How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?



In this article, the available evidence about the functional effects of the contractile protein mutations that cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) is assessed. The molecular mechanism of the contractile apparatus of cardiac muscle and its regulation by Ca2+ and PKA phosphorylation have been extensively studied. Therefore, when a number of point mutations in the contractile protein genes were found to cause the well-defined phenotypes of HCM and DCM, it was expected that the diseases could be explained at the molecular level. However, the search for a distinctive molecular phenotype did not yield rapid results. Now that a substantial number of mutations that cause HCM or DCM have been investigated in physiologically relevant systems and with a range of experimental techniques, a pattern is emerging. In the case of HCM, the hypothesis that the major effect of mutations is to increase myofibrillar Ca2+-sensitivity seems to be well established, but the mechanisms by which an increase in myofibrillar Ca2+-sensitivity induces hypertrophy remain obscure. In contrast, DCM mutations are not correlated with a specific effect on Ca2+-sensitivity. It has recently been proposed that DCM mutations uncouple troponin I phosphorylation from Ca2+-sensitivity changes, albeit based on only a few mutations so far. A plausible link between uncoupling and DCM has been proposed via blunting of the response to α-adrenergic stimulation.


Hypertrophic cardiomyopathy Dilated cardiomyopathy Mutation Genotype–phenotype links Thin filament Myosin Contractility Ca2+-regulation 



I am grateful to the British Heart Foundation for supporting the research reported in this article.


  1. 1.
    Geisterfer-Lowrance, A. A., Kass, S., Tanigawa, G., Vosberg, H. P., McKenna, W., Seidman, C. E., et al. (1990). A molecular basis for familial hypertrophic cardiomyopathy: A beta cardiac myosin heavy chain gene missense mutation. Cell, 62(5), 999–1006.PubMedCrossRefGoogle Scholar
  2. 2.
    Redwood, C. S., Moolman-Smook, J. C., & Watkins, H. (1999). Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy. Cardiovascular Research, 44, 20–36.PubMedCrossRefGoogle Scholar
  3. 3.
    Elliott, P., & McKenna, W. J. (2004). Hypertrophic cardiomyopathy. Lancet, 363, 1881–1891. doi: 10.1016/S0140-6736(04)16358-7.PubMedCrossRefGoogle Scholar
  4. 4.
    Kamisago, M., Sharma, S. D., DePalma, S. R., Solomon, S., Sharma, P., Smoot, L., et al. (2000). Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. The New England Journal of Medicine, 343(23), 1688–1696.PubMedCrossRefGoogle Scholar
  5. 5.
    Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., et al. (2004). Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. Journal of the American College of Cardiology, 44(10), 2033–2040.PubMedCrossRefGoogle Scholar
  6. 6.
    Moller, D. V., Andersen, P. S., Hedley, P., Ersboll, M. K., Bundgaard, H., Moolman-Smook, J., et al. (2009). The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy. European Journal of Human Genetics, 17, 1241–1249. doi: 10.1038/ejhg.2009.34.PubMedCrossRefGoogle Scholar
  7. 7.
    Fujino, N., Shimizu, M., Ino, H., Yamaguchi, M., Yasuda, T., Nagata, M., et al. (2002). A novel mutation Lys273Glu in the cardiac troponin T gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy. The American Journal of Cardiology, 89, 29–33.PubMedCrossRefGoogle Scholar
  8. 8.
    Copeland, O., Sadayappan, S., Messer, A. E., Stienen, G. J., Velden, J., & Marston, S. B. (2010). Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle. Journal of Molecular and Cellular Cardiology, 49, 1003–1011. doi: 10.1016/j.yjmcc.2010.09.007.PubMedCrossRefGoogle Scholar
  9. 9.
