title: Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy.
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.
authors.affiliation: BioMediTech, University of Tampere, 33014 Tampere, Finland.
authors.forename: Marisa
authors.identifier: 0000-0002-3202-0212
authors.initials: M
authors.lastname: Ojala
authors.affiliation: BioMediTech, University of Tampere, 33014 Tampere, Finland.
authors.forename: Chandra
authors.initials: C
authors.lastname: Prajapati
authors.affiliation: BioMediTech, University of Tampere, 33014 Tampere, Finland.
authors.forename: Risto-Pekka
authors.initials: RP
authors.lastname: Pölönen
authors.affiliation: BioMediTech, University of Tampere, 33014 Tampere, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rajala
authors.affiliation: BioMediTech, University of Tampere, 33014 Tampere, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Pekkanen-Mattila
authors.affiliation: School of Information Sciences, University of Tampere, 33014 Tampere, Finland.
authors.forename: Jyrki
authors.initials: J
authors.lastname: Rasku
authors.affiliation: BioMediTech, University of Tampere, 33014 Tampere, Finland.
authors.forename: Kim
authors.initials: K
authors.lastname: Larsson
authors.affiliation: BioMediTech, University of Tampere, 33014 Tampere, Finland; Medical School, University of Tampere, 33014 Tampere, Finland; Heart Hospital, Tampere University Hospital, 33521 Tampere, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Aalto-Setälä