Disease modeling of hypertrophic cardiomyopathy: using the technology of induced pluripotent stem cells to investigate the genotype-phenotyp relation of MYBPC3-mutation in hypertrophic cardiomyopathy

• Applicant: Dr. Astrid Breitbart
• Subject Area: Cardiology, Angiology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262590173

Hypertrophic cardiomoypathy (HCM) is a typically progressive disease that cause death through arrhythmias or heart failure. We now know that over 70% of cases of HCM have a genetic basis, principally involving mutations in genes encoding sarcomeric proteins. Inheritance is typically autosomal dominant, and the mechanism is thought mostly to result from incorporation of mutant proteins within key cellular locations like the sarcomere. Notably, mutations in cardiac myosin-binding protein C (MYBPC3) may present an exception to this rule, as they have been proposed by some to act through haploinsufficiency rather than as poison peptides. In the two decades since the first discoveries of cardiomyopathy-related mutations, there has been little advancement in patient treatment. Heart transplantation remains the definitive therapy, and this is limited by organ availability, the need for lifetime immunosuppression, and median survival times of 12-16 years.The aim of this study is to use two breakthrough stem cell technologies, the generation of patientspecific induced pluripotent stem cells (iPSCs), and their directed differentiation into cardiomyocytes, to understand the genotype-phenotype relationship of cardiomyopathy. In this study we generate humane iPSC lines from patients with hypertrophyic cardiomyoapthy due to MYBPC3 mutations and assessing the functional impact of MYBPC3 mutations in immature and maturing cardiomyocytes. Further we will directly test haploinsufficiency hypothesis by genetic modifications of the iPSCs. This program will bring much needed insights and new experimental tools to the cardiomyopathy field.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Charles Murry, Ph.D.