Troponin Mutations in Cardiomyopathies

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


Cardiomyopathies are a group of cardiac disorders characterized by structural and functional abnormalities of the myocardium of unexplained aetiology. By convention idiopathic cardiomyopathies are divided into 4 different diagnostic entities: Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM) and arrythmogenic right ventricle cardiomyopathy (ARVC) (Figure 18.1).1 Recent investigations have revealed that the conditions in many cases are hereditary.2, 3, 4


Mutation Carrier Dilate Cardiomyopathy Hypertrophic Cardiomyopathy Cardiac Troponin Disease Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

18.7. References

  1. 1.
    P. Richardson, W. McKenna, M. Bristow, B. Maisch, B. Mautner, J. O’Connell, E. Olsen, G. Thiene, J. Goodwin, I. Gyarfas, I. Martin, and P. Nordet, Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies, Circulation 93, 841–842 (1996).PubMedGoogle Scholar
  2. 2.
    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.Google Scholar
  3. 3.
    L. Mestroni, C. Rocco, D. Gregori, G. Sinagra, L. A. Di, S. Miocic, M. Vatta, B. Pinamonti, F. Muntoni, A. L. Caforio, W. J. Mckenna, A. Falaschi, and M. Giacca, Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group, J. Am. Coll. Cardiol. 34, 181–190 (1897).CrossRefGoogle Scholar
  4. 4.
    M. S. Hamid, M. Norman, A. Quraishi, S. Firoozi, R. Thaman, J. R. Gimeno, B. Sachdev, E. Rowland, P. M. Elliott, and W. J. McKenna, Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria, J. Am. Coll. Cardiol. 40, 1445–1450 (2002).PubMedCrossRefGoogle Scholar
  5. 5.
    B. J. Maron, J. M. Gardin, J. M. Flack, S. S. Gidding, T. T. Kurosaki, and D. E. Bild, 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, 785–789 (1995).PubMedGoogle Scholar
  6. 6.
    B. J. Maron, J. S. Gottdiener, and S. E. Epstein, Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy. A wide angle, two dimensional echocardiographic study of 125 patients, Am. J. Cardiol. 48, 418–428 (1981).PubMedCrossRefGoogle Scholar
  7. 7.
    H. G. Klues, A. Schiffers, and B. J. Maron, Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients, J. Am. Coll. Cardiol. 26, 1699–1708 (1995).PubMedCrossRefGoogle Scholar
  8. 8.
    B. J. Maron, R. O. Bonow, R. O. Cannon 3rd, M. B. Leon, and S. E. Epstein, Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (2), N. Engl. J. Med. 316, 844–852 (1987).PubMedCrossRefGoogle Scholar
  9. 9.
    P. Spirito, and B. J. Maron, Patterns of systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy: assessment by two-dimensional echocardiography, Am. J. Cardiol. 54, 1039–1046 (1984).PubMedCrossRefGoogle Scholar
  10. 10.
    B. J. Maron, P. Spirito, Y. Wesley, and J. Arce, Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy, N. Engl. J. Med. 315, 610–614 (1986).PubMedCrossRefGoogle Scholar
  11. 11.
    H. Niimura, L. L. Bachinski, S. Sangwatanaroj, H. Watkins, A. E. Chudley, W. McKenna, A. Kristinsson, R. Roberts, M. Sole, B. J. Maron, J. G. Seidman, and C. E. Seidman, Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy [see comments], N. Engl. J. Med. 338, 1248–1257 (1998).PubMedCrossRefGoogle Scholar
  12. 12.
    J. Mogensen, R. T. Murphy, T. Kubo, A. Bahl, J. C. Moon, I. C. Klausen, P. M. Elliott, and W. J. McKenna, Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy, J. Am. Coll. Cardiol. 44, 2315–2325 (2004).PubMedCrossRefGoogle Scholar
  13. 13.
    P. M. Elliott, J. Poloniecki, S. Dickie, S. Sharma, L. Monserrat, A. Varnava, N. G. Mahon, and W. J. McKenna, Sudden death in hypertrophic cardiomyopathy: identification of high risk patients, J. Am. Coll. Cardiol. 36(7), 2212–2218 (2000).PubMedCrossRefGoogle Scholar
  14. 14.
    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 [see comments], JAMA 276, 199–204 (1996).PubMedCrossRefGoogle Scholar
  15. 15.
    B. J. Maron, W. K. Shen, M. S. Link, A. E. Epstein, A. K. Almquist, J. P. Daubert, G. H. Bardy, S. Favale, R. F. Rea, G. Boriani, N. A. Estes, and P. Spirito, Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy, N. Engl. J. Med. 342(6), 365–373 (2000).PubMedCrossRefGoogle Scholar
  16. 16.
    P. M. Elliott, S. Sharma, A. Varnava, J. Poloniecki, E. Rowland, and W. J. McKenna, Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy, J. Am. Coll. Cardiol. 33, 1596–1601 (1999).PubMedCrossRefGoogle Scholar
  17. 17.
    B. J. Maron, W. J. McKenna, G. K. Danielson, L. J. Kappenberger, H. J. Kuhn, C. E. Seidman, P. M. Shah, W. H. Spencer III, P. Spirito, F. J. TenCate, E. D. Wigle, R. A. Vogel, J. Abrams, E. R. Bates, B. R. Brodie, P. G. Danias, G. Gregoratos, M. A. Hlatky, J. S. Hochman, S. Kaul, R. C. Lichtenberg, J. R. Lindner, R. A. O’Rourke, G. M. Pohost, R. S. Schofield, C. M. Tracy, W. L. Winters, Jr., W. W. Klein, S. G. Priori, A. Alonso-Garcia, C. Blimstrom-Lundqvist, G. De Backer, J. Deckers, M. Flather, J. Hradec, A. Oto, A. Parkhomenko, S. Silber, and A. Torbicki, American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines, Eur. Heart J. 24, 1965–1991 (2003).PubMedCrossRefGoogle Scholar
  18. 18.
    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, 999–1006 (1990).PubMedCrossRefGoogle Scholar
  19. 19.
    L. Thierfelder, H. Watkins, C. MacRae, R. Lamas, W. McKenna, H. P. Vosberg, J. G. Seidman, and C. E. Seidman, Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere, Cell 77, 701–712 (1994).PubMedCrossRefGoogle Scholar
  20. 20.
    G. Bonne, L. Carrier, J. Bercovici, C. Cruaud, P. Richard, B. Hainque, M. Gautel, S. Labeit, M. James, J. Beckmann, J. Weissenbach, H. P. Vosberg, M. Fiszman, M. Komajda, and K. Schwartz, Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy, Nat. Genet. 11, 438–440 (1995).PubMedCrossRefGoogle Scholar
  21. 21.
    H. Watkins, D. Conner, L. Thierfelder, J. A. Jarcho, C. MacRae, W. J. McKenna, B. J. Maron, J. G. Seidman, and C. E. Seidman, Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy, Nat. Genet. 11, 434–437 (1995).PubMedCrossRefGoogle Scholar
  22. 22.
    K. Poetter, H. Jiang, S. Hassanzadeh, S. R. Master, A. Chang, M. C. Dalakas, I. Rayment, J. R. Sellers, L. Fananapazir, and N. D. Epstein, 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. 13, 63–69 (1996).PubMedCrossRefGoogle Scholar
  23. 23.
    A. Kimura, H. Harada, J. E. Park, H. Nishi, M. Satoh, M. Takahashi, S. Hiroi, T. Sasaoka, N. Ohbuchi, T. Nakamura, T. Koyanagi, T. H. Hwang, J. A. Choo, K. S. Chung, A. Hasegawa, R. Nagai, O. Okazaki, H. Nakamura, M. Matsuzaki, T. Sakamoto, H. Toshima, Y. Koga, T. Imaizumi, and T. Sasazuki, Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyo-pathy, Nat. Genet. 16, 379–382 (1997).PubMedCrossRefGoogle Scholar
  24. 24.
    B. Hoffmann, H. Schmidt-Traub, A. Perrot, K. J. Osterziel, and R. Gessner, First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy, Hum. Mutat. 17(6), 524 (2001).PubMedCrossRefGoogle Scholar
  25. 25.
    M. Satoh, M. Takahashi, T. Sakamoto, M. Hiroe, F. Marumo, and A. Kimura, Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene, Biochem. Biophys. Res. Commun. 262, 411–417 (1999).PubMedCrossRefGoogle Scholar
  26. 26.
    H. Niimura, K. K. Patton, W. J. McKenna, J. Soults, B. J. Maron, J. G. Seidman, and C. E. Seidman, Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly, Circulation 105(4), 446–451 (2002).PubMedCrossRefGoogle Scholar
  27. 27.
