Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Dec 1;98(11):2456–2461. doi: 10.1172/JCI119063

Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action.

H Watkins 1, C E Seidman 1, J G Seidman 1, H S Feng 1, H L Sweeney 1
PMCID: PMC507702  PMID: 8958207

Abstract

Mutations in the beta-myosin heavy chain gene are believed to cause hypertrophic cardiomyopathy (HCM) by acting as dominant negative alleles. In contrast, a truncated cardiac troponin T (TnT) that causes HCM implies that altered stoichiometry of contractile proteins may also cause cardiac hypertrophy. Wild-type and HCM-mutant (truncated) TnT were studied in a novel quail myotube expression system. Unexpectedly, antibody staining demonstrated incorporation of both forms of human cardiac TnT into the sarcomeres of quail myotubes. Functional studies of wild type and mutant transfected myotubes of normal appearance revealed that calcium-activated force of contraction was normal upon incorporation of wild type TnT, but greatly diminished for the mutant TnT. These findings indicate that HCM-causing mutations in TnT and beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. This diminished force output is the likely stimulus for hypertrophy in the human heart.

Full Text

The Full Text of this article is available as a PDF (1.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bejsovec A., Anderson P. Functions of the myosin ATP and actin binding sites are required for C. elegans thick filament assembly. Cell. 1990 Jan 12;60(1):133–140. doi: 10.1016/0092-8674(90)90723-r. [DOI] [PubMed] [Google Scholar]
  2. Bonne G., Carrier L., Bercovici J., Cruaud C., Richard P., Hainque B., Gautel M., Labeit S., James M., Beckmann J. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet. 1995 Dec;11(4):438–440. doi: 10.1038/ng1295-438. [DOI] [PubMed] [Google Scholar]
  3. Chien K. R., Knowlton K. U., Zhu H., Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J. 1991 Dec;5(15):3037–3046. doi: 10.1096/fasebj.5.15.1835945. [DOI] [PubMed] [Google Scholar]
  4. Cuda G., Fananapazir L., Zhu W. S., Sellers J. R., Epstein N. D. Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy. J Clin Invest. 1993 Jun;91(6):2861–2865. doi: 10.1172/JCI116530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davies M. J. The current status of myocardial disarray in hypertrophic cardiomyopathy. Br Heart J. 1984 Apr;51(4):361–363. doi: 10.1136/hrt.51.4.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Geisterfer-Lowrance A. A., Kass S., Tanigawa G., Vosberg H. P., McKenna W., Seidman C. E., Seidman J. G. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990 Sep 7;62(5):999–1006. doi: 10.1016/0092-8674(90)90274-i. [DOI] [PubMed] [Google Scholar]
  7. Lankford E. B., Epstein N. D., Fananapazir L., Sweeney H. L. Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. J Clin Invest. 1995 Mar;95(3):1409–1414. doi: 10.1172/JCI117795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Nishi H., Kimura A., Harada H., Koga Y., Adachi K., Matsuyama K., Koyanagi T., Yasunaga S., Imaizumi T., Toshima H. A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy. Circulation. 1995 Jun 15;91(12):2911–2915. doi: 10.1161/01.cir.91.12.2911. [DOI] [PubMed] [Google Scholar]
  9. Parker T. G., Schneider M. D. Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu Rev Physiol. 1991;53:179–200. doi: 10.1146/annurev.ph.53.030191.001143. [DOI] [PubMed] [Google Scholar]
  10. Poetter K., Jiang H., Hassanzadeh S., Master S. R., Chang A., Dalakas M. C., Rayment I., Sellers J. R., Fananapazir L., Epstein N. D. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet. 1996 May;13(1):63–69. doi: 10.1038/ng0596-63. [DOI] [PubMed] [Google Scholar]
  11. Sadoshima J., Xu Y., Slayter H. S., Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993 Dec 3;75(5):977–984. doi: 10.1016/0092-8674(93)90541-w. [DOI] [PubMed] [Google Scholar]
  12. Schwartz K. Familial hypertrophic cardiomyopathy. Nonsense versus missense mutations. Circulation. 1995 Jun 15;91(12):2865–2867. doi: 10.1161/01.cir.91.12.2865. [DOI] [PubMed] [Google Scholar]
  13. Sweeney H. L., Holzbaur E. L. Mutational analysis of motor proteins. Annu Rev Physiol. 1996;58:751–792. doi: 10.1146/annurev.ph.58.030196.003535. [DOI] [PubMed] [Google Scholar]
  14. Sweeney H. L., Straceski A. J., Leinwand L. A., Tikunov B. A., Faust L. Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J Biol Chem. 1994 Jan 21;269(3):1603–1605. [PubMed] [Google Scholar]
  15. Thierfelder L., Watkins H., MacRae C., Lamas R., McKenna W., Vosberg H. P., Seidman J. G., Seidman C. E. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994 Jun 3;77(5):701–712. doi: 10.1016/0092-8674(94)90054-x. [DOI] [PubMed] [Google Scholar]
  16. Watkins H., Conner D., Thierfelder L., Jarcho J. A., MacRae C., McKenna W. J., Maron B. J., Seidman J. G., Seidman C. E. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet. 1995 Dec;11(4):434–437. doi: 10.1038/ng1295-434. [DOI] [PubMed] [Google Scholar]
  17. Watkins H., McKenna W. J., Thierfelder L., Suk H. J., Anan R., O'Donoghue A., Spirito P., Matsumori A., Moravec C. S., Seidman J. G. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995 Apr 20;332(16):1058–1064. doi: 10.1056/NEJM199504203321603. [DOI] [PubMed] [Google Scholar]
  18. Watkins H., Rosenzweig A., Hwang D. S., Levi T., McKenna W., Seidman C. E., Seidman J. G. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992 Apr 23;326(17):1108–1114. doi: 10.1056/NEJM199204233261703. [DOI] [PubMed] [Google Scholar]
  19. Watkins H., Seidman J. G., Seidman C. E. Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy. Hum Mol Genet. 1995;4(Spec No):1721–1727. doi: 10.1093/hmg/4.suppl_1.1721. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES