Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy

Marisa Ojala; Chandra Prajapati; Risto-Pekka Pölönen; Kristiina Rajala; Mari Pekkanen-Mattila; Jyrki Rasku; Kim Larsson; Katriina Aalto-Setälä

doi:10.1155/2016/1684792

Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy

Stem Cells Int. 2016:2016:1684792. doi: 10.1155/2016/1684792. Epub 2015 Dec 28.

Authors

Marisa Ojala¹, Chandra Prajapati¹, Risto-Pekka Pölönen¹, Kristiina Rajala¹, Mari Pekkanen-Mattila¹, Jyrki Rasku², Kim Larsson¹, Katriina Aalto-Setälä³

Affiliations

¹ BioMediTech, University of Tampere, 33014 Tampere, Finland.
² School of Information Sciences, University of Tampere, 33014 Tampere, Finland.
³ BioMediTech, University of Tampere, 33014 Tampere, Finland; Medical School, University of Tampere, 33014 Tampere, Finland; Heart Hospital, Tampere University Hospital, 33521 Tampere, Finland.

Abstract

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.