    C. Geier, A. Perrot, C. Ozcelik, P. Binner, D. Counsell, K. Hoffmann, B. Pilz, Y. Martiniak, K. Gehmlich, P. F. van der Ven, D. O. Furst, A. Vornwald, E. von Hodenberg, P. Nurnberg, T. Scheffold, R. Dietz, and K. J. Osterziel, Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy, Circulation 107(10), 1390–1395 (2003).PubMedCrossRefGoogle Scholar
  28. 28.
    A. Keren, and R. L. Popp, Assignment of patients into the classification of cardiomyopathies, Circulation 86, 1622–1633 (1992).PubMedGoogle Scholar
  29. 29.
    A. Angelini, V. Calzolari, G. Thiene, G. M. Boffa, M. Valente, L. Daliento, C. Basso, F. Calabrese, R. Razzolini, U. Livi, and R. Chioin, Morphologic spectrum of primary restrictive cardiomyopathy, Am. J. Cardiol. 80, 1046–1050 (1997).PubMedCrossRefGoogle Scholar
  30. 30.
    M. J. Saraiva, Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies, Expert Rev. Mol. Med. 2002, 1–11 (2002).PubMedCrossRefGoogle Scholar
  31. 31.
    J. A. Towbin, and N. E. Bowles, The failing heart, Nature 415(6868), 227–233 (2002).PubMedCrossRefGoogle Scholar
  32. 32.
    L. Mestroni, B. Maisch, W. J. McKenna, K. Schwartz, P. Charron, C. Rocco, F. Tesson, A. Richter, A. Wilke, and M. Komajda, Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy, Eur. Heart J. 20, 93–102 (1999).PubMedCrossRefGoogle Scholar
  33. 33.
    M. B. Codd, D. D. Sugrue, B. J. Gersh, and L. J. Melton, Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 80, 564–572 (1989).PubMedGoogle Scholar
  34. 34.
    J. N. Cohn, M. R. Bristow, K. R. Chien, W. S. Colucci, O. H. Frazier, L. A. Leinwand, B. H. Lorell, A. J. Moss, E. H. Sonnenblick, R. A. Walsh, S. C. Mockrin, and L. Reinlib, Report of the national heart, lung, and blood institute special emphasis panel on heart failure research, Circulation 95, 766–770 (1997).PubMedGoogle Scholar
  35. 35.
    Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors, N. Engl. J. Med. 327, 685–691 (1992).Google Scholar
  36. 36.
    M. A. Pfeffer, E. Braunwald, L. A. Moye, L. Basta, E. J. J. Brown, T. E. Cuddy, B. R. Davis, E. M. Geltman, S. Goldman, and G. C. Flaker, Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators, N. Engl. J. Med. 327, 669–677 (1992).PubMedCrossRefGoogle Scholar
  37. 37.
    F. Waagstein, M. R. Bristow, K. Swedberg, F. Camerini, M. B. Fowler, M. A. Silver, E. M. Gilbert, M. R. Johnson, F. G. Goss, and A. Hjalmarson, Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group, Lancet 342, 1441–1446 (1993).PubMedCrossRefGoogle Scholar
  38. 38.
    P. A. Poole-Wilson, K. Swedberg, J. G. Cleland, L. A. Di, P. Hanrath, M. Komajda, J. Lubsen, B. Lutiger, M. Metra, W. J. Remme, C. Torp-Pedersen, A. Scherhag, and A. Skene, Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial, Lancet 362(9377), 7–13 (2003).PubMedCrossRefGoogle Scholar
  39. 39.
    J.G. Cleland, D. J. Pennell, S. G. Ray, A. J. Coats, P. W. Macfarlane, G. D. Murray, J. D. Mule, Z. Vered, and A. Lahiri, Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure (CHRISTMAS trial): randomised controlled trial, Lancet 362(9377), 14–21 (2003).PubMedCrossRefGoogle Scholar
  40. 40.
    S.G. Molhoek, J. J. Bax, L. van Erven, M. Bootsma, E. Boersma, P. Steendijk, E. E. Van der Wall, and M. J. Schalij, Comparison of benefits from cardiac resynchronization therapy in patients with ischemic cardiomyopathy versus idiopathic dilated cardiomyopathy, Am. J. Cardiol. 93, 860–863 (2004).PubMedCrossRefGoogle Scholar
  41. 41.
    P.T. Mortensen, P. Sogaard, H. Mansour, J. Ponsonaille, D. Gras, A. Lazarus, W. Reiser, C. Alonso, C. M. Linde, M. Lunati, B. Kramm, and E. M. Harrison, Sequential biventricular pacing: evaluation of safety and efficacy, Pacing Clin. Electrophysiol. 27, 339–345 (2004).PubMedCrossRefGoogle Scholar
  42. 42.
    J.J. Blanc, V. Bertault-Valls, M. Fatemi, M. Gilard, P. Y. Pennec, and Y. Etienne, Midterm benefits of left univentricular pacing in patients with congestive heart failure, Circulation 109, 1741–1744 (2004).PubMedCrossRefGoogle Scholar
  43. 43.
    A. Auricchio, C. Stellbrink, C. Butter, S. Sack, J. Vogt, A. R. Misier, D. Bocker, M. Block, J. H. Kirkels, A. Kramer, and E. Huvelle, Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay, J. Am. Coll. Cardiol. 42, 2109–2116 (2003).PubMedCrossRefGoogle Scholar
  44. 44.
    J.G. Seidman, and C. Seidman, The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms, Cell 104(4), 557–567 (2001).PubMedCrossRefGoogle Scholar
  45. 45.
    R.T. Murphy, J. Mogensen, A. Shaw, T. Kubo, S. Hughes, and W. J. McKenna, Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy, Lancet 363, 371–372 (2004).PubMedCrossRefGoogle Scholar
  46. 46.
    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, 2033–2040 (2004).PubMedCrossRefGoogle Scholar
  47. 47.
    T.M. Olson, V. V. Michels, S. N. Thibodeau, Y. S. Tai, and M. T. Keating, Actin mutations in dilated cardiomyopathy, a heritable form of heart failure, Science 280, 750–752 (1998).PubMedCrossRefGoogle Scholar
  48. 48.
    T.M. Olson, N. Y. Kishimoto, F. G. Whitby, and V. V. Michels, Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy, J. Mol. Cell Cardiol. 33(4), 723–732 (2001).PubMedCrossRefGoogle Scholar
  49. 49.
    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).PubMedCrossRefGoogle Scholar
  50. 50.
    B. Gerull, M. Gramlich, J. Atherton, M. McNabb, K. Trombitas, S. Sasse-Klaassen, J. G. Seidman, C. Seidman, H. Granzier, S. Labeit, M. Frenneaux, and L. Thierfelder, Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy, Nat. Genet. 30(2), 201–204 (2002).PubMedCrossRefGoogle Scholar
  51. 51.
    M. Itoh-Satoh, T. Hayashi, H. Nishi, Y. Koga, T. Arimura, T. Koyanagi, M. Takahashi, S. Hohda, K. Ueda, T. Nouchi, M. Hiroe, F. Marumo, T. Imaizumi, M. Yasunami, and A. Kimura, Titin mutations as the molecular basis for dilated cardiomyopathy, Biochem. Biophys. Res. Commun. 291, 385–393 (2002).PubMedCrossRefGoogle Scholar
  52. 52.
    S. Daehmlow, J. Erdmann, T. Knueppel, C. Gille, C. Froemmel, M. Hummel, R. Hetzer, and V. Regitz-Zagrosek, Novel mutations in sarcomeric protein genes in dilated cardiomyopathy, Biochem. Biophys. Res. Commun. 298(1), 116–120 (2002).PubMedCrossRefGoogle Scholar
  53. 53.
    R. Knoll, M. Hoshijima, H. M. Hoffman, V. Person, I. Lorenzen-Schmidt, M. L. Bang, T. Hayashi, N. Shiga, H. Yasukawa, W. Schaper, W. McKenna, M. Yokoyama, N. J. Schork, J. H. Omens, A. D. McCulloch, A. Kimura, C. C. Gregorio, W. Poller, J. Schaper, H. P. Schultheiss, and K. R. Chien, The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy, Cell 111(7), 943–955 (2002).PubMedCrossRefGoogle Scholar
  54. 54.
    D. Fatkin, C. MacRae, T. Sasaki, M. R. Wolff, M. Porcu, M. Frenneaux, J. Atherton, H. J. J. Vidaillet, S. Spudich, G. U. De, et al., Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease, N. Engl. J. Med. 341, 1715–1724 (1897).CrossRefGoogle Scholar
  55. 55.
    S. Bione, E. Maestrini, S. Rivella, M. Mancini, S. Regis, G. Romeo, and D. Toniolo, Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy, Nat. Genet. 8, 323–327 (1994).PubMedCrossRefGoogle Scholar
  56. 56.
    D. Li, T. Tapscoft, O. Gonzalez, P. E. Burch, M. A. Quinones, W. A. Zoghbi, R. Hill, L. L. Bachinski, D. L. Mann, and R. Roberts, Desmin mutation responsible for idiopathic dilated cardiomyopathy, Circulation 100, 461–464 (1897).Google Scholar
  57. 57.
    S. Tsubata, K. R. Bowles, M. Vatta, C. Zintz, J. Titus, L. Muhonen, N. E. Bowles, and J. A. Towbin, Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy, J. Clin. Invest. 106(5), 655–662 (2000).PubMedGoogle Scholar
  58. 58.
    F. Muntoni, M. Cau, A. Ganau, R. Congiu, G. Arvedi, A. Mateddu, M. G. Marrosu, C. Cianchetti, G. Realdi, and A. Cao, Brief report: deletion of the dystrophin muscle-promoter region associated with Xlinked dilated cardiomyopathy, N. Engl. J. Med. 329, 921–925 (1993).PubMedCrossRefGoogle Scholar
  59. 59.
    E. E. Norgett, S. J. Hatsell, L. Carvajal-Huerta, J. C. Cabezas, J. Common, P. E. Purkis, N. Whittock, I. M. Leigh, H. P. Stevens, and D. P. Kelsell, Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma, Hum. Mol. Genet. 9, 2761–2766 (2000).PubMedCrossRefGoogle Scholar
  60. 60.
    T. M. Olson, S. Illenberger, N. Y. Kishimoto, S. Huttelmaier, M. T. Keating, and B. M. Jockusch, Metavinculin mutations alter actin interaction in dilated cardiomyopathy, Circulation 105(4), 431–437 (2002).PubMedCrossRefGoogle Scholar
  61. 61.
    B. Mohapatra, S. Jimenez, J. H. Lin, K. R. Bowles, K. J. Coveler, J. G. Marx, M. A. Chrisco, R. T. Murphy, P. R. Lurie, R. J. Schwartz, P. M. Elliott, M. Vatta, W. McKenna, J. A. Towbin, and N. E. Bowles, Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis, Mol. Genet. Metab. 80, 207–215 (2003).PubMedCrossRefGoogle Scholar
  62. 62.
    M. Vatta, B. Mohapatra, S. Jimenez, X. Sanchez, G. Faulkner, Z. Perles, G. Sinagra, J. H. Lin, T. M. Vu, Q. Zhou, K. R. Bowles, A. Di Lenarda, L. Schimmenti, M. Fox, M. A. Chrisco, R. T. Murphy, W. McKenna, P. Elliott, N. E. Bowles, J. Chen, G. Valle, and J. A. Towbin, Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction, J. Am. Coll. Cardiol. 42, 2014–2027 (2003).PubMedCrossRefGoogle Scholar
  63. 63.
    J. P. Schmitt, M. Kamisago, M. Asahi, G. H. Li, F. Ahmad, U. Mende, E. G. Kranias, D. H. MacLennan, J. G. Seidman, and C. E. Seidman, Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban, Science 299(5611), 1410–1413 (2003).PubMedCrossRefGoogle Scholar
  64. 64.
    M. Bienengraeber, T. M. Olson, V. A. Selivanov, E. C. Kathmann, F. O’Cochlain, F. Gao, A. B. Karger, J. D. Ballew, D. M. Hodgson, L. V. Zingman, Y. P. Pang, A. E. Alekseev, and A. Terzic, ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating, Nat. Genet. 36, 382–387 (2004).PubMedCrossRefGoogle Scholar
  65. 65.
    F. Ichida, S. Tsubata, K. R. Bowles, N. Haneda, K. Uese, T. Miyawaki, W. J. Dreyer, J. Messina, H. Li, N. E. Bowles, and J. A. Towbin, Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome, Circulation 103(9), 1256–1263 (2001).PubMedGoogle Scholar
  66. 66.
    R. Chen, T. Tsuji, F. Ichida, K. R. Bowles, X. Yu, S. Watanabe, K. Hirono, S. Tsubata, Y. Hamamichi, J. Ohta, Y. Imai, N. E. Bowles, T. Miyawaki, and J. A. Towbin, Mutation analysis of the G4.5 gene in patients with isolated left ventricular noncompaction, Mol. Genet. Metab. 77(4), 319–325 (2002).PubMedCrossRefGoogle Scholar
  67. 67.