    Copeland, O., Nowak, K., Laing, N., Ravenscroft, G., Messer, A. E., Bayliss, C. R., et al. (2010). Investigation of changes in skeletal muscle alpha-actin expression in normal and pathological human and mouse hearts. Journal of Muscle Research and Cell Motility, 31, 207–214. doi: 10.1007/s10974-010-9224-7.PubMedCrossRefGoogle Scholar
  10. 10.
    Jacques, A., Briceno, N., Messer, A., Gallon, C., Jalizadeh, S., Garcia, E., et al. (2008). The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy. Cardiovascular Research, 79, 481–491. doi: 10.1093/cvr/cvn094.PubMedCrossRefGoogle Scholar
  11. 11.
    Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., et al. (2003). Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscular Disorders, 13(7–8), 519–531.PubMedCrossRefGoogle Scholar
  12. 12.
    Feng, J. J., & Marston, S. (2009). Genotype-phenotype correlations in ACTA1 mutations that cause congenital myopathies. Neuromuscular Disorder, 19(1), 6–16. doi: 10.1016/j.nmd.2008.09.005.CrossRefGoogle Scholar
  13. 13.
    Redwood, C., Lohmann, K., Bing, W., Esoposito, G., Elliott, K., Abdulrazzak, H., et al. (2000). Investigation of a truncated troponin T that causes familial hypertrophic cardiomyopathy: Ca2+ regulatory properties of reconstituted thin filaments depend on the ratio of mutant to wild-type peptide. Circulation Research, 86, 1146–1152.PubMedGoogle Scholar
  14. 14.
    Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., et al. (1998). A truncated troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophioc cardiomyopathy. Journal of Clinical Investigation, 101, 2800–2811.PubMedCrossRefGoogle Scholar
  15. 15.
    Van Driest, S. L., Vasile, V. C., Ommen, S. R., Will, M. L., Tajik, A. J., Gersh, B. J., et al. (2004). Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 44(9), 1903–1910.PubMedCrossRefGoogle Scholar
  16. 16.
    Rottbauer, W., Gautel, M., Zehelein, J., Labeit, S., Franz, W. M., Fischer, C., et al. (1997). Novel splice donor site mutation in the cardiac myosin-binding protein-C gene in familial hypertrophic cardiomyopathy. Characterization of cardiac transcript and protein. Journal of Clinical Investigation, 100(2), 475–482.PubMedCrossRefGoogle Scholar
  17. 17.
    Moolman, J. A., Reith, S., Uhl, K., Bailey, S., Gautel, M., Jeschke, B., et al. (2000). A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance. Circulation, 101(12), 1396–1402.PubMedGoogle Scholar
  18. 18.
    Marston, S., Copeland, O., Jacques, A., Livesey, K., Tsang, V., McKenna, W. J., et al. (2009). Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circulation Research, 105(3), 219–222.PubMedCrossRefGoogle Scholar
  19. 19.
    Jacques, A., Hoskins, A., Kentish, J., & Marston, S. B. (2009). From genotype to phenotype: A longitudinal study of a patient with hypertrophic cardiomyopathy due to a mutation in the MYBPC3 gene. Journal of Muscle Research and Cell Motility, 29(6–8), 231–238. doi: 10.1007/s10974-009-9174-0.Google Scholar
  20. 20.
    Van Dijk, S., Dooijes, D., Dos Remedios, C., Michels, M., Lamers, J., Winegrad, S., et al. (2009). Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy. Haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. Circulation, 119, 1473–1483. doi: 10.1161/CIRCULATIONAHA.108.838672.PubMedCrossRefGoogle Scholar
  21. 21.
    Harris, S. P., Bartley, C. R., Hacker, T. A., McDonald, K. S., Douglas, P. S., Greaser, M. L., et al. (2002). Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circulation Research, 90(5), 594–601.PubMedCrossRefGoogle Scholar
  22. 22.
    Cuda, G., Fananazapir, L., Zhu, W. S., Sellers, J. R., & Epstein, N. D. (1993). Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiopmyopathy. Journal of Clinical Investigation, 91, 2861–2865.PubMedCrossRefGoogle Scholar
  23. 23.
    Sata, M., & Ikebe, M. (1996). Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome. Journal of Clinical Investigation, 98(12), 2866–2873.PubMedCrossRefGoogle Scholar
  24. 24.
    Fujita, H., Sugiura, S., Monomura, S., Omata, M., Sugi, H., & Sutoh, K. (1997). Characterization of mutant myosins of Dictiostelium discoideum equivalent to human familial hypertrophic cardiomyopathy. Journal of Clinical Investigation, 99, 1010–1015.PubMedCrossRefGoogle Scholar
  25. 25.
    Palmiter, K. A., Tyska, M. J., Haeberle, J. R., Alpert, N. R., Fananapazir, L., & Warshaw, D. M. (2000). R403Q and L908V mutant beta-cardiac myosin from patients with familial hypertrophic cardiomyopathy exhibit enhanced mechanical performance at the single molecule level. Journal of Muscle Research and Cell Motility, 21(7), 609–620.PubMedCrossRefGoogle Scholar
  26. 26.
    Tyska, M. J., Hayes, E., Giewat, M., Seidman, C. E., Seidman, J. G., & Warshaw, D. M. (2000). Single molecule mechanics of R403Q cardiac myosin isolated from mouse model of familial hypertrophic cardiomyopathy. Circulation Research, 86, 737–744.PubMedGoogle Scholar
  27. 27.
    Belus, A., Piroddi, N., Scellini, B., Tesi, C., Amati, G. D., Girolami, F., et al. (2008). The familial hypertrophic cardiomyopathy-associated myosin mutation R403Q accelerates tension generation and relaxation of human cardiac myofibrils. Journal de Physiologie, 586(Pt 15), 3639–3644.Google Scholar
  28. 28.
    Sivaramakrishnan, S., Ashley, E., Leinwand, L., & Spudich, J. (2009). Insights into human β-cardiac myosin function from single molecule and single cell studies. Journal of Cardiovascular Translational Research, 2(4), 426–440. doi: 10.1007/s12265-009-9129-2.PubMedCrossRefGoogle Scholar
  29. 29.
    Blanchard, E., Seidman, C., Seidman, J. G., LeWinter, M., & Maughan, D. (1999). Altered crossbridge kinetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. Circulation Research, 84(4), 475–483.PubMedGoogle Scholar
  30. 30.
    Palmer, B. M., Fishbaugher, D. E., Schmitt, J. P., Wang, Y., Alpert, N. R., Seidman, C. E., et al. (2004). Differential cross-bridge kinetics of FHC myosin mutations R403Q and R453C in heterozygous mouse myocardium. American Journal of Physiology. Heart and Circulatory Physiology, 287(1), H91–H99.PubMedCrossRefGoogle Scholar
  31. 31.
    Flashman, E., Redwood, C., Moolman-Smook, J., & Watkins, H. (2004). Cardiac myosin binding protein C: Its role in physiology and disease. Circulation Research, 94(10), 1279–1289.PubMedCrossRefGoogle Scholar
  32. 32.
    Barefield, D., & Sadayappan, S. (2010). Phosphorylation and function of cardiac myosin binding protein-C in health and disease. Journal of Molecular and Cellular Cardiology, 48(5), 866–875. doi: 10.1016/j.yjmcc.2009.11.014.PubMedCrossRefGoogle Scholar
  33. 33.
    Seidman, J. G., & Seidman, C. (2001). The genetic basis for cardiomyopathy: From mutation identification to mechanistic paradigms. Cell, 104(4), 557–567.PubMedCrossRefGoogle Scholar
  34. 34.
    Dong, W., Xing, J., Ouyang, Y., An, J., & Cheung, H. C. (2008). Structural kinetics of Cardiac troponin C mutants linked to familial hypertrophic and dilated cardiomyopathy in troponin complexes. The Journal of Biological Chemistry, 283(6), 3424–3432.PubMedCrossRefGoogle Scholar
  35. 35.
    Kerrick, W. G., Kazmierczak, K., Xu, Y., Wang, Y., & Szczesna-Cordary, D. (2009). Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice. The FASEB Journal, 23, 855–865. doi: 10.1096/fj.08-118182.PubMedCrossRefGoogle Scholar
  36. 36.
    Sich, N. M., O'Donnell, T. J., Coulter, S. A., John, O. A., Carter, M. S., Cremo, C. R., et al. (2010). Effects of actin-myosin kinetics on the calcium sensitivity of regulated thin filaments. The Journal of Biological Chemistry. doi: 10.1074/jbc.M110.142232.PubMedGoogle Scholar
  37. 37.
    Shaffer, J. F., Razumova, M. V., Tu, A. Y., Regnier, M., & Harris, S. P. (2007). Myosin S2 is not required for effects of myosin binding protein-C on motility. FEBS Letters, 581(7), 1501–1504.PubMedCrossRefGoogle Scholar
  38. 38.
    Hoskins, A. C., Jacques, A., Bardswell, S. C., McKenna, W. J., Tsang, V., Remedios, C., et al. (2010). Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology, 49, 737–745. doi: 10.1016/j.yjmcc.2010.06.006.PubMedCrossRefGoogle Scholar
  39. 39.
    Kulikovskaya, I., McClellan, G., Levine, R., & Winegrad, S. (2003). Effect of extraction of myosin binding protein C on contractility of rat heart. American Journal of Physiology. Heart and Circulatory Physiology, 285(2), H857–H865.PubMedGoogle Scholar
  40. 40.
    Gao, W. D., Perez, N. G., Seidman, C. E., Seidman, J. G., & Marban, E. (1999). Altered cardiac excitation-contraction coupling in mutant mice with familial hypertrophic cardiomyopathy. Journal of Clinical Investigation, 103(5), 661–666.PubMedCrossRefGoogle Scholar
  41. 41.
    Baudenbacher, F., Schober, T., Pinto, J. R., Sidorov, V. Y., Hilliard, F., Solaro, R. J., et al. (2008). Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. Journal of Clinical Investigation, 118(12), 3893–3903.PubMedGoogle Scholar
  42. 42.
    Haim, T. E., Dowell, C., Diamanti, T., Scheuer, J., & Tardiff, J. C. (2007). Independent FHC-related cardiac troponin T mutations exhibit specific alterations in myocellular contractility and calcium kinetics. Journal of Molecular and Cellular Cardiology, 42(6), 1098–1110.PubMedCrossRefGoogle Scholar
  43. 43.
    Kulkarni, P. A., Sano, M., & Schneider, M. D. (2004). Phosphorylation of RNA polymerase II in cardiac hypertrophy: Cell enlargement signals converge on cyclin T/Cdk9. Recent Progress in Hormone Research, 59, 125–139.PubMedCrossRefGoogle Scholar
  44. 44.
    Ashrafian, H., Redwood, C., Blair, E., & Watkins, H. (2003). Hypertrophic cardiomyopathy: A paradigm for myocardial energy depletion. Trends in Genetics, 19(5), 263–268.PubMedCrossRefGoogle Scholar
  45. 45.
    Montgomery, D. E., Tardiff, J. C., & Chandra, M. (2001). Cardiac troponin T mutations: Correlation between the type of mutation and the nature of myofilament dysfunction in transgenic mice. Journal de Physiologie, 536(Pt 2), 583–592.CrossRefGoogle Scholar
  46. 46.
    Crilley, J. G., Boehm, E. A., Blair, E., Rajagopalan, B., Blamire, A. M., Styles, P., et al. (2003). Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. Journal of the American College of Cardiology, 41(10), 1776–1782.PubMedCrossRefGoogle Scholar
  47. 47.
    Knoell, R., Postel, R., Wang, J., Kraetzner, R., Hennecke, G., Vacaru, A. M., et al. (2007). Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation, 116, 515–525. doi: 10.1161/CIRCULATIONAHA.107.689984.CrossRefGoogle Scholar
  48. 48.
    Knoell, R., Kostin, S., Klede, S., Savvatis, K., Klinge, L., Stehle, I., et al. (2010). A common MLP (muscle LIM protein) variant is associated with cardiomyopathy. Circulation Research, 106, 695–704. doi: 10.1161/CIRCRESAHA.109.206243.CrossRefGoogle Scholar
  49. 49.
    Knoell, R., Hoshijima, M., Hoffman, H. M., Person, V., Lorenzen-Schmidt, I., Bang, M. L., et al. (2002). The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell, 111, 943–955.CrossRefGoogle Scholar
  50. 50.
    Li, D., Tapscoft, T., Gonzalez, O., Burch, P. E., Quinones, M. A., Zoghbi, W. A., et al. (1999). Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation, 100(5), 461–464.PubMedGoogle Scholar
  51. 51.
    Olson, T. M., Michels, V. V., Thibodeau, S. N., Tai, Y. S., & Keating, M. T. (1998). Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science, 280(5364), 750–752.PubMedCrossRefGoogle Scholar
  52. 52.
    Robinson, P., Mirza, M., Knott, A., Abdulrazzak, H., Willott, R., Marston, S., et al. (2002). 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. The Journal of Biological Chemistry, 277, 40710–40716.PubMedCrossRefGoogle Scholar
  53. 53.
    Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., et al. (2005). Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. The Journal of Biological Chemistry, 280, 28498–28506.PubMedCrossRefGoogle Scholar
  54. 54.
    Robinson, P., Griffiths, P. J., Watkins, H., & Redwood, C. S. (2007). Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. Circulation Research, 101(12), 1266–1273.PubMedCrossRefGoogle Scholar
  55. 55.
    \Dyer, E., Jacques, A., Hoskins, A., Ward, D., Gallon, C., Messer, A., et al. (2009). Functional analysis of a unique troponin C mutation, Gly159Asp that causes familial dilated cardiomyopathy, studied in explanted heart muscle. Circulation: Heart Failure, 2, 456–464. doi: 10.1161/CIRCHEARTFAILURE.108.818237.CrossRefGoogle Scholar
  56. 56.
    Song, W., Dyer, E., Stuckey, D., Leung, M.-C., Memo, M., Mansfield, C., et al. (2010). Investigation of a transgenic mouse model of familial dilated cardiomyopathy. Journal of Molecular and Cellular Cardiology, 49, 380–389. doi: 10.1016/j.yjmcc.2010.05.009.PubMedCrossRefGoogle Scholar
  57. 57.
    Messer, A., Gallon, C., McKenna, W., Elliott, P., Dos Remedios, C., & Marston, S. (2009). The use of phosphate-affinity SDS-PAGE to measure the troponin I phosphorylation site distribution in human heart muscle. Proteomics - Clinical Application, 3, 1371–1382. doi: 10.1002/prca.200900071.Google Scholar
  58. 58.
    Hayashi, T., Arimura, T., Itoh-Satoh, M., Ueda, K., Hohda, S., Inagaki, N., et al. (2004). Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. Journal of the American College of Cardiology, 44, 2192–2201. doi: 10.1016/j.jacc.2004.08.058.PubMedCrossRefGoogle Scholar
  59. 59.
    Nier, V., Schultz, I., Brenner, B., Forssmann, W., & Raida, M. (1999). Variability in the ratio of mutant to wildtype myosin heavy chain present in the soleus muscle of patients with familial hypertrophic cardiomyopathy. A new approach for the quantification of mutant to wildtype protein. FEBS Letters, 461(3), 246–252.PubMedCrossRefGoogle Scholar
  60. 60.
    Malinchik, S., Cuda, G., Podolsky, R. J., & Horowits, R. (1997). Isometric tension and mutant myosin heavy chain content in single skeletal myofibers from hypertrophic cardiomyopathy patients. Journal of Molecular and Cellular Cardiology, 29(2), 667–676.PubMedCrossRefGoogle Scholar
  61. 61.
    Song, W., Stuckey, D. J., Dyer, E., Wells, D., Harding, S. E., Carr, C. A., et al. (2009). Mouse HCM model expression E99K ACTC mutation reproduces the clinical HCM phenotype. The Journal of General Physiology, 134, 15a.CrossRefGoogle Scholar
  62. 62.
    Bottinelli, R., Coviello, D. A., Redwood, C. S., Pellegrino, M. A., Maron, B. J., Spirito, P., et al. (1998). A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. Circulation Research, 82, 106–115.PubMedGoogle Scholar
  63. 63.
    Debold, E. P., Saber, W., Cheema, Y., Bookwalter, C. S., Trybus, K. M., Warshaw, D. M., et al. (2010). Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro. Journal of Molecular and Cellular Cardiology, 48(2), 286–292. doi: 10.1016/j.yjmcc.2009.09.014.PubMedCrossRefGoogle Scholar
  64. 64.
    Szczesna-Cordary, D., Guzman, G., Ng, S. S., & Zhao, J. (2004). Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction. The Journal of Biological Chemistry, 279, 3535–3542. doi: 10.1074/jbc.M307092200.PubMedCrossRefGoogle Scholar
  65. 65.
    Yamashita, H., Tyska, M. J., Warshaw, D. M., Lowey, S., & Trybus, K. M. (2000). Functional consequences of mutations in the smooth muscle myosin heavy chain at sites implicated in familial hypertrophic cardiomyopathy. The Journal of Biological Chemistry, 275, 28045–28052. doi: 10.1074/jbc.M005485200.PubMedGoogle Scholar
  66. 66.
    Elliott, K., Watkins, H., & Redwood, C. S. (2000). Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy. The Journal of Biological Chemistry, 275(29), 22069–22074.PubMedCrossRefGoogle Scholar
  67. 67.
    Takahashi-Yanaga, F., Morimoto, S., Harada, K., Minakami, R., Shiraishi, F., Ohta, M., et al. (2001). Functional consequences of the mutations in human cardiac troponin I gene found in familial hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology, 33, 2095–2107. doi: 10.1006/jmcc.2001.1473.PubMedCrossRefGoogle Scholar
  68. 68.
    Redwood CS, Lohmann K, Marston SB, Knott A, Purcell I, Esposito G et al. (2000) Ca2+ regulatory properties of a truncated troponin T that causes FHC depend on the ratio of mutant to wild-type peptide. Circulation Research, 86, 1146–1152.Google Scholar
  69. 69.
    Szczesna, D., Zhang, R., Zhao, J., Jones, M., Guzman, G., & Jd, P. (2000). Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. The Journal of Biological Chemistry, 275(1), 624–630.PubMedCrossRefGoogle Scholar
  70. 70.
    Lu, Q. W., Morimoto, S., Harada, K., Du, C. K., Takahashi-Yanaga, F., Miwa, Y., et al. (2003). Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca(2+) desensitization. Journal of Molecular and Cellular Cardiology, 35(12), 1421–1427.PubMedCrossRefGoogle Scholar
  71. 71.
    Heller, M. J., Nili, M., Homsher, E., & Tobacman, L. S. (2003). Cardiomyopathic tropomyosin mutations that increase thin filament Ca2+ sensitivity and tropomyosin N-domain flexibility. The Journal of Biological Chemistry, 278(43), 41742–41748.PubMedCrossRefGoogle Scholar
  72. 72.
    Bing, W., Knott, A., Redwood, C., Esposito, G., Purcell, I., Watkins, H., et al. (2000). Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha-tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay. Journal of Molecular and Cellular Cardiology, 32, 1489–1498.PubMedCrossRefGoogle Scholar
  73. 73.
    Muthuchamy, M., Pieples, K., Rethinasamy, P., Hoit, B., Grupp, I. L., Boivin, G. P., et al. (1999). Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction. Circulation Research, 85(1), 47–56.PubMedGoogle Scholar
  74. 74.
    Daehmlow, S., Erdmann, J., Knueppel, T., Gille, C., Froemmel, C., Hummel, M., et al. (2002). Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochemical and Biophysical Research Communications, 298, 116–120.PubMedCrossRefGoogle Scholar
  75. 75.
    Schmitt, J. P., Kamisago, M., Asahi, M., Li, G. H., Ahmad, F., Mende, U., et al. (2003). Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science, 299(5611), 1410–1413.PubMedCrossRefGoogle Scholar
  76. 76.
    Villard, E., Duboscq-Bidot, L., Charron, P., Benaiche, A., Conraads, V., Sylvius, N., et al. (2005). Mutation screening in dilated cardiomyopathy: Prominent role of the beta myosin heavy chain gene. European Heart Journal, 26, 794–803. doi: 10.1093/eurheartj/ehi193.PubMedCrossRefGoogle Scholar
  77. 77.
    Nanni, L., Pieroni, M., Chimenti, C., Simionati, B., Zimbello, R., Maseri, A., et al. (2003). Hypertrophic cardiomyopathy: Two homozygous cases with “typical” hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. Biochemical and Biophysical Research Communications, 309, 391–398. doi: 10.1016/j.bbrc.2003.08.014.PubMedCrossRefGoogle Scholar
  78. 78.
    Stefanelli, C. B., Rosenthal, A., Borisov, A. B., Ensing, G. J., & Russell, M. W. (2004). Novel troponin T mutation in familial dilated cardiomyopathy with gender-dependant severity. Molecular Genetics and Metabolism, 83(1–2), 188–196.PubMedCrossRefGoogle Scholar
  79. 79.
    Matsumoto, F., Maeda, K., Chatake, T., Maéda, Y., & Fujiwara, S. (2009). Functional aberration of myofibrils by cardiomyopathy-causing mutations in the coiled-coil region of the troponin-core domain. Biochemical and Biophysical Research Communications, 382(1), 205–209. doi: 10.1016/j.bbrc.2009.03.009.PubMedCrossRefGoogle Scholar
  80. 80.
    Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D., de Jonge, N., et al. (2009). Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy. Circulation Research, 105(4), 375–382.PubMedCrossRefGoogle Scholar
  81. 81.
    Olson, T. M., Kishimoto, N. Y., Whitby, F. G., & Michels, V. V. (2001). Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. Journal of Molecular and Cellular Cardiology, 33(4), 723–732.PubMedCrossRefGoogle Scholar
  82. 82.
    Rajan, S., Ahmed, R. P., Jagatheesan, G., Petrashevskaya, N., Boivin, G. P., Urboniene, D., et al. (2007). Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity. Circulation Research, 101(2), 205–214.PubMedCrossRefGoogle Scholar
  83. 83.
    Lakdawala, N. K., Dellefave, L., Redwood, C. S., Sparks, E., Cirino, A. L., Depalma, S., et al. (2010). Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: The distinctive natural history of sarcomeric dilated cardiomyopathy. Journal of the American College of Cardiology, 55, 320–329. doi: 10.1016/j.jacc.2009.11.017.PubMedCrossRefGoogle Scholar
  84. 84.
    Richard, P., Charron, P., Carrier, L., Ledeuil, C., Cheav, T., Pichereau, C., et al. (2003). Hypertrophic cardiomyopathy distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation, 107, 2227–2232.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.NHLIImperial College LondonLondonUK

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