的作用。方法和结果：外显子组测序和系统生物信息学分析鉴定出一种罕见的MYL4错义变体（c.31G> a）。E11K])在一个大型多重心房心肌病家族谱系中。该突变与心房静止共分离（被选为主要表现特征），其对数的比值值为5.3。MYL4突变敲入大鼠的表型证实了该突变的致病作用。MYL4基因敲除大鼠表现出类似的心房心肌病表型，而邻近4-氨基酸缺失的大鼠则没有表现出表型。MYL4 p.E11K敲入大鼠和MYL4敲除大鼠均表现进行性心房电生理、收缩和纤维化异常，与受影响患者相似。对MYL4 p.E11K突变大鼠的生化分析显示，促凋亡和促纤维化信号被激活，心房-心肌细胞末端脱氧核苷酸转移酶dUTP缺口末端标记染色增加，表明凋亡细胞死亡增强，通过体外腺病毒将突变基因转移到新生大鼠心肌细胞中可以模拟这一结果。结论：MYL4基因变异的功能丧失导致人类和大鼠进行性心房心肌病。我们的研究结果确定MYL4是心房收缩、电和结构完整性所需的关键基因。这些结果提高了我们对心房心肌病分子基础的认识，并为进一步的机制分析引入了新的模型。
Background-There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritable atrial cardiomyopathy manifesting as progressive atrial-selective electromechanical dysfunction, tachyarrhythmias, and bradyarrhythmias requiring pacemaker implantation. Myosin light-chain 4 (MYL4), encoding the atrial-selective essential myosin light chain, was identified as a candidate gene. We used genetically modified rat models to investigate the role of MYL4 in atrial cardiomyopathy.Methods and Results-Exome sequencing and systematic bioinformatic analyses identified a rare missense variant of MYL4 (c.31G>A [p.E11K]) in a large multiplex atrial cardiomyopathy family pedigree. The mutation cosegregated with atrial standstill (selected as the principal presenting trait) with a logarithm of the odds score of 5.3. The phenotype of rats with MYL4 mutation knock-in confirmed the causative role of the mutation. MYL4 knockout rats showed a similar atrial cardiomyopathy phenotype, whereas rats with an adjacent 4-amino-acid deletion showed no phenotype. Both MYL4 p.E11K knock-in rats and MYL4 knockout rats showed progressive atrial electrophysiological, contractile, and fibrotic abnormalities, similar to affected patients. Biochemical analyses of MYL4 p.E11K mutation rats showed activation of proapoptotic and profibrotic signaling, along with increased atrial-cardiomyocyte terminal deoxynucleotidyl transferase dUTP nick end labeling staining, suggesting enhanced apoptotic cell death, findings that were mimicked by in vitro adenoviral transfer of the mutant gene to neonatal-rat cardiomyocytes.Conclusions-Loss-of-function MYL4 gene variants cause progressive atrial cardiomyopathy in humans and rats. Our findings identify MYL4 as a key gene required for atrial contractile, electrical and structural integrity. These results improve our understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis.