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Sarcomeric Protein Mutations in Dilated Cardiomyopathy

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Abstract

This review aims to provide a concise summary of the DCM associated mutations identified in the proteins of the sarcomere and cytoskeleton, and discuss the reported effects of the mutations, as determined by functional studies, and in relation to the known structure of the protein affected. The mechanisms by which single missense mutations in the proteins of the sarcomere can lead to similar diseases as those caused by mutations in the proteins of the sarcolemma and cytoskeleton, are still unknown. However, a wide variety of mutations being associated with DCM suggests a complex mechanism shared by the proteins affected. The DCM mutations reviewed here are those of the β-myosin heavy chain (β-MHC), myosin binding protein-C (MyBP-C), actin, α- tropomyosin (Tm), troponin T (TnT), troponin I (TnI), troponin C (TnC), of the sarcomere, and titin, T-cap, desmin, vinculin, and muscle LIM protein (MLP) of the cytoskeleton.

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Abbreviations

DCM:

Dilated cardiomyopathy

Tn:

troponin

β-MHC:

beta-myosin heavy chain

cMyBP-C:

cardiac myosin binding protein-C

Tm:

tropomyosin

MLP:

muscle LIM protein

HCM:

hypertrophic cardiomyopathy

PKC:

protein kinase C

MMP:

matrix metalloproteinase

References

  1. Richardson P, et al., Report of the 1995 world health organization/international society and federation of cardiology task force on the definition and classification of cardiomyopathies. Circulation 1996;93(5):841–842.

    Google Scholar 

  2. Kamisago M, et al., Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000;343(23):1688–1696.

    Article  CAS  PubMed  Google Scholar 

  3. Mestroni L, et al., Familial dilated cardiomyopathy: Evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol 1999;34(1):181–190.

    Article  CAS  PubMed  Google Scholar 

  4. Harada K, Potter JD. 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 2004;279(15):14488–14495.

    Article  CAS  PubMed  Google Scholar 

  5. Knollmann BC, et al., Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy. J Biol Chem 2001;276(13):10039–10048.

    Article  CAS  PubMed  Google Scholar 

  6. Szczesna D, et al., Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. J Biol Chem 2000;275(1):624–630.

    Article  CAS  PubMed  Google Scholar 

  7. Venkatraman G, et al., Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform. J Biol Chem, 2004.

  8. Venkatraman G, et al., Different functional properties of troponin T mutants that cause dilated cardiomyopathy. J Biol Chem 2003;278(43):41670–41676.

    Article  CAS  PubMed  Google Scholar 

  9. Daehmlow S, et al., Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochem Biophys Res Commun 2002;298(1):116–120.

    Article  CAS  PubMed  Google Scholar 

  10. Nanni L, et al., Hypertrophic cardiomyopathy: Two homozygous cases with “typical” hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. Biochem Biophys Res Commun 2003;309(2):391–398.

    Article  CAS  PubMed  Google Scholar 

  11. Villard E, et al., Mutation screening in dilated cardiomyopathy: Prominent role of the beta myosin heavy chain gene. Eur Heart J 2005;26(8):794–803.

    Article  CAS  PubMed  Google Scholar 

  12. Karkkainen S, et al., Two novel mutations in the beta-myosin heavy chain gene associated with dilated cardiomyopathy. Eur J Heart Fail 2004;6(7):861–868.

    CAS  PubMed  Google Scholar 

  13. Hartzell HC, Sale WS. Structure of C protein purified from cardiac mus cle. J Cell Biol 1985;100(1):208–215.

    Article  CAS  PubMed  Google Scholar 

  14. Swan RC, Fischman DA. Electron microscopy of C-protein molecules from chicken skeletal muscle. J Muscle Res Cell Motil 1986;7(2):160–166.

    Article  CAS  PubMed  Google Scholar 

  15. Gautel M, et al., Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: A modulator of cardiac contraction? Embo J 1995;14(9):1952–1960.

    CAS  PubMed  Google Scholar 

  16. Weisberg A, Winegrad S. Alteration of myosin cross bridges by phosphorylation of myosin-binding protein C in cardiac muscle. Proc Natl Acad Sci USA, 1996. 93(17):8999–9003.

    Google Scholar 

  17. Harris SP, et al., Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res 2002;90(5):594–601.

    Article  CAS  PubMed  Google Scholar 

  18. Konno T, et al., A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients. J Am Coll Cardiol 2003;41(5):781–786.

    Article  CAS  PubMed  Google Scholar 

  19. Shimizu M, et al., Gene mutations in adult Japanese patients with dilated cardiomyopathy. Circ J 2005;69(2):150–153.

    Article  CAS  PubMed  Google Scholar 

  20. Rayment I, et al., Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. Proc Natl Acad Sci USA, 1995;92(9):3864–3868.

    CAS  PubMed  Google Scholar 

  21. Olson TM, et al., Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 1998;280(5364):750–752.

    Article  CAS  PubMed  Google Scholar 

  22. Geeves MA, Holmes KC. Structural mechanism of muscle contraction. Annu Rev Biochem, 1999;68:687–728.

    Google Scholar 

  23. Olson TM, et al., Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J Mol Cell Cardiol, 2001;33(4):723–732.

    Article  CAS  PubMed  Google Scholar 

  24. Regitz-Zagrosek V, et al., Novel mutation in the alpha-tropomyosin gene and transition from hypertrophic to hypocontractile dilated cardiomyopathy. Circulation 2000;102(17):E112–E116.

    CAS  PubMed  Google Scholar 

  25. Golitsina N, et al., Effects of two familial hypertrophic cardiomyopathy- causing mutations on alpha-tropomyosin structure and function. Biochemistry 1997;36(15):4637–4642.

    Article  CAS  PubMed  Google Scholar 

  26. Golitsina N, et al., Effects of two familial hypertrophic cardiomyopathy- causing mutations on alpha-tropomyosin structure and function. Biochemistry 1999;38(12):3850.

    Google Scholar 

  27. Prabhakar R, et al., A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol 2001;33(10):1815–1528.

    Article  CAS  PubMed  Google Scholar 

  28. Bing W, et al., 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. J Mol Cell Cardiol 2000;32(8):1489–1498.

    Article  CAS  PubMed  Google Scholar 

  29. Wernicke D, et al., alpha-Tropomyosin mutations Asp(175)Asn and Glu(180)Gly affect cardiac function in transgenic rats in different ways. Am J Physiol Regul Integr Comp Physiol 2004;287(3):R685–R695.

    CAS  PubMed  Google Scholar 

  30. Gomes AV, Potter JD. Molecular and cellular aspects of troponin cardiomyopathies. Ann N Y Acad Sci 2004;1015:214–224.

    Article  CAS  PubMed  Google Scholar 

  31. Potter JD, Sheng Z, Pan B, Zhao J. A direct regulatory role for troponin T and a dual role for troponin C in the Ca2+ regulation of muscle contraction. The Journal of Biological Chemistry 1995;270(6):2557–2562.

    CAS  PubMed  Google Scholar 

  32. Zhang R, et al., Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation. Circ Res, 1995;76(6):1028–1035.

    CAS  PubMed  Google Scholar 

  33. Zhang R, Zhao J, Potter JD. Phosphorylation of both serine residues in cardiac troponin I is required to decrease the Ca2+ affinity of cardiac troponin C. J Biol Chem 1995;270(51):30773–30780.

    Article  CAS  PubMed  Google Scholar 

  34. Noland TA, Jr., et al., Cardiac troponin I mutants. Phosphorylation by protein kinases C and A and regulation of Ca(2+)-stimulated MgATPase of reconstituted actomyosin S-1. J Biol Chem 1995;270(43):25445–25454.

    Google Scholar 

  35. Noland TA, Jr, et al., Differential regulation of cardiac actomyosin S-1 MgATPase by protein kinase C isozyme-specific phosphorylation of specific sites in cardiac troponin I and its phosphorylation site mutants. Biochemistry 1996;35(47):14923–14931.

    Article  CAS  PubMed  Google Scholar 

  36. Noland TA, Jr, Raynor RL, Kuo JF. Identification of sites phosphorylated in bovine cardiac troponin I and troponin T by protein kinase C and comparative substrate activity of synthetic peptides containing the phosphorylation sites. J Biol Chem 1989;264(34):20778–20785.

    CAS  PubMed  Google Scholar 

  37. Bowling N, et al., Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation 1999;99(3):384–391.

    CAS  PubMed  Google Scholar 

  38. Sumandea MP, et al., Molecular and integrated biology of thin filament protein phosphorylation in heart muscle. Ann N Y Acad Sci 2004;1015:39–52.

    Article  CAS  PubMed  Google Scholar 

  39. Noguchi T, et al., Thin-filament-based modulation of contractile performance in human heart failure. Circulation 2004;110(8):982–987.

    Article  PubMed  Google Scholar 

  40. Gomes AV, Harada K, Potter JD. A mutation in the N-terminus of Troponin I that is associated with hypertrophic cardiomyopathy affects the Ca2+ sensitivity, phosphorylation kinetics and proteolytic susceptibility of troponin. Journal of Molecular and Cellular Cardiology, 2005, in press.

  41. Bodor GS, et al., Troponin I phosphorylation in the normal and failing adult human heart. Circulation, 1997;96(5):1495–1500.

    CAS  PubMed  Google Scholar 

  42. Wattanapermpool J, Guo X, Solaro RJ. The unique amino-terminal peptide of cardiac troponin I regulates myofibrillar activity only when it is phosphorylated. J Mol Cell Cardiol 1995;27(7):1383–1391.

