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Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains

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Abstract

Genetic cardiomyopathies, a group of cardiovascular disorders based on ventricular morphology and function, are among the leading causes of morbidity and mortality worldwide. Such genetically driven forms of hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathies are chronic, debilitating diseases that result from biomechanical defects in cardiac muscle contraction and frequently progress to heart failure (HF). Locus and allelic heterogeneity, as well as clinical variability combined with genetic and phenotypic overlap between different cardiomyopathies, have challenged proper clinical prognosis and provided an incentive for identification of pathogenic variants. This review attempts to provide an overview of inherited cardiomyopathies with a focus on their genetic etiology in myosin regulatory (RLC) and essential (ELC) light chains, which are EF-hand protein family members with important structural and regulatory roles. From the clinical discovery of cardiomyopathy-linked light chain mutations in patients to an array of exploratory studies in animals, and reconstituted and recombinant systems, we have summarized the current state of knowledge on light chain mutations and how they induce physiological disease states via biochemical and biomechanical alterations at the molecular, tissue, and organ levels. Cardiac myosin RLC phosphorylation and the N-terminus ELC have been discussed as two important emerging modalities with important implications in the regulation of myosin motor function, and thus cardiac performance. A comprehensive understanding of such triggers is absolutely necessary for the development of target-specific rescue strategies to ameliorate or reverse the effects of myosin light chain-related inherited cardiomyopathies.

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References

  1. Abraham TP, Jones M, Kazmierczak K, Liang H-Y, Pinheiro AC, Wagg CS, Lopaschuk GD, Szczesna-Cordary D (2009) Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice. Cardiovasc Res 82(1):84–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Alamo L, Ware JS, Pinto A, Gillilan RE, Seidman JG, Seidman CE, Padron R (2017) Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes. Elife 6

  3. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL (2015) Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med 17(11):880–888

    Article  PubMed  Google Scholar 

  4. Alvarez-Acosta L, Mazzanti A, Fernández X, Ortí M, Barriales-Villa R, García D, Maneiro E, Rebolo P, Álvarez E, Monserrat L (2014) Regulatory light chain (MYL2) mutations in familial hypertrophic cardiomyopathy. JCVD 2(2):82–90

    Google Scholar 

  5. Andersen PS, Havndrup O, Bundgaard H, Moolman-Smook JC, Larsen LA, Mogensen J, Brink PA, Børglum AD, Corfield VA, Kjeldsen K, Vuust J, Christiansen M (2001) Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations. J Med Genet 38(12):e43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Andersen PS, Hedley PL, Page SP, Syrris P, Moolman-Smook JC, McKenna WJ, Elliott PM, Christiansen M (2012) A novel myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity. Biochem Res Int 2012:685108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Anderson RL, Trivedi DV, Sarkar SS, Henze M, Ma W, Gong H, Rogers CS, Gorham JM, Wong FL, Morck MM, Seidman JG, Ruppel KM, Irving TC, Cooke R, Green EM, Spudich JA (2018) Deciphering the super relaxed state of human beta-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proc Natl Acad Sci U S A 115(35):E8143–E8152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Arad M, Penas-Lado M, Monserrat L, Maron BJ, Sherrid M, Ho CY, Barr S, Karim A, Olson TM, Kamisago M, Seidman JG, Seidman CE (2005) Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112(18):2805–2811

    Article  CAS  PubMed  Google Scholar 

  9. Arrell DK, Neverova I, Fraser H, Marban E, Van Eyk JE (2001) Proteomic analysis of pharmacologically preconditioned cardiomyocytes reveals novel phosphorylation of myosin light chain 1. Circ Res 89(6):480–487

    Article  CAS  PubMed  Google Scholar 

  10. Aydt EM, Wolff G, Morano I (2007) Molecular modeling of the myosin-S1(A1) isoform. J Struct Biol 159(1):158–163

    Article  CAS  PubMed  Google Scholar 

  11. Barth PG, Wanders RJ, Ruitenbeek W, Roe C, Scholte HR, van der Harten H, van Moorsel J, Duran M, Dingemans KP (1998) Infantile fibre type disproportion, myofibrillar lysis and cardiomyopathy: a disorder in three unrelated Dutch families. Neuromuscul Disord 8(5):296–304

    Article  CAS  PubMed  Google Scholar 

  12. Burghardt TP, Sikkink LA (2013) Regulatory light chain mutants linked to heart disease modify the cardiac myosin lever arm. Biochemistry 52(7):1249–1259

