Large Animal Models - Subgroup Cardiovascular Models


Animal Model of Familial Hypertrophic Cardiomyopathy

  • Generation of knock-in animal model for FHC with missense mutations in head domain of ventricular (β-cardiac) myosin heavy chain (e.g., R723G, R719W).
  • Characterization of phenotype development in the transgenic pigs compared to FHC-patients.
  • Identification and testing of novel therapeutic approaches, e.g., via changes in allelic imbalance (unequal expression of mutant / wild-type mRNA and protein).

Research Focus


  • Transgenic porcine fibroblasts successfully generated via TALE-nuclease technology.
  • Successful somatic cell nuclear transfer (SCNT).
  • Embryos successfully transferred to synchronized recipients.
  • Expression of mutant myosin in muscle tissue demonstrated at mRNA level.
  • First functional studies.


  • Generation of transgenic breeding lines of 4 different FHC mutations in the head domain of ß-cardiac myosin.
  • Structural / functional analysis of myocardium and skeletal muscle for effects of FHC-related mutations (comparison with effects in humans).
  • Study development of FHC-phenotype vs. development of allelic imbalance (unequal ratio of mutant / wildtype mRNA and protein).

Further Research Projects

In collaboration with U. Martin und R. Zweigerdt (HTTG) we currently establish a model system of FHC at the cellular level, which is based on iPSC-derived cardiomyocytes, generated from dermal fibroblasts of FHC-patients. Such FHC-patient-specific cardiomyocytes, which co-express wildtype and mutated ßcardiac myosin allow us to further study mechanisms of unequal allelic expression of mutated and wildtype myosin. We found this “allelic imbalance” in all patients for which we so far analyzed β-cardiac myosin expression at mRNA and protein level (Tripathi et al., BRC 2011). We hypothesize that unequal expression of mutated and wildtype myosin in individual cardiomyocytes could be a major initial trigger for disease development.

Thus, by longitudinal studies in the FHC-pig model we will be able to analyze whether, e.g., the allelic imbalance changes over time and correlates with disease progression. In addition, with a model system of human cardiomyocytes expressing different β-myosin mutations, we will investigate mechanisms of gene regulation and test whether the expression of the mutated myosin can be specifically suppressed by modifying allelic imbalance. Here the large animal model will be essential to test such techniques in vivo. Particularly for severely affected FHC-patients, it would be highly desirable to restore normal sarcomere function with such an approach.


2013 - ongoing


Montag J, Syring M, Rose J, Weber AL, Ernstberger P, Mayer AK, Becker E, Keyser B, Dos Remedios C, Perrot A, van der Velden J, Francino A, Navarro-Lopez F, Ho CY, Brenner B, Kraft T. Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy. J Muscle Res Cell Motil. 2017. Epub 2017/11/05.


Kraft T, Witjas-Paalberends ER, Boontje NM, Tripathi S, Brandis A, Montag J, Hodgkinson JL, Francino A, Navarro-Lopez F, Brenner B, Stienen GJ, van der Velden J. Familial hypertrophic cardiomyopathy: functional effects of myosin mutation R723G in cardiomyocytes. J Mol Cell Cardiol. 2013;57:13-22. Epub 2013/01/16.

2006 - 2012


Tripathi S, Schultz I, Becker E, Montag J, Borchert B, Francino A, Navarro-Lopez F, Perrot A, Ozcelik C, Osterziel KJ, McKenna WJ, Brenner B, Kraft T. Unequal allelic expression of wild-type and mutated beta-myosin in familial hypertrophic cardiomyopathy. Basic Res Cardiol. 2011;106(6):1041-55. Epub 2011/07/20.


Seebohm B, Matinmehr F, Kohler J, Francino A, Navarro-Lopez F, Perrot A, Ozcelik C, McKenna WJ, Brenner B, Kraft T. Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance. Biophys J. 2009;97(3):806-24. Epub 2009/08/05.


Köhler J, Winkler G, Schulte I, Scholz T, McKenna W, Brenner B, Kraft T. Mutation of the myosin converter domain alters cross-bridge elasticity. Proc Natl Acad Sci U S A. 2002;99(6):3557-62. Epub 2002/03/21.

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