    Article  CAS  PubMed  Google Scholar 

  43. Fujino N, et al., Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy. Clin Cardiol 2001;24(5):397–402.

    CAS  PubMed  Google Scholar 

  44. Fujino N, et al., A novel mutation Lys273Glu in the cardiac troponin T gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy. Am J Cardiol 2002;89(1):29–33.

    Article  CAS  PubMed  Google Scholar 

  45. Mogensen J, et al., Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2004;44(10):2033–2040.

    Article  CAS  PubMed  Google Scholar 

  46. Li D, et al., Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation 2001;104(18):2188–2193.

    CAS  PubMed  Google Scholar 

  47. Stefanelli CB, et al., Novel troponin T mutation in familial dilated cardiomyopathy with gender-dependant severity. Mol Genet Metab 2004;83(1/2):188–196.

    CAS  PubMed  Google Scholar 

  48. Morimoto S, Lu QW, Harada K, Takahashi-Yanaga F, Minakami R, Ohta M, Sasaguri T, Ohtsuki I. Ca2+-desensitizing effect of a deletion mutation deltaK210 in cardiac troponin T that causes familial dilated cardiomyopathy. PNAS 2002;99(2):913–918.

    Article  CAS  PubMed  Google Scholar 

  49. Murphy RT, et al., Novel mutation in cardiac troponin I in recessive idiopath ic dilated cardiomyopathy. Lancet 2004;363(9406):371–372.

    Article  CAS  PubMed  Google Scholar 

  50. Gregorio CC, et al., The NH2 terminus of titin spans the Z-disc: its interaction with a novel 19-kD ligand (T-cap) is required for sarcomeric integrity. J Cell Biol 1998;143(4):1013–1027.

    Article  CAS  PubMed  Google Scholar 

  51. Sorimachi H, et al., Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: Implications for the nature of vertebrate Z-discs. J Mol Biol 1997;270(5):688–695.

    Article  CAS  PubMed  Google Scholar 

  52. Makarenko I, et al., Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res 2004;95(7):708–716.

    Article  CAS  PubMed  Google Scholar 

  53. Zou P, et al., Solution scattering suggests cross-linking function of telethon in in the complex with titin. J Biol Chem 2003;278(4):2636–2644.

    Article  CAS  PubMed  Google Scholar 

  54. Itoh-Satoh M, et al., Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem Biophys Res Commun 2002;291(2):385–393.

    Article  CAS  PubMed  Google Scholar 

  55. Granzier H, Labeit S. Cardiac titin: An adjustable multi-functional spring . J Physiol 2002;541(Pt 2):335–342.

    CAS  PubMed  Google Scholar 

  56. Arber S, et al., MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 1997;88(3):393–403.

    Article  CAS  PubMed  Google Scholar 

  57. Knoll R, et al., The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 2002;111(7):943–955.

    Article  CAS  PubMed  Google Scholar 

  58. Mohapatra B, et al., Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Mol Genet Metab 2003;80(1/2):207–215.

    CAS  PubMed  Google Scholar 

  59. Hayashi T, et al., Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol, 2004;44(11):2192–2201.

    Article  CAS  PubMed  Google Scholar 

  60. Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci USA, 2000;97(26):14632–14637.

    CAS  PubMed  Google Scholar 

  61. Milner DJ, et al., Disruption of muscle architecture and myocardial degenerat ion in mice lacking desmin. J Cell Biol 1996;134(5):1255–1270.

    Article  CAS  PubMed  Google Scholar 

  62. Olson TM, et al., Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation 2002;105(4):431–437.

    Article  CAS  PubMed  Google Scholar 

  63. Epstein ND, Davis JS. Sensing stretch is fundamental. Cell 2003;112(2):147–150.

    Article  CAS  PubMed  Google Scholar 

  64. Wang W, et al., Intracellular action of matrix metall- oproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 2002;106(12):1543–1549.

    CAS  PubMed  Google Scholar 

  65. Sariahmetogly M, Skrzypiec M, Leon H, Sawicka J, Holmes C, Berthiamume GS, Sawicki G, Schulz R. Phosphorylation status of matrix metalloproteinase-2 and potential role in myocardial ischemia-reperfusion injury. Circulation 2004;110(17):III–267.

    Google Scholar 

  66. Li YY, et al., Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 2001;104(10):1147–1152.

    CAS  PubMed  Google Scholar 

  67. Spinale FG, et al., A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 2000;102(16):1944–1949.

    CAS  PubMed  Google Scholar 

  68. Gerull B, et al., Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 2002;30(2):201–204.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to James D. Potter Ph.D.

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This work was supported by NIH Grants HL67415 and HL-42325

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Chang, A.N., Potter, J.D. Sarcomeric Protein Mutations in Dilated Cardiomyopathy. Heart Fail Rev 10, 225–235 (2005). https://doi.org/10.1007/s10741-005-5252-6

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