    Article  CAS  PubMed  Google Scholar 

  13. Burghardt TP, Sun X, Wang Y, Ajtai K (2015) In vitro and in vivo single myosin step-sizes in striated muscle. J Muscle Res Cell Motil 36(6):463–477

    Article  CAS  PubMed  Google Scholar 

  14. Burghardt TP, Ajtai K, Sun X, Takubo N, Wang Y (2016) In vivo myosin step-size from zebrafish skeletal muscle. Open Biol. 6(5)

  15. Burghardt TP, Sun X, Wang Y, Ajtai K (2017) Auxotonic to isometric contraction transitioning in a beating heart causes myosin step-size to down shift. PLoS One 12(4):e0174690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Caleshu C, Sakhuja R, Nussbaum RL, Schiller NB, Ursell PC, Eng C, De Marco T, McGlothlin D, Burchard EG, Rame JE (2011) Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy. Am J Med Genet A 155(9):2229–2235

    Article  CAS  PubMed Central  Google Scholar 

  17. Chiou KR, Chu CT, Charng MJ (2015) Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan. J Cardiol 65(3):250–256

    Article  PubMed  Google Scholar 

  18. Claes G R, et al. (2016) Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers. Eur Heart J 37(23):1815–1822

  19. Codd MB, Sugrue DD, Gersh BJ, Melton LJ 3rd (1989) Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 80(3):564–572

    Article  CAS  PubMed  Google Scholar 

  20. Debold EP, Schmitt JP, Patlak JB, Beck SE, Moore JR, Seidman JG, Seidman C, Warshaw DM (2007) Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse {alpha}-cardiac myosin in the laser trap assay. Am J Physiol Heart Circ Physiol 293(1):H284–H291

    Article  CAS  PubMed  Google Scholar 

  21. Duggal D, Nagwekar J, Rich R, Huang W, Midde K, Fudala R, Das H, Gryczynski I, Szczesna-Cordary D, Borejdo J (2015) Effect of a myosin regulatory light chain mutation K104E on actin-myosin interactions. Am J Physiol Heart Circ Physiol 308(10):H1248–H1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dumka D, Talent J, Akopova I, Guzman G, Szczesna-Cordary D, Borejdo J (2006) E22K mutation of RLC that causes familial hypertrophic cardiomyopathy in heterozygous mouse myocardium: effect on cross-bridge kinetics. Am J Physiol Heart Circ Physiol 291(5):H2098–H2106

    Article  CAS  PubMed  Google Scholar 

  23. Epstein ND (1998) The molecular biology and pathophysiology of hypertrophic cardiomyopathy due to mutations in the beta myosin heavy chains and the essential and regulatory light chains. Adv Exp Med Biol 453:105–114

    Article  CAS  PubMed  Google Scholar 

  24. Epstein ND, Davis JS (2006) When is a fly in the ointment a solution and not a problem? Circ Res 98(9):1110–1112

    Article  CAS  PubMed  Google Scholar 

  25. Farman GP (2014) Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on beta-myosin cross-bridge mechanics. 117(12): pp. 1471–7

  26. Flavigny J, Richard P, Isnard R, Carrier L, Charron P, Bonne G, Forissier JF, Desnos M, Dubourg O, Komajda M, Schwartz K, Hainque B (1998) Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy. J Mol Med 76(3–4):208–214

    Article  CAS  PubMed  Google Scholar 

  27. Fodor WL, Darras B, Seharaseyon J, Falkenthal S, Francke U, Vanin EF (1989) Human ventricular/slow twitch myosin alkali light chain gene characterization, sequence, and chromosomal location. J Biol Chem 264(4):2143–2149

    CAS  PubMed  Google Scholar 

  28. Fokstuen S, Munoz A, Melacini P, Iliceto S, Perrot A, Ozcelik C, Jeanrenaud X, Rieubland C, Farr M, Faber L, Sigwart U, Mach F, Lerch R, Antonarakis SE, Blouin JL (2011) Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice. J Med Genet 48(8):572–576

    Article  CAS  PubMed  Google Scholar 

  29. Gallego-Delgado M, Delgado JF, Brossa-Loidi V, Palomo J, Marzoa-Rivas R, Perez-Villa F, Salazar-Mendiguchía J, Ruiz-Cano MJ, Gonzalez-Lopez E, Padron-Barthe L, Bornstein B, Alonso-Pulpon L, Garcia-Pavia P (2016) Idiopathic restrictive cardiomyopathy is primarily a genetic disease. J Am Coll Cardiol 67(25):3021–3023

    Article  PubMed  Google Scholar 

  30. Garcia-Pavia P, Vazquez ME, Segovia J, Salas C, Avellana P, Gomez-Bueno M, Vilches C, Gallardo ME, Garesse R, Molano J, Bornstein B, Alonso-Pulpon L (2011) Genetic basis of end-stage hypertrophic cardiomyopathy. Eur J Heart Fail 13(11):1193–1201

    Article  CAS  PubMed  Google Scholar 

  31. Geeves MA, Holmes KC (2005) The molecular mechanism of muscle contraction. Adv Protein Chem 71:161–193

    Article  CAS  PubMed  Google Scholar 

  32. Geisterfer-Lowrance AA, Christe M, Conner DA, Ingwall JS, Schoen FJ, Seidman CE, Seidman JG (1996) A mouse model of familial hypertrophic cardiomyopathy. Science 272(5262):731–734

    Article  CAS  PubMed  Google Scholar 

  33. Gomes AV, Kazmierczak K, Cheah JX, Gilda JE, Yuan CC, Zhou Z, Szczesna-Cordary D (2015) Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains. J Muscle Res Cell Motil 36(6):447–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Grabarek Z (2006) Structural basis for diversity of the EF-hand calcium-binding proteins. J Mol Biol 359(3):509–525

    Article  CAS  PubMed  Google Scholar 

  35. Green EM, Wakimoto H, Anderson RL, Evanchik MJ, Gorham JM, Harrison BC, Henze M, Kawas R, Oslob JD, Rodriguez HM, Song Y, Wan W, Leinwand LA, Spudich JA, McDowell RS, Seidman JG, Seidman CE (2016) A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 351(6273):617–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Greenberg MJ, Watt JD, Jones M, Kazmierczak K, Szczesna-Cordary D, Moore JR (2009) Regulatory light chain mutations associated with cardiomyopathy affect myosin mechanics and kinetics. J Mol Cell Cardiol 46(1):108–115

    Article  CAS  PubMed  Google Scholar 

  37. Greenberg MJ, Kazmierczak K, Szczesna-Cordary D, Moore JR (2010) Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry. Proc Natl Acad Sci U S A 107(40):17403–17408

    Article  PubMed  PubMed Central  Google Scholar 

  38. Guhathakurta P, Prochniewicz E, Thomas DD (2015) Amplitude of the actomyosin power stroke depends strongly on the isoform of the myosin essential light chain. Proc Natl Acad Sci U S A 112(15):4660–4665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Guhathakurta P, Prochniewicz E, Roopnarine O, Rohde JA, Thomas DD (2017) A cardiomyopathy mutation in the myosin essential light chain alters actomyosin structure. Biophys J 113(1):91–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Henry GD, Winstanley MA, Dalgarno DC, Scott GM, Levine BA, Trayer IP (1985) Characterization of the actin-binding site on the alkali light chain of myosin. Biochim Biophys Acta 830(3):233–243

    Article  CAS  PubMed  Google Scholar 

  41. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366(7):619–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hernandez OM, Jones M, Guzman G, Szczesna-Cordary D (2007) Myosin essential light chain in health and disease. Am J Physiol Heart Circ Physiol 292(4):H1643–H1654

    Article  CAS  PubMed  Google Scholar 

  43. Hershberger RE, Hedges DJ, Morales A (2013) Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 10(9):531–547

    Article  CAS  PubMed  Google Scholar 

  44. Holmes KC, Geeves MA (2000) The structural basis of muscle contraction. Philos Trans R Soc Lond Ser B Biol Sci 355(1396):419–431

    Article  CAS  Google Scholar 

  45. Hooijman P, Stewart MA, Cooke R (2011) A new state of cardiac myosin with very slow ATP turnover: a potential cardioprotective mechanism in the heart. Biophys J 100(8):1969–1976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Houdusse A, Cohen C (1996) Structure of the regulatory domain of scallop myosin at 2 A resolution: implications for regulation. Structure 4(1):21–32

    Article  CAS  PubMed  Google Scholar 

  47. Houdusse A, Silver M, Cohen C (1996) A model of Ca2+-free calmodulin binding to unconventional myosins reveals how calmodulin acts as a regulatory switch. Structure 4(12):1475–1490

    Article  CAS  PubMed  Google Scholar 

  48. Huang W, Szczesna-Cordary D (2015) Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations. J Muscle Res Cell Motil 36(6):433–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang W, Liang J, Kazmierczak K, Muthu P, Duggal D, Farman GP, Sorensen L, Pozios I, Abraham T, Moore JR, Borejdo J, Szczesna-Cordary D (2014) Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice. J Mol Cell Cardiol 74:318–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Huang W, Liang J, Yuan CC, Kazmierczak K, Zhou Z, Morales A, McBride KL, Fitzgerald-Butt SM, Hershberger RE, Szczesna-Cordary D (2015) Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain. FEBS J 282(12):2379–2393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hughes SE, McKenna WJ (2005) New insights into the pathology of inherited cardiomyopathy. Heart 91(2):257–264

    Article  PubMed  PubMed Central  Google Scholar 

  52. James J, Zhang Y, Wright K, Witt S, Glascock E, Osinska H, Klevitsky R, Martin L, Yager K, Sanbe A, Robbins J (2002) Transgenic rabbits expressing mutant essential light chain do not develop hypertrophic cardiomyopathy. J Mol Cell Cardiol 34(7):873–882

    Article  CAS  PubMed  Google Scholar 

  53. Jay A, Chikarmane R, Poulik J, Misra VK (2013) Infantile hypertrophic cardiomyopathy associated with a novel MYL3 mutation. Cardiology 124(4):248–251

    Article  CAS  PubMed  Google Scholar 

  54. Kabaeva ZT, Perrot A, Wolter B, Dietz R, Cardim N, Correia JM, Schulte HD, Aldashev AA, Mirrakhimov MM, Osterziel KJ (2002) Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy. Eur J Hum Genet 10(11):741–748

    Article  CAS  PubMed  Google Scholar 

  55. Karabina A, Kazmierczak K, Szczesna-Cordary D, Moore JR (2015) Myosin regulatory light chain phosphorylation enhances cardiac beta-myosin in vitro motility under load. Arch Biochem Biophys 580:14–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kaski JP, Syrris P, Esteban MT, Jenkins S, Pantazis A, Deanfield JE, McKenna WJ, Elliott PM (2009) Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2(5):436–441

    Article  CAS  PubMed  Google Scholar 

  57. Kazmierczak K, Xu Y, Jones M, Guzman G, Hernandez OM, Kerrick WGL, Szczesna-Cordary D (2009) The role of the N-terminus of the myosin essential light chain in cardiac muscle contraction. J Mol Biol 387(3):706–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kazmierczak K, Muthu P, Huang W, Jones M, Wang Y, Szczesna-Cordary D (2012) Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice. Biochem J 442(1):95–103

    Article  CAS  PubMed  Google Scholar 

  59. Kazmierczak K, Paulino EC, Huang W, Muthu P, Liang J, Yuan CC, Rojas AI, Hare JM, Szczesna-Cordary D (2013) Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 305(4):H575–H589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kazmierczak K, Yuan C-C, Liang J, Huang W, Rojas AI, Szczesna-Cordary D (2014) Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations. Front Physiol 5:353

    Article  PubMed  PubMed Central  Google Scholar 

  61. Kazmierczak K, Liang J, Yuan CC, Yadav S, Sitbon YH, Walz K, Ma W, Irving TC, Cheah JX, Gomes AV, Szczesna-Cordary D (2018) Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain. FASEB J, p. fj201801402R

  62. Kerrick WGL, 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. FASEB J 23:855–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kushwaha SS, Fallon JT, Fuster V (1997) Restrictive cardiomyopathy. N Engl J Med 336(4):267–276

    Article  CAS  PubMed  Google Scholar 

  64. Lee W, Hwang TH, Kimura A, Park SW, Satoh M, Nishi H, Harada H, Toyama J, Park JE (2001) Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy. Am Heart J 141(2):184–189

    Article  CAS  PubMed  Google Scholar 

  65. Levine RJ, Yang Z, Epstein ND, Fananapazir L, Stull JT, Sweeney HL (1998) Structural and functional responses of mammalian thick filaments to alterations in myosin regulatory light chains. J Struct Biol 122(1–2):149–161

    Article  CAS  PubMed  Google Scholar 

  66. Lin BL, Song T, Sadayappan S (2017) Myofilaments: movers and rulers of the sarcomere. Compr Physiol 7(2):675–692

    Article  PubMed  Google Scholar 

  67. Logvinova DS, Levitsky DI (2018) Essential light chains of myosin and their role in functioning of the myosin motor. Biochemistry (Mosc) 83(8):944–960

    Article  CAS  Google Scholar 

  68. Lossie J, Ushakov DS, Ferenczi MA, Werner S, Keller S, Haase H, Morano I (2012) Mutations of ventricular essential myosin light chain disturb myosin binding and sarcomeric sorting. Cardiovasc Res 93(3):390–396

    Article  CAS  PubMed  Google Scholar 

  69. Lossie J, Kohncke C, Mahmoodzadeh S, Steffen W, Canepari M, Maffei M, Taube M, Larcheveque O, Baumert P, Haase H, Bottinelli R, Regitz-Zagrosek V, Morano I (2014) Molecular mechanism regulating myosin and cardiac functions by ELC. Biochem Biophys Res Commun 450(1):464–469

    Article  CAS  PubMed  Google Scholar 

  70. Lowey S, Saraswat LD, Liu H, Volkmann N, Hanein D (2007) Evidence for an interaction between the SH3 domain and the N-terminal extension of the essential light chain in class II Myosins. J Mol Biol 371(4):902–913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lowey S, Bretton V, Joel PB, Trybus KM, Gulick J, Robbins J, Kalganov A, Cornachione AS, Rassier DE (2018) Hypertrophic cardiomyopathy R403Q mutation in rabbit beta-myosin reduces contractile function at the molecular and myofibrillar levels. Proc Natl Acad Sci U S A 115(44):11238–11243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ma N, Zhang J, Itzhaki I, Zhang SL, Chen H, Haddad F, Kitani T, Wilson KD, Tian L, Shrestha R, Wu H, Lam CK, Sayed N, Wu JC (2018) Determining the pathogenicity of a genomic variant of uncertain significance using CRISPR/Cas9 and human-induced pluripotent stem cells. Circulation 138:2666–2681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Marian AJ, Braunwald E (2017) Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 121(7):749–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Maron BJ, Bonow RO, Seshagiri TNR, Roberts WC, Epstein SE (1982) Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the apical region of the left ventricle (apical hypertrophic cardiomyopathy). Am J Cardiol 49(8):1838–1848

    Article  CAS  PubMed  Google Scholar 

  75. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE (1995) 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

    Article  CAS  PubMed  Google Scholar 

  76. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB, American Heart A, H.F. Council on Clinical Cardiology, C. Transplantation, C. Quality of, R. Outcomes, G. Functional, G. Translational Biology Interdisciplinary Working, E. Council on, and Prevention (2006) Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 113(14):1807–1816

    Article  PubMed  Google Scholar 

  77. Maron BJ, Maron MS, Semsarian C (2012) Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 60(8):705–715

    Article  PubMed  Google Scholar 

  78. McNally EM, Golbus JR, Puckelwartz MJ (2013) Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 123(1):19–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. McNamara JW, Li A, Dos Remedios CG, Cooke R (2015) The role of super-relaxed myosin in skeletal and cardiac muscle. Biophys Rev 7(1):5–14

    Article  CAS  PubMed  Google Scholar 

  80. Miller MS, Palmer BM, Ruch S, Martin LA, Farman GP, Wang Y, Robbins J, Irving TC, Maughan DW (2005) The essential light chain N-terminal extension alters force and Fiber kinetics in mouse cardiac muscle. J Biol Chem 280(41):34427–34434

    Article  CAS  PubMed  Google Scholar 

  81. Milligan RA, Whittaker M, Safer D (1990) Molecular structure of F-actin and location of surface binding sites. Nature 348(6298):217–221

    Article  CAS  PubMed  Google Scholar 

  82. Morano I, Ritter O, Bonz A, Timek T, Vahl CF, Michel G (1995) Myosin light chain-actin interaction regulates cardiac contractility. Circ Res 76(5):720–725

    Article  CAS  PubMed  Google Scholar 

  83. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE (2008) Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 358(18):1899–1908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Morner S, Richard P, Kazzam E, Hellman U, Hainque B, Schwartz K, Waldenstrom A (2003) Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. J Mol Cell Cardiol 35(7):841–849

    Article  CAS  PubMed  Google Scholar 

  85. Muthu P, Wang L, Yuan CC, Kazmierczak K, Huang W, Hernandez OM, Kawai M, Irving TC, Szczesna-Cordary D (2011) Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction. FASEB J 25(12):4394–4405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Muthu P, Kazmierczak K, Jones M, Szczesna-Cordary D (2012) The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts. J Cell Mol Med 16(4):911–919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Muthu P, Liang J, Schmidt W, Moore JR, Szczesna-Cordary D (2014) In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain. Arch Biochem Biophys 552–553(15 June–1 July 2014):29–39

    Article  CAS  PubMed  Google Scholar 

  88. Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, Ommen SR, Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C, Torricelli F, Cecchi F (2008) Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 83(6):630–638

    Article  CAS  PubMed  Google Scholar 

  89. Olson TM, Karst ML, Whitby FG, Driscoll DJ (2002) Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation 105(20):2337–2340

    Article  CAS  PubMed  Google Scholar 

  90. Parvari R, Levitas A (2012) The mutations associated with dilated cardiomyopathy. Biochem Res Int 2012:12

    Article  Google Scholar 

  91. Petzhold D, Lossie J, Keller S, Werner S, Haase H, Morano I (2011) Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity. Cardiovasc Res 90(3):513–520

    Article  CAS  PubMed  Google Scholar 

  92. Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND (1996) 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(1):63–69

    Article  CAS  PubMed  Google Scholar 

  93. Poggesi C, Ho CY (2014) Muscle dysfunction in hypertrophic cardiomyopathy: what is needed to move to translation? J Muscle Res Cell Motil 35(1):37–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rayment I (1996) The structural basis of the myosin ATPase activity. J Biol Chem 271(27):15850–15853

    Article  CAS  PubMed  Google Scholar 

  95. Rayment I, Rypniewski WR, Schmidt-Base K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM (1993) Three-dimensional structure of myosin subfragment-1: a molecular motor. Science 261(5117):50–58

    Article  CAS  PubMed  Google Scholar 

  96. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet J-P, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M, EUROGENE Heart Failure Project (2003) Hypertrophic cardiomyopathy: Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107(17):2227–2232 and erratum (2004), 109(25), p.3258

    Article  PubMed  Google Scholar 

  97. Rivenes SM, Kearney DL, Smith EOB, Towbin JA, Denfield SW (2000) Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation 102(8):876–882

    Article  CAS  PubMed  Google Scholar 

  98. Robertson SP, Johnson JD, Potter JD (1981) The time-course of Ca2+ exchange with calmodulin, troponin, parvalbumin, and myosin in response to transient increases in Ca2+. Biophys J 34(3):559–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Roopnarine O (2003) Mechanical defects of muscle fibers with myosin light chain mutants that cause cardiomyopathy. Biophys J 84(4):2440–2449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sanbe A, Nelson D, Gulick J, Setser E, Osinska H, Wang X, Hewett TE, Klevitsky R, Hayes E, Warshaw DM, Robbins J (2000) In vivo analysis of an essential myosin light chain mutation linked to familial hypertrophic cardiomyopathy. Circ Res 87(4):296–302

    Article  CAS  PubMed  Google Scholar 

  101. Santos S, Marques V, Pires M, Silveira L, Oliveira H, Lanca V, Brito D, Madeira H, Fonseca E, Freitas A, Carreira I, Gaspar I, Monteiro C, Fernandes A (2012) High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort. BMC Med Genet 13(1):17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Scheid LM, Mosqueira M, Hein S, Kossack M, Juergensen L, Mueller M, Meder B, Fink RH, Katus HA, Hassel D (2016) Essential light chain S195 phosphorylation is required for cardiac adaptation under physical stress. Cardiovasc Res 111(1):44–55

    Article  CAS  PubMed  Google Scholar 

  103. Scruggs SB, Hinken AC, Thawornkaiwong A, Robbins J, Walker LA, de Tombe PP, Geenen DL, Buttrick PM, Solaro RJ (2009) Ablation of ventricular myosin regulatory light chain phosphorylation in mice causes cardiac dysfunction in situ and affects neighboring myofilament protein phosphorylation. J Biol Chem 284(8):5097–5106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Scruggs SB, Reisdorph R, Armstrong ML, Warren CM, Reisdorph N, Solaro RJ, Buttrick PM (2010) A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain. Mol Cell Proteomics 9(9):1804–1818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Seidman CE, Seidman JG (1998) Molecular genetic studies of familial hypertrophic cardiomyopathy. Basic Res Cardiol 93(Suppl 3):13–16

    Article  CAS  PubMed  Google Scholar 

  106. Spudich JA (2014) Hypertrophic and dilated cardiomyopathy: four decades of basic research on muscle lead to potential therapeutic approaches to these devastating genetic diseases. Biophys J 106(6):1236–1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Spudich JA, Aksel T, Bartholomew SR, Nag S, Kawana M, Yu EC, Sarkar SS, Sung J, Sommese RF, Sutton S, Cho C, Adhikari AS, Taylor R, Liu C, Trivedi D, Ruppel KM (2016) Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human beta-cardiac myosin. J Exp Biol 219(Pt 2):161–167

    Article  PubMed  PubMed Central  Google Scholar 

  108. Stewart MA, Franks-Skiba K, Chen S, Cooke R (2010) Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers. Proc Natl Acad Sci U S A 107(1):430–435

    Article  PubMed  Google Scholar 

  109. Sutoh K (1982) An actin-binding site on the 20K fragment of myosin subfragment 1. Biochemistry 21(19):4800–4804

    Article  CAS  PubMed  Google Scholar 

  110. Szczesna D, Ghosh D, Li Q, Gomes AV, Guzman G, Arana C, Zhi G, Stull JT, Potter JD (2001) Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation. J Biol Chem 276(10):7086–7092

    Article  CAS  PubMed  Google Scholar 

  111. Szczesna D, Zhao J, Jones M, Zhi G, Stull J, Potter JD (2002) Phosphorylation of the regulatory light chains of myosin affects Ca2+ sensitivity of skeletal muscle contraction. J Appl Physiol 92(4):1661–1670

    Article  CAS  PubMed  Google Scholar 

  112. Szczesna-Cordary D (2003) Regulatory light chains of striated muscle myosin. Structure, function and malfunction. Curr Drug Targets Cardiovasc Haematol Disord 3(2):187–197

    Article  Google Scholar 

  113. Szczesna-Cordary D, de Tombe PP (2016) Myosin light chain phosphorylation, novel targets to repair a broken heart? Cardiovasc Res 111(1):5–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Szczesna-Cordary D, Guzman G, Ng SS, Zhao J (2004) Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction. J Biol Chem 279(5):3535–3542

    Article  CAS  PubMed  Google Scholar 

  115. Szczesna-Cordary D, Guzman G, Zhao J, Hernandez O, Wei J, Diaz-Perez Z (2005) The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice. J Cell Sci 118(Pt 16):3675–3683

    Article  CAS  PubMed  Google Scholar 

  116. Szczesna-Cordary D, Jones M, Moore JR, Watt J, Kerrick WGL, Xu Y, Wang Y, Wagg C, Lopaschuk GD (2007) Myosin regulatory light chain E22K mutation results in decreased cardiac intracellular calcium and force transients. FASEB J 21(14):3974–3985

    Article  CAS  PubMed  Google Scholar 

  117. Teekakirikul P, Padera RF, Seidman JG, Seidman CE (2012) Hypertrophic cardiomyopathy: translating cellular cross talk into therapeutics. J Cell Biol 199(3):417–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Timson DJ, Trayer HR, Trayer IP (1998) The N-terminus of A1-type myosin essential light chains binds actin and modulates myosin motor function. Eur J Biochem 255(3):654–662

    Article  CAS  PubMed  Google Scholar 

  119. Trayer HR, Trayer IP (1985) Differential binding of rabbit fast muscle myosin light chain isoenzymes to regulated actin. FEBS Lett 180(2):170–173

    Article  CAS  PubMed  Google Scholar 

  120. Trayer IP, Trayer HR, Levine BA (1987) Evidence that the N-terminal region of A1-light chain of myosin interacts directly with the C-terminal region of actin. A proton magnetic resonance study. Eur J Biochem 164(1):259–266

    Article  CAS  PubMed  Google Scholar 

  121. Trivedi DV, Adhikari AS, Sarkar SS, Ruppel KM, Spudich JA (2018) Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light. Biophys Rev 10(1):27–48

    Article  CAS  PubMed  Google Scholar 

  122. Tyska MJ, Hayes E, Giewat M, Seidman CE, Seidman JG, Warshaw DM (2000) Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy. Circ Res 86(7):737–744

    Article  CAS  PubMed  Google Scholar 

  123. Vemuri R, Lankford EB, Poetter K, Hassanzadeh S, Takeda K, Yu ZX, Ferrans VJ, Epstein ND (1999) The stretch-activation response may be critical to the proper functioning of the mammalian heart. Proc Natl Acad Sci U S A 96(3):1048–1053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wang Y, Xu Y, Kerrick WGL, Wang Y, Guzman G, Diaz-Perez Z, Szczesna-Cordary D (2006) Prolonged Ca2+ and force transients in myosin RLC transgenic mouse fibers expressing malignant and benign FHC mutations. J Mol Biol 361(2):286–299

    Article  CAS  PubMed  Google Scholar 

  125. Wang Y, Ajtai K, Burghardt TP (2013) The Qdot-labeled actin super-resolution motility assay measures low-duty cycle muscle myosin step size. Biochemistry 52(9):1611–1621

    Article  CAS  PubMed  Google Scholar 

  126. Wang Y, Ajtai K, Burghardt TP (2014) Ventricular myosin modifies in vitro step-size when phosphorylated. J Mol Cell Cardiol 72:231–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wang Y, Ajtai K, Kazmierczak K, Szczesna-Cordary D, Burghardt TP (2016) N-Terminus of cardiac myosin essential light chain modulates myosin step-size. Biochemistry 55(1):186–198

    Article  CAS  PubMed  Google Scholar 

  128. Wang L, Kazmierczak K, Yuan CC, Yadav S, Kawai M, Szczesna-Cordary D (2017) Cardiac contractility, motor function, and cross-bridge kinetics in N47K-RLC mutant mice. FEBS J 284(12):1897–1913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wang Y, Yuan CC, Kazmierczak K, Szczesna-Cordary D, Burghardt TP (2018) Single cardiac ventricular myosins are autonomous motors. Open Biol, 8(4)

  130. Weterman MA, Barth PG, van Spaendonck-Zwarts KY, Aronica E, Poll-The BT, Brouwer OF, van Tintelen JP, Qahar Z, Bradley EJ, de Wissel M, Salviati L, Angelini C, van den Heuvel L, Thomasse YE, Backx AP, Nurnberg G, Nurnberg P, Baas F (2013) Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy. Brain 136(Pt 1):282–293

    Article  PubMed  Google Scholar 

  131. Winstanley MA, Trayer HR, Trayer IP (1977) Role of the myosin light chains in binding to actin. FEBS Lett 77(2):239–242

    Article  CAS  PubMed  Google Scholar 

  132. Yadav S, Kazmierczak K, Liang J, Sitbon YH, Szczesna-Cordary D (2019) Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain. FEBS J 286(1):151–168

  133. Yuan CC, Muthu P, Kazmierczak K, Liang J, Huang W, Irving TC, Kanashiro-Takeuchi RM, Hare JM, Szczesna-Cordary D (2015) Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice. Proc Natl Acad Sci U S A 112(30):E4138–E4146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yuan CC, Kazmierczak K, Liang J, Kanashiro-Takeuchi R, Irving TC, Gomes AV, Wang Y, Burghardt TP, Szczesna-Cordary D (2017) Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice. Cardiovasc Res 113(10):1124–1136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Yuan CC, Kazmierczak K, Liang J, Zhou Z, Yadav S, Gomes AV, Irving TC, Szczesna-Cordary D (2018) Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice. Proc Natl Acad Sci U S A 115(10):E2338–E2347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhou Z, Huang W, Liang J, Szczesna-Cordary D (2016) Molecular and functional effects of a splice site mutation in the MYL2 gene associated with cardioskeletal myopathy and early cardiac death in infants. Front Physiol 7:240

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Institutes of Health R01-HL123255 (DSC) and the American Heart Association 17PRE33650085 (SY).

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  1. Sunil Yadav and Yoel H. Sitbon contributed equally to this work.

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  1. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 NW 10th Ave., Miami, FL, 33136, USA

    Sunil Yadav, Yoel H. Sitbon, Katarzyna Kazmierczak & Danuta Szczesna-Cordary

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  1. Sunil Yadav
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  2. Yoel H. Sitbon
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  3. Katarzyna Kazmierczak
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  4. Danuta Szczesna-Cordary
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Correspondence to Danuta Szczesna-Cordary.

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This article is part of the special issue on Sarcomeric Mutations in Pflügers Archiv—European Journal of Physiology

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Yadav, S., Sitbon, Y.H., Kazmierczak, K. et al. Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains. Pflugers Arch - Eur J Physiol 471, 683–699 (2019). https://doi.org/10.1007/s00424-019-02257-4

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