Leslie A. Leinwand, PhD
Pediatric Hypertrophic Cardiomyopathy Caused by Myosin Mutations
University of Colorado, Boulder, CO
2013 Amount Awarded – $45,837
The vast majority of genes causing hypertrophic cardiomyopathy (HCM) encode proteins of the cardiac sarcomere, including the molecular motor protein, myosin heavy chain (MyHC). Greater than 300 mutations in MyHC have been described that cause HCM, dilated cardiomyopathy and skeletal myopathy. MyHC is responsible for heart function, and it is still not known what is wrong with this mutated motor protein. Currently there are only treatments for symptoms of the primary defect. While most cases of HCM have been described in adults, more recently, infants and children with unexplained cardiac hypertrophy have been studied and novel mutations have been found in sarcomeric genes. Infants and children with HCM have a much worse prognosis than adults, and 40% will die or require a cardiac transplant. It is believed that novel mutations found in the pediatric population represent a class of mutations that may share a common mechanism, and this study will test this hypothesis using a expression system developed precisely for the purposes of understanding the mechanisms underlying HCM. In this system, recombinant human cardiac myosin's bearing adult and pediatric mutations will be tested for their functional properties compared to wild type proteins. In addition, the effects of a myosin activator will be tested on these pediatric mutations. This small molecule drug has already been shown to be safe in people and to be effective in treating adults with heart failure. The advantage of this approach is that it has the potential to treat the root cause of the disease rather than downstream symptoms.