The Effect of Pediatric Specific Hypertrophic Cardiomyopathy Mutations on the Biomechanics of Beta Cardiac Myosin

Hypertrophic cardiomyopathy (HCM) is a genetic disease that affects 1 in 500 people. In infants it is particularly severe and is the leading cause of sudden cardiac death in pediatric populations. A high percentage of HCM is attributed to mutations in beta cardiac myosin, the motor protein responsible for ventricular contraction. This study explores how pediatric-specific HCM mutations in beta cardiac myosin (D239N, H251N, and P710R) alter the biochemical and biomechanical properties of beta cardiac myosin at the molecular and cellular levels. Because these mutations manifest early in life, we hypothesize that they will be more severe than mutations that are not pediatric-specific. We investigated the biomechanical properties of these mutations at the molecular level using a purified S1 domain of human beta cardiac myosin. Specifically, we looked at the effects of these mutations on the ATPase activity and the unloaded velocity (in vitro motility) of beta cardiac S1. Upon comparison with WT beta cardiac S1, we find significant differences between the biomechanical properties of the WT and the pediatric-specific myosin mutations, which are more drastic as compared to mutations that are not pediatric-specific. To fully characterize the system, we are currently performing single molecule optical trap force measurements to determine the intrinsic force of these mutations. Future studies will involve creating iPSC-derived cardiomyocytes to study the mechanics of these mutations at the cellular level. The results from this study will increase the understanding of how genetic mutations that cause HCM lead to the presentation of the disease, and will uncover potential targets for therapeutic design to treat the cause of the disease instead of the symptoms.