Skip to main content
Log in

Alpha-tropomyosin mutations in inherited cardiomyopathies

  • Review
  • Published:
Journal of Muscle Research and Cell Motility Aims and scope Submit manuscript

Abstract

The inherited cardiac diseases hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be caused by missense mutations in the TPM1 gene which encodes the thin filament regulatory protein α-tropomyosin. Different mutations are responsible for either HCM or DCM, suggesting that distinct changes in tropomyosin structure and function can lead to the different diseases. Various biophysical and physiological approaches have been used to investigate the structure–function effects of the mutations, and animal models developed. The reported effects of the mutations include changes to the secondary structure of tropomyosin, its binding to actin and its position on the thin filament, and alterations to actin–myosin interactions and myofilament Ca2+ sensitivity. The latter changes have been found to be particularly consistent, with HCM mutations increasing Ca2+ sensitivity and DCM mutations in general decreasing this parameter and uncoupling the effect of troponin phosphorylation upon Ca2+ responsiveness. As well as impacting on contractility, these changes are likely to alter intracellular Ca2+ handling and signaling, and a combination of these alterations may provide the trigger for disease remodeling.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  • 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. doi:10.1161/CIRCULATIONAHA.105.547448

    Article  PubMed  CAS  Google Scholar 

  • Ashrafian H, Redwood C, Blair E, Watkins H (2003) Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion. Trends Genet 19(5):263–268. doi:10.1016/S0168-9525(03)00081-7

    Article  PubMed  CAS  Google Scholar 

  • Bai F, Weis A, Takeda AK, Chase PB, Kawai M (2011) Enhanced active cross-bridges during diastole: molecular pathogenesis of tropomyosin’s HCM mutations. Biophys J 100(4):1014–1023. doi:10.1016/j.bpj.2011.01.001

    Article  PubMed  CAS  Google Scholar 

  • Bai F, Groth HL, Kawai M (2012) DCM-related tropomyosin mutants E40K/E54K over-inhibit the actomyosin interaction and lead to a decrease in the number of cycling cross-bridges. PLoS One 7(10):e47471. doi:10.1371/journal.pone.0047471

    Article  PubMed  CAS  Google Scholar 

  • Behrmann E, Muller M, Penczek PA, Mannherz HG, Manstein DJ, Raunser S (2012) Structure of the rigor actin–tropomyosin–myosin complex. Cell 150(2):327–338. doi:10.1016/j.cell.2012.05.037

    Article  PubMed  CAS  Google Scholar 

  • Bing W, Redwood CS, Purcell IF, Esposito G, Watkins H, Marston SB (1997) Effects of two hypertrophic cardiomyopathy mutations in alpha-tropomyosin, Asp175Asn and Glu180Gly, on Ca2+ regulation of thin filament motility. Biochem Biophys Res Commun 236(3):760–764. doi:10.1006/bbrc.1997.7045

    Article  PubMed  CAS  Google Scholar 

  • Bing W, Knott A, Redwood C, Esposito G, Purcell I, Watkins H, Marston S (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. J Mol Cell Cardiol 32(8):1489–1498. doi:10.1006/jmcc.2000.1182

    Article  PubMed  CAS  Google Scholar 

  • Borovikov YS, Karpicheva OE, Avrova SV, Robinson P, Redwood CS (2009a) The effect of the dilated cardiomyopathy-causing mutation Glu54Lys of alpha-tropomyosin on actin–myosin interactions during the ATPase cycle. Arch Biochem Biophys 489(1–2):20–24. doi:10.1016/j.abb.2009.07.018

    Article  PubMed  CAS  Google Scholar 

  • Borovikov YS, Karpicheva OE, Chudakova GA, Robinson P, Redwood CS (2009b) Dilated cardiomyopathy mutations in alpha-tropomyosin inhibit its movement during the ATPase cycle. Biochem Biophys Res Commun 381(3):403–406. doi:10.1016/j.bbrc.2009.02.054

    Article  PubMed  CAS  Google Scholar 

  • Borovikov YS, Avrova SV, Karpicheva OE, Robinson P, Redwood CS (2011a) The effect of the dilated cardiomyopathy-causing Glu40Lys TPM1 mutation on actin–myosin interactions during the ATPase cycle. Biochem Biophys Res Commun 411(3):496–500. doi:10.1016/j.bbrc.2011.06.138

    Article  PubMed  CAS  Google Scholar 

  • Borovikov YS, Rysev NA, Karpicheva OE, Redwood CS (2011b) Hypertrophic cardiomyopathy-causing Asp175asn and Glu180gly Tpm1 mutations shift tropomyosin strands further towards the open position during the ATPase cycle. Biochem Biophys Res Commun 407(1):197–201. doi:10.1016/j.bbrc.2011.02.139

    Article  PubMed  CAS  Google Scholar 

  • Bottinelli R, Coviello DA, Redwood CS, Pellegrino MA, Maron BJ, Spirito P, Watkins H, Reggiani C (1998) A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. Circ Res 82(1):106–115

    Article  PubMed  CAS  Google Scholar 

  • Chang AN, Harada K, Ackerman MJ, Potter JD (2005) Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin. J Biol Chem 280(40):34343–34349. doi:10.1074/jbc.M505014200

    Article  PubMed  CAS  Google Scholar 

  • Chang B, Nishizawa T, Furutani M, Fujiki A, Tani M, Kawaguchi M, Ibuki K, Hirono K, Taneichi H, Uese K, Onuma Y, Bowles NE, Ichida F, Inoue H, Matsuoka R, Miyawaki T (2011) Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. Mol Genet Metab 102(2):200–206. doi:10.1016/j.ymgme.2010.09.009

    Article  PubMed  Google Scholar 

  • 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. doi:10.1136/jmg.2010.083345

    Article  PubMed  CAS  Google Scholar 

  • Frisso G, Limongelli G, Pacileo G, Del Giudice A, Forgione L, Calabro P, Iacomino M, Detta N, Di Fonzo LM, Maddaloni V, Calabro R, Salvatore F (2009) A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy. Clin Genet 76(1):91–101. doi:10.1111/j.1399-0004.2009.01190.x

    Article  PubMed  CAS  Google Scholar 

  • Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG (1990) A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 62(5):999–1006

    Article  PubMed  CAS  Google Scholar 

  • Golitsina N, An Y, Greenfield NJ, Thierfelder L, Iizuka K, Seidman JG, Seidman CE, Lehrer SS, Hitchcock-DeGregori SE (1997) Effects of two familial hypertrophic cardiomyopathy-causing mutations on alpha-tropomyosin structure and function. Biochemistry 36(15):4637–4642. doi:10.1021/bi962970y

    Article  PubMed  CAS  Google Scholar 

  • Gordon AM, Homsher E, Regnier M (2000) Regulation of contraction in striated muscle. Physiol Rev 80(2):853–924

    PubMed  CAS  Google Scholar 

  • Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7(8):589–600. doi:10.1038/nrm1983

    Article  PubMed  CAS  Google Scholar 

  • Heller MJ, Nili M, Homsher E, Tobacman LS (2003) Cardiomyopathic tropomyosin mutations that increase thin filament Ca2+ sensitivity and tropomyosin N-domain flexibility. J Biol Chem 278(43):41742–41748. doi:10.1074/jbc.M303408200

    Article  PubMed  CAS  Google Scholar 

  • Hershberger RE, Norton N, Morales A, Li D, Siegfried JD, Gonzalez-Quintana J (2010) Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circ Cardiovasc Genet 3(2):155–161. doi:10.1161/CIRCGENETICS.109.912345

    Article  PubMed  CAS  Google Scholar 

  • Hoedemaekers YM, Caliskan K, Michels M, Frohn-Mulder I, van der Smagt JJ, Phefferkorn JE, Wessels MW, ten Cate FJ, Sijbrands EJ, Dooijes D, Majoor-Krakauer DF (2010) The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet 3(3):232–239. doi:10.1161/CIRCGENETICS.109.903898

    Article  PubMed  Google Scholar 

  • Holthauzen LM, Correa F, Farah CS (2004) Ca2+-induced rolling of tropomyosin in muscle thin filaments: the alpha- and beta-band hypothesis revisited. J Biol Chem 279(15):15204–15213. doi:10.1074/jbc.M308904200

    Article  PubMed  CAS  Google Scholar 

  • Jagatheesan G, Rajan S, Petrashevskaya N, Schwartz A, Boivin G, Arteaga G, de Tombe PP, Solaro RJ, Wieczorek DF (2004) Physiological significance of troponin T binding domains in striated muscle tropomyosin. Am J Physiol Heart Circ Physiol 287(4):H1484–H1494. doi:10.1152/ajpheart.01112.2003

    Article  PubMed  CAS  Google Scholar 

  • Janco M, Kalyva A, Scellini B, Piroddi N, Tesi C, Poggesi C, Geeves MA (2012) Alpha-tropomyosin with a D175N or E180G mutation in only one chain differs from tropomyosin with mutations in both chains. Biochemistry 51(49):9880–9890. doi:10.1021/bi301323n

    Article  PubMed  CAS  Google Scholar 

  • Johnson M, Coulton AT, Geeves MA, Mulvihill DP (2010) Targeted amino-terminal acetylation of recombinant proteins in E. coli. PLoS One 5(12):e15801. doi:10.1371/journal.pone.0015801

    Article  PubMed  CAS  Google Scholar 

  • Jongbloed RJ, Marcelis CL, Doevendans PA, Schmeitz-Mulkens JM, Van Dockum WG, Geraedts JP, Smeets HJ (2003) Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy. J Am Coll Cardiol 41(6):981–986

    Article  PubMed  CAS  Google Scholar 

  • Karibe A, Tobacman LS, Strand J, Butters C, Back N, Bachinski LL, Arai AE, Ortiz A, Roberts R, Homsher E, Fananapazir L (2001) Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis. Circulation 103(1):65–71

    Article  PubMed  CAS  Google Scholar 

  • Kawai M, Ishiwata S (2006) Use of thin filament reconstituted muscle fibres to probe the mechanism of force generation. J Muscle Res Cell Motil 27(5–7):455–468. doi:10.1007/s10974-006-9075-4

    Article  PubMed  Google Scholar 

  • Klaassen S, Probst S, Oechslin E, Gerull B, Krings G, Schuler P, Greutmann M, Hurlimann D, Yegitbasi M, Pons L, Gramlich M, Drenckhahn JD, Heuser A, Berger F, Jenni R, Thierfelder L (2008) Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 117(22):2893–2901. doi:10.1161/CIRCULATIONAHA.107.746164

    Article  PubMed  CAS  Google Scholar 

  • Kremneva E, Boussouf S, Nikolaeva O, Maytum R, Geeves MA, Levitsky DI (2004) Effects of two familial hypertrophic cardiomyopathy mutations in alpha-tropomyosin, Asp175Asn and Glu180Gly, on the thermal unfolding of actin-bound tropomyosin. Biophys J 87(6):3922–3933. doi:10.1529/biophysj.104.048793

    Article  PubMed  CAS  Google Scholar 

  • Lakdawala NK, Dellefave L, Redwood CS, Sparks E, Cirino AL, Depalma S, Colan SD, Funke B, Zimmerman RS, Robinson P, Watkins H, Seidman CE, Seidman JG, McNally EM, Ho CY (2010) Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy. J Am Coll Cardiol 55(4):320–329. doi:10.1016/j.jacc.2009.11.017

    Article  PubMed  CAS  Google Scholar 

  • Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP, Johnson N, Mendelsohn NJ, Morel C, Care M, Chung WK, Jones C, Psychogios A, Duffy E, Rehm HL, White E, Seidman JG, Seidman CE, Ho CY (2012) Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail 18(4):296–303. doi:10.1016/j.cardfail.2012.01.013

    Article  PubMed  Google Scholar 

  • Li XE, Tobacman LS, Mun JY, Craig R, Fischer S, Lehman W (2011) Tropomyosin position on F-actin revealed by EM reconstruction and computational chemistry. Biophys J 100(4):1005–1013. doi:10.1016/j.bpj.2010.12.3697

    Article  PubMed  CAS  Google Scholar 

  • Li XE, Suphamungmee W, Janco M, Geeves MA, Marston SB, Fischer S, Lehman W (2012) The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy. Biochem Biophys Res Commun 424(3):493–496. doi:10.1016/j.bbrc.2012.06.141

    Article  PubMed  CAS  Google Scholar 

  • Loong CK, Zhou HX, Chase PB (2012) Familial hypertrophic cardiomyopathy related E180G mutation increases flexibility of human cardiac alpha-tropomyosin. FEBS Lett 586(19):3503–3507. doi:10.1016/j.febslet.2012.08.005

    Article  PubMed  CAS  Google Scholar 

  • Ly S, Lehrer SS (2012) Long-range effects of familial hypertrophic cardiomyopathy mutations E180G and D175N on the properties of tropomyosin. Biochemistry 51(32):6413–6420. doi:10.1021/bi3006835

    Article  PubMed  CAS  Google Scholar 

  • Maron BJ (2002) Hypertrophic cardiomyopathy: a systematic review. JAMA 287(10):1308–1320

    Article  PubMed  Google Scholar 

  • Marston SB (2011) How do mutations in contractile proteins cause the primary familial cardiomyopathies? J Cardiovasc Transl Res 4(3):245–255. doi:10.1007/s12265-011-9266-2

    Article  PubMed  Google Scholar 

  • McLachlan AD, Stewart M (1976) The 14-fold periodicity in alpha-tropomyosin and the interaction with actin. J Mol Biol 103(2):271–298

    Article  PubMed  CAS  Google Scholar 

  • McLachlan AD, Stewart M, Smillie LB (1975) Sequence repeats in alpha-tropomyosin. J Mol Biol 98(2):281–291

    Article  PubMed  CAS  Google Scholar 

  • McNally EM, Golbus JR, Puckelwartz MJ (2013) Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 123(1):19–26. doi:10.1172/JCI62862

    Article  PubMed  CAS  Google Scholar 

  • Memo M, Leung MC, Ward DG, Dos Remedios C, Morimoto S, Zhang L, Ravenscroft G, McNamara E, Nowak KJ, Marston SB, Messer AE (2013) Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca2+ sensitivity. Cardiovasc Res. doi:10.1093/cvr/cvt071

    PubMed  Google Scholar 

  • Michele DE, Metzger JM (2000) Contractile dysfunction in hypertrophic cardiomyopathy: elucidating primary defects of mutant contractile proteins by gene transfer. Trends Cardiovasc Med 10(4):177–182

    Article  PubMed  CAS  Google Scholar 

  • Michele DE, Albayya FP, Metzger JM (1999) Direct, convergent hypersensitivity of calcium-activated force generation produced by hypertrophic cardiomyopathy mutant alpha-tropomyosins in adult cardiac myocytes. Nat Med 5(12):1413–1417. doi:10.1038/70990

    Article  PubMed  CAS  Google Scholar 

  • Michele DE, Coutu P, Metzger JM (2002a) Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins. Physiol Genomics 9(2):103–111. doi:10.1152/physiolgenomics.00099.2001

    PubMed  CAS  Google Scholar 

  • Michele DE, Gomez CA, Hong KE, Westfall MV, Metzger JM (2002b) Cardiac dysfunction in hypertrophic cardiomyopathy mutant tropomyosin mice is transgene-dependent, hypertrophy-independent, and improved by beta-blockade. Circ Res 91(3):255–262

    Article  PubMed  CAS  Google Scholar 

  • Mirza M, Marston S, Willott R, Ashley C, Mogensen J, McKenna W, Robinson P, Redwood C, Watkins H (2005) Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J Biol Chem 280(31):28498–28506. doi:10.1074/jbc.M412281200

    Article  PubMed  CAS  Google Scholar 

  • Mirza M, Robinson P, Kremneva E, Copeland O, Nikolaeva O, Watkins H, Levitsky D, Redwood C, El-Mezgueldi M, Marston S (2007) The effect of mutations in alpha-tropomyosin (E40K and E54K) that cause familial dilated cardiomyopathy on the regulatory mechanism of cardiac muscle thin filaments. J Biol Chem 282(18):13487–13497. doi:10.1074/jbc.M701071200

