Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays1. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac (β-myosin heavy chain (cβMHQ2,3) cardiac troponin T (cThT)4,5, α-tropomyosin (αTM)5'6, cardiac myosin binding protein C (cMBP-C)7–9, ventricular myosin essential light chain (vMLC1)10 and ventricular myosin regulatory light chain (vMLC2)10 genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle11, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnl), cardiac actin (cACT) and cardiac troponin C (cTnC)12 in 184 unrelated patients with HCM and found mutations in the cTnl gene in several patients13. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnl is the seventh HCM gene.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Maron, B.J., Bonow, R.O., Cannon, R.O., Leon, M.B. & Epstein, S.E. Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology, and therapy. N. Engl. J. Med. 316, 780–789 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. Jarcho, J.A. et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N. Engl. J. Med. 321, 1372–1378 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Geisterfer-Lowrance, A.A.T. et al. A molecular basis for familial hypertrophic cardiomyopathy: a β cardiac myosin heavy chain gene missense mutation. Cell 62, 999–1006 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Watkins, H. et al. A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nature Genet. 3, 333–337 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Thierfelder, L. et al. α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 77, 701–712 (1994).

    Article  PubMed  Google Scholar 

  6. Thierfelder, L. et al. A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc. Natl. Acad. Sd. USA 90, 6270–6274 (1993).

    Article  CAS  Google Scholar 

  7. Carrier, L. et al. Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nature Genet 4, 311–313 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Watkins, H. et al. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nature Genet. 11, 434–437 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Bonne, G. et al. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nature Genet 11, 438–440 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Poetter, K. et al. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nature Genet. 13, 63–69 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Hamada, H., Petrino, M.G. & Kakunaga, T. Molecular structure and evolutionary origin of human cardiac muscle actin gene. Proc. Natl. Acad. Sci. USA 79, 5901–5905 (1992).

    Article  Google Scholar 

  12. Schreier, T., Kedes, L. & Gahlmann, R., Cloning, structural analysis, and expression of the human slow twitch skeletal muscle/cardiac troponin C gene. J. Biol. Chem. 265, 21247–21253 (1990).

    CAS  PubMed  Google Scholar 

  13. Bhavsar, P.K., Brand, N.J., Yacoub, M.H. & Barton, P.J.R. Isolation and characterization of the human cardiac troponin I gene (TNNI3). Genomics 35, 11–23 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Liew, C.C. et al. Complete sequence and organization of the human cardiac beta-myosin heavy chain gene. Nucl. Adds Res. 18, 3647–3651 (1990).

    Article  CAS  Google Scholar 

  15. Fodor, W.L. Human ventricular/slow twitch myosin alkali light chain gene characterization, sequence, and chromosomal location. J. Biol. Chem. 264, 2143–2149 (1989).

    CAS  PubMed  Google Scholar 

  16. Bermingham, N. et al. Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse. Genomics 30, 620–622 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Ko, Y.L. et al. Mapping the locus for familial hypertrophic cardiomyopathy to chromosome 11 in a family with a case of apical hypertrophic cardiomyopathy of the Japanese type. Hum. Genet. 97, 457–461 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Schwarts, K., Carrier, L., Guicheney, P. & Komajda, M. Molecular basis of familial cardiomyopathy. Circulation 91, 532–540 (1995).

    Article  Google Scholar 

  19. Watkins, H. et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N. Engl. J. Med. 332,, 1058–1064 (1995).

    Article  Google Scholar 

  20. MacRae, C.A. et al. Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3. J. Clin. Invest. 96, 1216–1220 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Beall, C.J. & Fyrberg, E. Muscle abnormalities in Drosophila melanogaster heldup mutants are caused by missing or aberrant troponin-l isoforms. J. Cell Biol. 114, 941–951 (1991).

    Google Scholar 

  22. Farah, C.S. & Reinach, F.C. The troponin complex and regulation of muscle contraction. FASEB J. 9, 755–767 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Solaro, R.J. Troponin C—troponin I interactions and molecular signaling in cardiac myofilaments. Adv. Exp. Med. Biol. 382, 109–115 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Syska, H., Wilkinson, J.M., Grand, R.J.A. & Perry, S.V. The relationship between biological activity and primary structure of troponin I from white skeletal muscle of the rabbit. Biochem. J. 153, 375–387 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Talbot, J.A. & Hodges, R.S. Synthetic studies on the inhibitory region of rabbit skeletal troponin I. J. Biol. Chem. 256, 2798–2802 (1981).

    CAS  PubMed  Google Scholar 

  26. Farah, C.S. et al. Structural and regulatory function of the NH2 and COOH'terminal regions of skeletal muscle troponin I. J. Biol. Chem. 269, 5230–5240 (1994).

    CAS  PubMed  Google Scholar 

  27. Tao, T., Gowell, E., Strasburg, G.M., Gergely, J. & Leavis, P.C. Ca2+ dependence of the distance between Cys-98 of troponin C and Cys-133 of troponin I in the ternary complex: resonance energy transfer measurements. Biochemistry 28, 5902–5908 (1989).

    Article  CAS  PubMed  Google Scholar 

  28. Lin, D., Bobkova, A., Homsher, E. & Tobacman, L.S. Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy. J. Clin. Invest. 97, 2842–2848 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nishi, H. et al. A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy. Circulation 91, 2911–2915 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Akinori Kimura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kimura, A., Harada, H., Park, JE. et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 16, 379–382 (1997). https://doi.org/10.1038/ng0897-379

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0897-379

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing