Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction

To investigate the functional consequences of a tropomyosin (TM) mutation a ssociated with familial hypertrophic cardiomyopathy (FHC), we generated tra nsgenic mice that express mutant alpha-TM in the adult heart. The missense mutation, which results in the substitution of asparagine for aspartic acid at amino acid position 175, occurs in a troponin T binding region of TM. S I nuclease mapping and Western blot analyses demonstrate that increased exp ression of the alpha-TM 175 transgene in different lines causes a concomita nt decrease in levels of endogenous alpha-TM mRNA and protein expression. I n vivo physiological analyses show a severe impairment of both contractilit y and relaxation in hearts of the FHC mice, with a significant change in le ft ventricular fractional shortening. Myofilaments that contain alpha-TM 17 5 demonstrate an increased activation of the thin filament through enhanced Ca2+ sensitivity of steady-state force. Histological analyses show patchy areas of mild ventricular myocyte disorganization and hypertrophy, with occ asional thrombi formation in the left atria. Thus, the FHC alpha-TM transge nic mouse can serve as a model system for the examination of pathological a nd physiological alterations imparted through aberrant TM isoforms.