    A. Suomalainen, A. Paetau, H. Leinonen, A. Majander, L. Peltonen, and H. Somer, Inherited idiopathic dilated cardiomyopathy with multiple deletions of mitochondrial DNA, Lancet 340, 1319–1320 (1992).PubMedCrossRefGoogle Scholar
  68. 68.
    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, 1108–1114 (1992).PubMedCrossRefGoogle Scholar
  69. 69.
    H. Watkins, W. J. McKenna, L. Thierfelder, H. J. Suk, R. Anan, A. O’Donoghue, P. Spirito, A. Matsumori, C. S. Moravec, C. Seidman, and J. G. Seidman, Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy, N. Engl. J. Med. 332, 1058–1064 (1995).PubMedCrossRefGoogle Scholar
  70. 70.
    A. Kumar, K. Crawford, L. Close, M. Madison, J. Lorenz, T. Doetschman, S. Pawlowski, J. Duffy, J. Neumann, J. Robbins, G. P. Boivin, B. A. O’Toole, and J. L. Lessard, Rescue of cardiac alpha-actin-deficient mice by enteric smooth muscle gamma-actin, Proc. Natl. Acad. Sci. USA 94, 4406–4411 (1997).PubMedCrossRefGoogle Scholar
  71. 71.
    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).PubMedGoogle Scholar
  72. 72.
    M. Muthuchamy, K. Pieples, P. Rethinasamy, B. Hoit, I. L. Grupp, G. P. Boivin, B. Wolska, C. Evans, R. J. Solaro, and D. F. Wieczorek, Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction, Circ. Res. 85, 47–56 (1999).PubMedGoogle Scholar
  73. 73.
    D. Burton, H. Abdulrazzak, A. Knott, K. Elliott, C. Redwood, H. Watkins, S. Marston, and C. Ashley, Two mutations in troponin I that cause hypertrophic cardiomyopathy have contrasting effects on cardiac muscle contractility, Biochem. J. 362 (Pt2), 443–451 (2002).PubMedCrossRefGoogle Scholar
  74. 74.
    K. Elliott, H. Watkins, and C. S. Redwood, Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy, J. Biol. Chem. 275(29), 22069–22074 (2000).PubMedCrossRefGoogle Scholar
  75. 75.
    A. Hinkle, and L. S. Tobacman, Folding and function of the troponin tail domain. Effects of cardiomyopathic troponin T mutations, J. Biol. Chem. 278, 506–513 (2003).PubMedCrossRefGoogle Scholar
  76. 76.
    R. Lang, A. V. Gomes, J. Zhao, P. R. Housmans, T. Miller, and J. D. Potter, Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy, J. Biol. Chem. 277(14), 11670–11678 (2002).PubMedCrossRefGoogle Scholar
  77. 77.
    S. Morimoto, Q. W. Lu, K. Harada, F. Takahashi-Yanaga, R. Minakami, M. Ohta, T. Sasaguri, and I. Ohtsuki, Ca(2+)-desensitizing effect of a deletion mutation Delta K210 in cardiac troponin T that causes familial dilated cardiomyopathy, Proc. Natl. Acad. Sci. USA 99(2), 913–918 (2002).PubMedCrossRefGoogle Scholar
  78. 78.
    Y. Nakamura, H. Suzuki, M. Sakaguchi, and K. Mihara, Targeting and assembly of rat mitochondrial translocase of outer membrane 22 (TOM22) into the TOM complex, J. Biol. Chem. 279, 21223–21232 (2004).PubMedCrossRefGoogle Scholar
  79. 79.
    C. Y. Hong, J. H. Park, R. S. Ahn, S. Y. Im, H. S. Choi, J. Soh, S. H. Mellon, and K. Lee, Molecular mechanism of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha, Mol. Cell. Biol. 24, 2593–2604 (2004).PubMedCrossRefGoogle Scholar
  80. 80.
    A. A. Hagege, O. Dubourg, M. Desnos, R. Mirochnik, G. Isnard, G. Bonne, L. Carrier, P. Guicheney, J. B. Bouhour, K. Schwartz, and M. Komajda, Familial hypertrophic cardiomyopathy. Cardiac ultrasonic abnormalities in genetically affected subjects without echocardiographic evidence of left ventricular hypertrophy, Eur. Heart J. 19, 490–499 (1998).PubMedCrossRefGoogle Scholar
  81. 81.
