Ojala Marisa, Prajapati Chandra, Pölönen Risto-Pekka, Rajala Kristiina, Pekkanen-Mattila Mari, Rasku Jyrki, Larsson Kim, Aalto-Setälä Katriina
BioMediTech, University of Tampere, 33014 Tampere, Finland.
School of Information Sciences, University of Tampere, 33014 Tampere, Finland.
Stem Cells Int. 2016;2016:1684792. doi: 10.1155/2016/1684792. Epub 2015 Dec 28.
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, Ca(2+) 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.
肥厚型心肌病（HCM）是一种遗传性心脏疾病，会影响心肌组织的结构。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没有症状。迄今为止，已有1400多种突变与HCM相关，其中大多数位于编码肌节蛋白的基因中。然而，该疾病的病理生理机制仍 largely unknown。芬兰HCM的两个奠基者突变分别位于肌球蛋白结合蛋白C（MYBPC3-Gln1061X）和α-原肌球蛋白（TPM1-Asp175Asn）基因中。我们研究了携带MYBPC3-Gln1061X或TPM1-Asp175Asn突变的患者特异性人诱导多能干细胞（hiPSC）衍生的HCM心肌细胞（CM）的特性。两种类型的HCM-CM均表现出HCM的病理表型，但更重要的是，我们发现携带MYBPC3-Gln1061X或TPM1-Asp175Asn基因突变的CM在细胞大小、Ca(2+)处理、电生理特性以及基因表达谱方面存在差异。这些发现表明，尽管携带MYBPC3-Gln1061X或TPM1-Asp175Asn基因突变的患者临床表型相似，但遗传背景以及细胞水平的功能特性可能不同，这表明这两种突变背后的病理生理机制也会有所不同。
