Skip to main content
SpringerLink
Log in

Molecular Pathogenic Mechanisms of Cardiomyopathies Caused by Mutations in Cardiac Troponin T

  • Conference paper
Book cover Regulatory Mechanisms of Striated Muscle Contraction

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 592))

Abstract

Troponin plays a central role in the Ca2+ regulation of contraction in vertebrate skeletal and cardiac muscles. It consists of three subunits with distinct structure and function, troponin T (TnT), troponin I (TnI), and troponin C (TnC), and their accurate and complex intermolecular interaction in response to the rapid rise and fall of Ca2+ in cardiac and skeletal myocytes plays a key role in maintaining the normal cardiac pump function and body movement. Over past decade, a great number of mutations in human genes for the troponin subunits have been shown to cause striated muscle disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

19.5. References

  1. F. Ahmad, J. G. Seidman, and C. E. Seidman, The genetic basis for cardiac remodeling. Annu. Rev. Genomics Hum. Genet. 6, 185–216 (2005).

    Article  PubMed  CAS  Google Scholar 

  2. S. S. Sung, A. E. Brassington, K. Grannatt, A. Tutherford, F. G. Whitby, P. A. Krakowiad, L. B. Jorde, J. C. Carey, and M. Bamshad, Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am. J. Hum. Genet. 72(3), 681–690 (2003).

    Article  PubMed  CAS  Google Scholar 

  3. S. S. Sung, A. E. Brassington, P. A. Krakowiak, J. C. Carey, L. B. Jorde, and M. Bamshad, Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Am. J. Hum. Genet. 73(1), 212–214 (2003).

    Article  PubMed  Google Scholar 

  4. J. J. Johnston, R. I. Kelley, T. O. Crawford, D. H. Morton, R. Agarwala, T. Koch, A. A. Schaffer, C. A. Francomano, and L. G. Biesecker, A novel nemaline myopathy in the amish caused by a mutation in troponin T. Am. J. Hum. Genet. 67(4), 814–821 (2000).

    Article  PubMed  CAS  Google Scholar 

  5. S. Ebashi, Third component participating in the superprecipitation of “natural actomyosin”. Nature 200, 1010 (1963).

    Article  PubMed  CAS  Google Scholar 

  6. G. W. Dec, and V. Fuster, Idiopathic dilated cardiomyopathy. N. Engl. J. Med. 331(23), 1564–1575 (1994).

    Article  PubMed  CAS  Google Scholar 

  7. B. J. Maron, Hypertrophic cardiomyopathy: a systematic review. JAMA 287(10), 1308–1320 (2002).

    Article  PubMed  Google Scholar 

  8. S. S. Kushwaha, J. T. Fallon, and V. Fuster, Restrictive cardiomyopathy. N. Engl. J. Med. 336(4), 267–276 (1997).

    Article  PubMed  CAS  Google Scholar 

  9. B. J. Maron, J. M. Gardin, J. M. Flack, et al., Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 92(4), 785–789 (1995).

    PubMed  CAS  Google Scholar 

  10. B. J. Maron, J. Shirani, L. C. Poliac, R. Mathenge, W. C. Roberts, and F. O. Mueller, Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA 276(3), 199–204 (1996).

    Article  PubMed  CAS  Google Scholar 

  11. W. McKenna, J. Deanfield, A. Faruqui, D. England, C. Oakley, and J. Goodwin, Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. Am. J. Cardiol. 47(3), 532–538 (1981).

    Article  PubMed  CAS  Google Scholar 

  12. A. A. Geisterfer-Lowrance, S. Kass, G. Tanigawa, H. P. Vosberg, W. McKenna, C. E. Seidman, and J. G. Seidman, A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 62(5), 999–1006 (1990).

    Article  PubMed  CAS  Google Scholar 

  13. H. Watkins, C. MacRae, L. Thierfelder, Y. H. Chou, M. Frenneaux, W. McKenna, J. G. Seidman, and C. E. Seidman, A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nat. Genet. 3(4), 333–337 (1993).

    Article  PubMed  CAS  Google Scholar 

  14. K. Harada, and J. D. Potter, Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH-and Ca2+-sensitivity of cardiac muscle contraction. J. Biol. Chem. 279(15), 14488–14495 (2004).

    Article  PubMed  CAS  Google Scholar 

  15. H. Watkins, W. J. McKenna, L. Thierfelder, Wat, Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N. Engl. J. Med. 332(16), 1058–1064 (1995).

    Article  PubMed  CAS  Google Scholar 

  16. P. Richard, P. Charron, L. Carrier, C. Ledeuil, T. Cheav, C. Pichereau, A. Benaiche, R. Isnard, O. Dubourg, M. Burban, J. P. Gueffet, A. Millaire, M. Desnos, K. Schwartz, B. Hainque, and M. Komajda, Hypertrophic cardiomyopathy distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107(17), 2227–2232 (2003).

    Article  PubMed  Google Scholar 

  17. F. Torricelli, F. Girolami, I. Olivotto, I. Passerini, S. Frusconi, D. Vargiu, P. Richard, and F. Cecchi, Prevalence and clinical profile of troponin T mutations among patients with hypertrophic cardiomyopathy in tuscany. Am. J. Cardiol. 92(11), 1358–1362 (2003).

    Article  PubMed  CAS  Google Scholar 

  18. N. D. Epstein, G. M. Cohn, F. Cyran, and L. Fananapazir, Differences in clinical expression of hypertrophic cardio-myopathy associated with two distinct mutations in the β-myosin heavy chain gene: a 908Leu → Val mutation and a 403Arg → Gln mutation. Circulation 86(2), 345–352 (1992).

    PubMed  CAS  Google Scholar 

  19. H. Watkins, A. Rosenzweig, D.-S. Hwang, T. Levi, W. McKenna, C. E. Seidman, and J. G. Seidman, Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N. Engl. J. Med. 326(17), 1108–1114 (1992).

    Article  PubMed  CAS  Google Scholar 

  20. R. Anan, G. Greve, L. Thierfelder, H. Watkins, W. J. McKenna, S. Solomon, C. Vecchio, H. Shono, S. Nakao, H. Tanaka, A. Mares, Jr., J. A. Towbin, P. Spirito, R. Roberts, J. G. Seidman, and C. E. Seidman, Prognostic implications of novel cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J. Clin. Invest. 93(1), 280–285 (1994).

    PubMed  CAS  Google Scholar 

  21. H. Watkins, C. E. Seidman, J. G. Seidman. H. S. Feng, and H. L. Sweeney, Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. J. Clin. Invest. 98(11), 2456–2461 (1996).

    PubMed  CAS  Google Scholar 

  22. H. L. Sweeney, H. S. Feng, Z. Yang, and H. Watkins, Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function. Proc. Natl. Acad. Sci. USA 95(24), 14406–14410 (1998).

    Article  PubMed  CAS  Google Scholar 

  23. A. J. Marian, G. Zhao, Y. Seta, R. Roberts, and Q. Yu, Expression of a mutant (Arg92Gln) human cardiac troponin T, known to cause hypertrophic cardiomyopathy, impairs adult cardiac myocyte contractility. Circ. Res. 81(1), 76–85 (1997).

    PubMed  CAS  Google Scholar 

  24. E. M. Rust, F. P. Albayya, and J. M. Metzger, Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins. J. Clin. Invest. 103(10), 1459–1467 (1999).

    PubMed  CAS  Google Scholar 

  25. S. Morimoto, F. Yanaga, R. Minakami, and I. Ohtsuki, Ca2+-sensitizing effects of the mutations at Ile-79 and Arg-92 of troponin T in hypertrophic cardiomyopathy. Am. J. Physiol. Cell Physiol. 275(1 Pt 1), C200–C207 (1998).

    CAS  Google Scholar 

  26. F. Yanaga, S. Morimoto, and I. Ohtsuki, Ca2+ sensitization and potentiation of the maximum level of myofibrillar ATPase activity caused by mutations of troponin T found in familial hypertrophic cardiomyopathy. J. Biol. Chem. 274(13), 8806–8812 (1999).

    Article  PubMed  CAS  Google Scholar 

  27. D. Szczesna, R. Zhang, J. Zhao, M. Jones, G. Guzman, and J. D. Potter, Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. J. Biol. Chem. 275(1), 624–630 (2000).

    Article  PubMed  CAS  Google Scholar 

  28. T. Miller, D. Szczesna, P. R. Housmans, J. Zhao, F. de Freitas, A. V. Gomes, L. Culbreath, J. McCue, Y. Wang, Y. Xu, W. G. Kerrick, and J. D. Potter, Abnormal contractile function in transgenic mice expressing a familial hypertrophic cardiomyopathy-linked troponin T (I79N) mutation. J. Biol. Chem. 276(6), 3743–3755 (2001).

    Article  PubMed  CAS  Google Scholar 

  29. J. C. Tardiff, T. E. Hewett, B. M. Palmer, C. Olsson, S. M. Factor, R. L. Moore, J. Robbins, and L. A. Leinwand, Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. J. Clin. Invest. 104(4), 469–481 (1999).

    PubMed  CAS  Google Scholar 

  30. M. Chandra, V. L. M. Rundell, J. C. Tardiff, L. A. Leinwand, P. P. De Tombe, and R. J. Solaro, Ca2+ activation of myofilaments from transgenic mouse hearts expressing R92Q mutant cardiac troponin T. Am. J. Physiol. Heart. Circ. Physiol. 280(2), H705–H713 (2001).

    PubMed  CAS  Google Scholar 

  31. S. Morimoto, Q.-W. Lu, K. Harada, F. Takahashi-Yanaga, R. Minakami, M. Ohta, T. Sasaguri, and I. Ohtsuki, Ca2+-desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy. Proc. Natl. Acad. Sci. USA 99(2), 913–918 (2002).

    Article  PubMed  CAS  Google Scholar 

  32. S. Morimoto, C.-K. Du, K. Harada, M. Ohta, N. Oka, Q.-W. Lu, R. Minakami, M. Suzuki, T. Sasaguri, K. Yamamura, and I. Ohtsuki, Cardiac function of a transgenic mouse model of ΔGlu160 troponin T mutation-linked familial hypertrophic cardiomyopathy. Biophys. J. 86, 386A (2004).

    Google Scholar 

  33. T. E. Haim, C. Dowell, T. Dhjamanti, J. Scheuer, and J. C. Tardiff, Independent mutations in Cardiac Troponin T lead to impairments in calcium handling that relate to alterations in myocellular function. Biophys. J. 86, 47A–48A (2004).

    Google Scholar 

  34. H. Nakaura, S. Morimoto, F. Yanaga, M. Nakata, H. Nishi, T. Imaizumi, and I. Ohtsuki, Functional changes in troponin T by a splice donor site mutation that causes hypertrophic cardiomyopathy. Am. J. Physiol. Cell Physiol. 277(2 Pt 1), C225–C232 (1999).

    CAS  Google Scholar 

  35. G. Cuda, L. Fananapazir, W.-S. Zhu, J. R. Sellers, and N. D. Epstein, Skeletal muscle expression and abnormal function of β-myosin in hypertrophic cardiomyopathy. J. Clin. Invest. 91(6), 2861–2865 (1993).

    PubMed  CAS  Google Scholar 

  36. H. L. Sweeney, A. J. Straceski, L. A. Leinwand, B. A. Tikunov, and L. Faust, Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. J. Biol. Chem. 269(3), 1603–1605 (1994).

    PubMed  CAS  Google Scholar 

  37. E. B. Lankford, N. D. Epstein, L. Fananapazir, and H. L. Sweeney, Abnormal contractile properties of muscle fibers expressing β-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. J. Clin. Invest. 95(3), 1409–1414 (1995).

    PubMed  CAS  Google Scholar 

  38. H. Fujita, S. Sugiura, S. Momomura, M. Omata, H. Sugi, and K. Sutoh, Characterization of mutant myosins of dictyostelium discoideum equivalent to human familial hypertrophic cardiomyopathy mutants — molecular force level of mutant myosins may have a prognostic implication. J. Clin. Invest. 99(5), 1010–1015 (1997).

    PubMed  CAS  Google Scholar 

  39. E. K. Kasper, W. R. Agema, G. M. Hutchins, J. W. Deckers, J. M. Hare, and K. L. Baughman, The causes of dilated cardiomyopathy: a clinicopathologic review of 673 consecutive patients. J. Am. Coll. Cardiol. 23(3), 586–590 (1994).

    Article  PubMed  CAS  Google Scholar 

  40. E. M. Gilbert, and M. R. Bristow, Idiopathic dilated cardiomyopathy. In: The Heart, edited by J. W. Hurst (MacGraw-Hill, New York, 1994), pp. 1609–1619.

    Google Scholar 

  41. D. Fatkin, and R. M. Graham, Molecular mechanisms of inherited cardiomyopathies. Physiol. Rev. 82(4), 945–980 (2002).

    PubMed  CAS  Google Scholar 

  42. J. Mogensen, R. T. Murphy, T. Shaw, A. Bahl, C. Redwood, H. Watkins, M. Burke, P. M. Elliott, and W. J. McKenna, Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 44(10), 2033–2040 (2004).

    Article  PubMed  CAS  Google Scholar 

  43. M. Kamisago, S. D. Sharma, S. R. DePalma, S. Solomon, P. Sharma, B. McDonough, L. Smoot, M. P. Mullen, P. K. Woolf, E. D. Wigle, J. G. Seidman, and C. E. Seidman, Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N. Engl. J. Med. 343(23), 1688–1696 (2000).

    Article  PubMed  CAS  Google Scholar 

  44. E. L. Hanson, P. M. Jakobs, H. Keegan, K. Coates, S. Bousman, N. H. Dienel, M. Litt, and R. E. Hershberger, Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy. J. Card. Fail. 8(1), 28–32 (2002).

    Article  PubMed  CAS  Google Scholar 

  45. P. Robinson, M. Mirza, A. Knott, H. Abdulrazzak, R. Willott, S. Marston, H. Watkins, and C. Redwood, Alterations in thin filament regulation induced by a human cardiac troponin T mutant that causes dilated cardiomyopathy are distinct from those induced by troponin T mutants that cause hypertrophic cardiomyopathy. J. Biol. Chem. 277(43), 40710–40716 (2002).

    Article  PubMed  CAS  Google Scholar 

  46. G. Venkatraman, K. Harada, A. V. Gomes, W. G. Kerrick, and J. D. Potter, Different functional properties of troponin T mutants that cause dilated cardiomyopathy. J. Biol. Chem. 278(43), 41670–41676 (2003).

    Article  PubMed  CAS  Google Scholar 

  47. J. C. Ruegg, Calcium in Muscle Activation (Springer-Verlag, Berlin; Tokyo, 1986).

    Google Scholar 

  48. M. Tanokura, Y. Tawada, A. Ono, and I. Ohtsuki, Chymotryptic subfragments of troponin T from rabbit skeletal muscle. Interaction with tropomyosin, troponin I and troponin C. J. Biochem. (Tokyo) 93(2), 331–337 (1983).

    CAS  Google Scholar 

  49. S. Takeda, A. Yamashita, K. Maeda, and Y. Maeda, Structure of the core domain of human cardiac troponin in the Ca2+-saturated form. Nature 424, 35–41 (2003).

    Article  PubMed  CAS  Google Scholar 

  50. S. Morimoto, C.-K. Du, M. Ohta, Q.-W. Lu, K. Harada, K. Nishii, R. Minakami, N. Oka, N. Tadano, J. Miyazaki, K. Yamamura, and I. Ohtsuki, A knock-in mouse model for familial dilated cardiomyopathy caused by the mutation ΔK210 in cardiac troponin T. Biophys. J. 88(1), 480A (2005).

    Google Scholar 

  51. D. Li, G. Z. Czernuszewicz, O. Gonzalez, T. Tapscott, A. Karibe, J. B. Durand, R. Brugada, R. Hill, J. M. Gregoritch, J. L. Anderson, M. Quinones, L. L. Bachinski, and R. Roberts, Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation 104(8), 2188–2193 (2001).

    PubMed  CAS  Google Scholar 

  52. Q.-W. Lu, S. Morimoto, K. Harada, C. K. Du, F. Takahashi-Yanaga, Y. Miwa, T. Sasaguri, and I. Ohtsuki, Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization. J. Mol. Cell. Cardiol. 35(12), 1421–1427 (2003).

    Article  PubMed  CAS  Google Scholar 

  53. G. Venkatraman, A. V. Gomes, W. G. L. Kerrick, and J. D. Potter, Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform. J. Biol. Chem. 280(18), 17584–17592 (2005).

    Article  PubMed  CAS  Google Scholar 

  54. I. Ohtsuki, K. Maruyama, and S. Ebashi, Regulatory and cytoskeletal proteins of vertebrate skeletal muscle. Adv. Protein Chem. 38, 1–67 (1986).

    Article  PubMed  CAS  Google Scholar 

  55. T. Palm, S. Graboski, S. E. Hitchcock-DeGregori, and N. J. Greenfield, Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region. Biophys. J. 81(5), 2827–2837 (2001).

    Article  PubMed  CAS  Google Scholar 

  56. J. James, Y. Zhang, H. Osinska, A. Sanbe, R. Klevitsky, T. E. Hewett, and J. Robbins, Transgenic modeling of a cardiac troponin I mutation linked to familial hypertrophic cardiomyopathy. Circ. Res. 87(9), 805–811 (2000).

    PubMed  CAS  Google Scholar 

  57. D. E. Montgomery, J. C. Tardiff, and M. Chandra, Cardiac troponin T mutations: correlation between the type of mutation and the nature of myofilament dysfunction in transgenic mice. J. Physiol. 536(Pt 2), 583–592 (2001).

    Article  PubMed  CAS  Google Scholar 

  58. M. M. Javadpour, J. C. Tardiff, I. Pinz, and J. S. Ingwall, Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T. J. Clin. Invest. 112(5), 768–775 (2003).

    Article  PubMed  CAS  Google Scholar 

  59. J. G. Crilley, E. A. Boehm, E. Blair, B. Rajagopalan, A. M. Blamire, P. Styles, W. J. McKenna, I. Ostman-Smith, K. Clarke, and H. Watkins, Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J. Am. Coll. Cardiol. 41(10), 1776–1782 (2003).

    Article  PubMed  CAS  Google Scholar 

  60. M. Mirza, S. Marston, R. Willott, C. Ashley, J. Mogensen, W. McKenna, P. Robinson, C. Redwood, and H. Watkins, Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J. Biol. Chem. 280(31), 28498–28506 (2005).

    Article  PubMed  CAS  Google Scholar 

  61. A. N. Chang, K. Harada, M. J. Ackerman, and J. D. Potter, Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin. J. Biol. Chem. 280(40), 34343–34349 (2005).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Sachio Morimoto

Authors
  1. Sachio Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. National Institute of Physiological Sciences, Okazaki, Japan

    Setsuro Ebashi

  2. The Jikei University School of Medicine, Tokyo, Japan

    Iwao Ohtsuki

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer

About this paper

Cite this paper

Morimoto, S. (2007). Molecular Pathogenic Mechanisms of Cardiomyopathies Caused by Mutations in Cardiac Troponin T. In: Ebashi, S., Ohtsuki, I. (eds) Regulatory Mechanisms of Striated Muscle Contraction. Advances in Experimental Medicine and Biology, vol 592. Springer, Tokyo. https://doi.org/10.1007/978-4-431-38453-3_19

Download citation

Publish with us

Policies and ethics

Search

Navigation