    J. Mogensen, I. C. Klausen, A. K. Pedersen, H. Egeblad, P. Bross, T. A. Kruse, N. Gregersen, P. S. Hansen, U. Baandrup, and A. D. Borglum, Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy, J. Clin. Invest. 103, R39–R43 (1999).PubMedCrossRefGoogle Scholar
  82. 82.
    P. Charron, O. Dubourg, M. Desnos, R. Isnard, A. Hagege, A. Millaire, L. Carrier, G. Bonne, F. Tesson, P. Richard, J. B. Bouhour, K. Schwartz, and M. Komajda, Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population, Circulation 96, 214–219 (1997).PubMedGoogle Scholar
  83. 83.
    L. Thierfelder, C. MacRae, H. Watkins, J. Tomfohrde, M. Williams, W. McKenna, K. Bohm, G. Noeske, M. Schlepper, A. Bowcock, H. Vosberg, J. G. Seidman, and C. Seidman, A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2, Proc. Natl. Acad. Sci. USA 90, 6270–6274 (1993).PubMedCrossRefGoogle Scholar
  84. 84.
    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, 333–337 (1993).PubMedCrossRefGoogle Scholar
  85. 85.
    W. J. McKenna, P. Spirito, M. Desnos, O. Dubourg, and M. Komajda, Experience from clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adult members of affected families, Heart 77, 130–132 (1997).PubMedGoogle Scholar
  86. 86.
    S. Morner, P. Richard, E. Kazzam, B. Hainque, K. Schwartz, and A. Waldenstrom, Deletion in the cardiac troponin I gene in a family from northern Sweden with hypertrophic cardiomyopathy, J. Mol. Cell Cardiol. 32(3), 521–525 (2000).PubMedCrossRefGoogle Scholar
  87. 87.
    S. Morner, P. Richard, E. Kazzam, U. Hellman, B. Hainque, K. Schwartz, and A. Waldenstrom, Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden, J. Mol. Cell. Cardiol. 35, 841–849 (2003).PubMedCrossRefGoogle Scholar
  88. 88.
    H. Kokado, M. Shimizu, H. Yoshio, H. Ino, K. Okeie, Y. Emoto, T. Matsuyama, M. Yamaguchi, T. Yasuda, N. Fujino, H. Ito, and H. Mabuchi, Clinical features of hypertrophic cardiomyopathy caused by a Lys183 deletion mutation in the cardiac troponin I gene, Circulation 102(6), 663–669 (2000).PubMedGoogle Scholar
  89. 89.
    J. Erdmann, S. Daehmlow, S. Wischke, M. Senyuva, U. Werner, J. Raible, N. Tanis, S. Dyachenko, M. Hummel, R. Hetzer, and V. Regitz-Zagrosek, Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy, Clin. Genet. 64(4), 339–349 (2003).PubMedCrossRefGoogle Scholar
  90. 90.
    S. L. Van Driest, E. G. Ellsworth, S. R. Ommen, A. J. Tajik, B. J. Gersh, and M. J. Ackerman, Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy, Circulation 108, 445–451 (2003).PubMedCrossRefGoogle Scholar
  91. 91.
    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, 1358–1362 (2003).PubMedCrossRefGoogle Scholar
  92. 92.
    M. J. Ackerman, S. L. VanDriest, S. R. Ommen, M. L. Will, R. A. Nishimura, A. J. Tajik, and B. J. Gersh, Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective, J. Am. Coll. Cardiol. 39, 2042–2048 (2002).PubMedCrossRefGoogle Scholar
  93. 93.
    D. S. Van, M. J. Ackerman, S. R. Ommen, R. Shakur, M. L. Will, R. A. Nishimura, A. J. Tajik, and B. J. Gersh, Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy, Circulation 106(24), 3085–3090 (2002).CrossRefGoogle Scholar
  94. 94.
    O. Havndrup, H. Bundgaard, P. S. Andersen, L. A. Larsen, J. Vuust, K. Kjeldsen, and M. Christiansen, The Val606Met mutation in the cardiac beta-myosin heavy chain gene in patients with familial hypertrophic cardiomyopathy is associated with a high risk of sudden death at young age, Am. J. Cardiol. 87, 1315–1317 (2001).PubMedCrossRefGoogle Scholar
  95. 95.
