RESEARCH

Reductions in Myosin binding protein C3 (MyBP-C) are the most common cause of hypertrophic cardiomyopathy. 

We developed a 384-well plate screening platform using induced pluripotent stem cell cardiomyocytes. 

This platform allows us to evaluate small molecules which induce alterations in MyBP-C protein levels in a high throughput manner, uncovering dynamic pathways which regulate MyBP-C homeostasis. These pathways may influence disease penetrance or progression. Further, this work may uncover novel therapeutic targets. 

To better understand how alterations in MyBP-C protein levels lead to hypertrophic cardiomyopathy disease phenotypes, we adapted a system developed by the Wandless laboratory (DOI: https://doi.org/10.1016/j.cell.2006.07.025). 

This system allows post-translational control of MyBP-C protein levels using a small molecule called Sheild. In doing so, we hope to understand the dose-dependent relationships between MyBP-C and physiologic markers of disease such as contractility.  

This system may have applications in understanding other genetic cardiomyopathies caused by loss-of-function variants. 

Pathogenic variants in myosin binding protein C (MYBPC3) are the most common cause of hypertrophic cardiomyopathy. The majority of known pathogenic variants result in a premature stop codon (commonly called truncating variants). These truncating variants cause loss of function and haploinsufficiency. Conversely, the majority of missense variants in MYBPC3 are classified as variants of uncertain significance.  

Developing strategies and methods that allow efficient computational and experimental evaluation of missense variants of uncertain significance are needed to uncover, yet unidentified, pathogenic missense variants.