Transgenic Modeling of a Cardiac Troponin I Mutation Linked to Familial Hypertrophic Cardiomyopathy

Abstract—Multiple mutations in cardiac troponin I (cTnI) have been associated with familial hypertrophic cardiomyopathy. Two mutations are located in the cTnI inhibitory domain, a highly negatively charged region that alternately binds to either actin or troponin C, depending on the intracellular concentration of calcium. This region is critical to the inhibition of actin-myosin crossbridge formation when intracellular calcium is low. We modeled one of the inhibitory domain mutations, arginine145→glycine (TnI146Gly in the mouse sequence), by cardiac-specific expression of the mutated protein in transgenic mice. Multiple lines were generated with varying degrees of expression to establish a dose relationship; the severity of phenotype could be correlated directly with transgene expression levels. Transgenic mice overexpressing wild-type cTnI were generated as controls and analyzed in parallel with the TnI146Gly animals. The control mice showed no abnormalities, indicating that the phenotype of TnI146Gly wa...