    J. Zhang, A. Kumar, H. J. Stalker, G. Virdi, V. J. Ferrans, K. Horiba, F. J. Fricker, and M. R. Wallace, Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy, Clin. Genet. 59, 248–256 (2001).PubMedCrossRefGoogle Scholar
  96. 96.
    E. Arbustini, P. Morbini, M. Grasso, R. Fasani, L. Verga, O. Bellini, B. Dal Bello, C. Campana, G. Piccolo, O. Febo, C. Opasich, A. Gavazzi, and V. J. Ferrans, Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits, J. Am. Coll. Cardiol. 31, 645–653 (1998).PubMedCrossRefGoogle Scholar
  97. 97.
    Y. Miyamoto, H. Akita, N. Shiga, E. Takai, C. Iwai, K. Mizutani, H. Kawai, A. Takarada, and M. Yokoyama, Frequency and clinical characteristics of dilated cardiomyopathy caused by desmin gene mutation in a Japanese population, Eur. Heart J. 22, 2284–2289 (2001).PubMedCrossRefGoogle Scholar
  98. 98.
    A. Kaminska, S. V. Strelkov, B. Goudeau, M. Olive, A. Dagvadorj, A. Fidzianska, M. Simon-Casteras, A. Shatunov, M. C. Dalakas, I. Ferrer, H. Kwiecinski, P. Vicart, and L. G. Goldfarb, Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy, Hum. Genet. 114, 306–313 (2004).PubMedCrossRefGoogle Scholar
  99. 99.
    S. Feld, and A. Caspi, Familial cardiomyopathy with variable hypertrophic and restrictive features and common HLA haplotype, Isr. J. Med. Sci. 28, 277–280 (1992).PubMedGoogle Scholar
  100. 100.
    J. Mogensen, T. Kubo, M. Duque, W. Uribe, A. Shaw, R. Murphy, J. R. Gimeno, P. Elliott, and W. J. McKenna, Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations, J. Clin. Invest. 111, 209–216 (2003).PubMedCrossRefGoogle Scholar
  101. 101.
    M. K. Baig, J. H. Goldman, A. L. Caforio, A. S. Coonar, P. J. Keeling, and W. J. McKenna, Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease, J. Am. Coll. Cardiol. 31, 195–201 (1897).CrossRefGoogle Scholar
  102. 102.
    B. M. Mayosi, S. Khogali, B. Zhang, and H. Watkins, Cardiac and skeletal actin gene mutations are not a common cause of dilated cardiomyopathy [letter], J. Med. Genet. 36, 796–797 (1999).PubMedGoogle Scholar
  103. 103.
    S. Karkkainen, K. Peuhkurinen, P. Jaaskelainen, R. Miettinen, P. Karkkainen, J. Kuusisto, and M. Laakso, No variants in the cardiac actin gene in Finnish patients with dilated or hypertrophic cardiomyopathy, Am. Heart J. 143(6), E6 (2002).PubMedCrossRefGoogle Scholar
  104. 104.
    E. Takai, H. Akita, N. Shiga, K. Kanazawa, S. Yamada, M. Terashima, Y. Matsuda, C. Iwai, K. Kawai, Y. Yokota, and M. Yokoyama, Mutational analysis of the cardiac actin gene in familial and sporadic dilated cardiomyopathy, Am. J. Med. Genet. 86, 325–327 (1999).PubMedCrossRefGoogle Scholar
  105. 105.
    B. L. Siu, H. Niimura, J. A. Osborne, D. Fatkin, C. MacRae, S. Solomon, D. W. Benson, J. G. Seidman, and C. E. Seidman, Familial dilated cardiomyopathy locus maps to chromosome 2q31, Circulation 99, 1022–1026 (1897).Google Scholar
  106. 106.
    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, R. Roberts, Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy, Circulation 104(18), 2188–2193 (2001).PubMedGoogle Scholar
  107. 107.
    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).PubMedCrossRefGoogle Scholar
  108. 108.
    P. Ray, H. Pimenta, R. Paulmurugan, F. Berger, M. E. Phelps, M. Iyer, and S. S. Gambhir, Noninvasive quantitative imaging of protein-protein interactions in living subjects, Proc. Natl. Acad. Sci. USA 99, 3105–3110 (2002).PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Jens Mogensen
    • 1
    • 2
  1. 1.Departments of CardiologySkejby University Hospital AarhusDenmark
  2. 2.The Heart HospitalUniversity College LondonUK

Personalised recommendations