α-tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways


  • D. Wernicke
  • C. Thiel
  • C.M. Duja-Isac
  • K.V. Essine
  • M. Spindler
  • D.J.R. Nunez
  • R. Plehm
  • N. Wessel
  • A. Hammes
  • R.J. Edwards
  • A. Lippoldt
  • U. Zacharias
  • H. Stroemer
  • S. Neubauer
  • M.J. Davies
  • I. Morano
  • L. Thierfelder


  • American Journal of Physiology Regulatory Integrative and Comparative Physiology


  • Am J Physiol Regul Integr Comp Physiol 287 (3): R685-R695


  • To study the mechanisms by which missense mutations in {alpha}-tropomyosin cause familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing {alpha}-tropomyosin with one of two disease-causing mutations, Asp175Asn or Glu180Gly, and analyzed phenotypic changes at molecular, morphological, and physiological levels. The transgenic proteins were stably integrated into the sarcomere, as shown by immunohistochemistry using a human-specific anti-{alpha}-tropomyosin antibody, ARG1. In transgenic rats with either {alpha}-tropomyosin mutation, molecular markers of cardiac hypertrophy were induced. Ca2+ sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp175Asn, but not Glu 180Gly, was decreased. Furthermore, elevated frequency and amplitude of spontaneous Ca2+ waves were detected only in cardiomyocytes from animals with mutation Asp175Asn, suggesting an increase in intracellular Ca2+ concentration compensating for the reduced Ca 2+ sensitivity of isometric force generation. Accordingly, in Langendorff-perfused heart preparations, myocardial contraction and relaxation were accelerated in animals with mutation Asp175Asn. The results allow us to propose a hypothesis of the pathogenetic changes caused by {alpha}-tropomyosin mutation Asp175Asn in familial hypertrophic cardiomyopathy on the basis of changes in Ca2+ handling as a sensitive mechanism to compensate for alterations in sarcomeric structure.