Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy.
Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy.
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DOI：
10.1155/2016/1684792
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发表时间：
2016
影响因子：
4.3
通讯作者：
Aalto-Setälä K
中科院分区：
文献类型：
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作者：
Ojala M;Prajapati C;Pölönen RP;Rajala K;Pekkanen-Mattila M;Rasku J;Larsson K;Aalto-Setälä K
肥厚型心肌病（HCM）是一种影响心肌组织结构的遗传性心脏病。临床症状包括心律失常，进行性心力衰竭，甚至心源性猝死，但突变携带者也可能完全无症状。迄今为止，超过1400个突变已与HCM有关，主要是在编码肌节蛋白的基因中。然而，该疾病的病理生理学机制在很大程度上仍然未知。芬兰HCM的两个创始突变位于肌球蛋白结合蛋白C（MYBPC 3-Gln 1061 X）和α-原肌球蛋白（TPM 1-Asp 175 Asn）基因。我们研究了HCM心肌细胞（CM）的特性，这些细胞来源于携带MYBPC 3-Gln 1061 X或TPM 1-Asp 175 Asn突变的患者特异性人诱导多能干细胞（hiPSC）。两种类型的HCM-CM显示HCM的病理表型，但更重要的是，我们发现携带MYBPC 3-Gln 1061 X或TPM 1-Asp 175 Asn基因突变的CM之间的差异，在其细胞大小，Ca 2+处理，电生理特性，以及它们的基因表达谱。这些结果表明，即使携带MYBPC 3-Gln 1061 X或TPM 1-Asp 175 Asn基因突变的患者的临床表型相似，遗传背景以及细胞水平上的功能特性可能不同，表明两种突变背后的病理生理机制也可能不同。
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, which affects the structure of heart muscle tissue. The clinical symptoms include arrhythmias, progressive heart failure, and even sudden cardiac death but the mutation carrier can also be totally asymptomatic. To date, over 1400 mutations have been linked to HCM, mostly in genes encoding for sarcomeric proteins. However, the pathophysiological mechanisms of the disease are still largely unknown. Two founder mutations for HCM in Finland are located in myosin-binding protein C (MYBPC3-Gln1061X) and α-tropomyosin (TPM1-Asp175Asn) genes. We studied the properties of HCM cardiomyocytes (CMs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn mutation. Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size, Ca2+ handling, and electrophysiological properties, as well as their gene expression profiles. These findings suggest that even though the clinical phenotypes of the patients carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation are similar, the genetic background as well as the functional properties on the cellular level might be different, indicating that the pathophysiological mechanisms behind the two mutations would be divergent as well.