A MOUSE MODEL OF MYOSIN BINDING-PROTEIN-C HUMAN FAMILIAL HYPERTROPHICCARDIOMYOPATHY

Familial hypertrophic cardiomyopathy can be caused by mutations in gen es encoding sarcomeric proteins, including the cardiac isoform of myos in binding protein C (MyBP-C), and multiple mutations which cause trun cated forms of the protein to be made are linked to the disease. We ha ve created transgenic mice in which varying amounts of a mutated MyBP- C, lacking the myosin and titin binding domains, are expressed in the heart. The transgenically encoded, truncated protein is stable but is not incorporated efficiently into the sarcomere. The transgenic muscle fibers showed a leftward shift in the pCa(2+)-force curve and, import antly, their power output was reduced. Additionally, expression of the mutant protein leads to decreased levels of endogenous MyBP-C, result ing in a striking pattern of sarcomere disorganization and dysgenesis.