    Article  PubMed  CAS  Google Scholar 

  • Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ (2004) Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 44(10):2033–2040. doi:10.1016/j.jacc.2004.08.027

    Article  PubMed  CAS  Google Scholar 

  • Monteiro PB, Lataro RC, Ferro JA, Reinach Fde C (1994) Functional alpha-tropomyosin produced in Escherichia coli. A dipeptide extension can substitute the amino-terminal acetyl group. J Biol Chem 269(14):10461–10466

    PubMed  CAS  Google Scholar 

  • 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. doi:10.1056/NEJMoa075463

    Article  PubMed  CAS  Google Scholar 

  • Murakami K, Stewart M, Nozawa K, Tomii K, Kudou N, Igarashi N, Shirakihara Y, Wakatsuki S, Yasunaga T, Wakabayashi T (2008) Structural basis for tropomyosin overlap in thin (actin) filaments and the generation of a molecular swivel by troponin-T. Proc Natl Acad Sci USA 105(20):7200–7205. doi:10.1073/pnas.0801950105

    Article  PubMed  CAS  Google Scholar 

  • Muthuchamy M, Pieples K, Rethinasamy P, Hoit B, Grupp IL, Boivin GP, Wolska B, Evans C, Solaro RJ, Wieczorek DF (1999) Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction. Circ Res 85(1):47–56

    Article  PubMed  CAS  Google Scholar 

  • Nakajima-Taniguchi C, Matsui H, Nagata S, Kishimoto T, Yamauchi-Takihara K (1995) Novel missense mutation in alpha-tropomyosin gene found in Japanese patients with hypertrophic cardiomyopathy. J Mol Cell Cardiol 27(9):2053–2058

    Article  PubMed  CAS  Google Scholar 

  • Oechslin E, Jenni R (2011) Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? Eur Heart J 32(12):1446–1456. doi:10.1093/eurheartj/ehq508

    Article  PubMed  Google Scholar 

  • 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. doi:10.4065/83.6.630

    PubMed  CAS  Google Scholar 

  • Olson TM, Kishimoto NY, Whitby FG, Michels VV (2001) Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. J Mol Cell Cardiol 33(4):723–732. doi:10.1006/jmcc.2000.1339

    Article  PubMed  CAS  Google Scholar 

  • Otsuka H, Arimura T, Abe T, Kawai H, Aizawa Y, Kubo T, Kitaoka H, Nakamura H, Nakamura K, Okamoto H, Ichida F, Ayusawa M, Nunoda S, Isobe M, Matsuzaki M, Doi YL, Fukuda K, Sasaoka T, Izumi T, Ashizawa N, Kimura A (2012) Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. Circ J 76(2):453–461

    Article  PubMed  CAS  Google Scholar 

  • Pak PH, Maughan WL, Baughman KL, Kieval RS, Kass DA (1998) Mechanism of acute mechanical benefit from VDD pacing in hypertrophied heart: similarity of responses in hypertrophic cardiomyopathy and hypertensive heart disease. Circulation 98(3):242–248

    Article  PubMed  CAS  Google Scholar 

  • Perry SV (2001) Vertebrate tropomyosin: distribution, properties and function. J Muscle Res Cell Motil 22(1):5–49

    Article  PubMed  CAS  Google Scholar 

  • Perry SV (2003) What is the role of tropomyosin in the regulation of muscle contraction? J Muscle Res Cell Motil 24(8):593–596

    Article  PubMed  CAS  Google Scholar 

  • Prabhakar R, Boivin GP, Grupp IL, Hoit B, Arteaga G, Solaro RJ, Wieczorek DF (2001) A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol 33(10):1815–1828. doi:10.1006/jmcc.2001.1445

    Article  PubMed  CAS  Google Scholar 

  • Probst S, Oechslin E, Schuler P, Greutmann M, Boye P, Knirsch W, Berger F, Thierfelder L, Jenni R, Klaassen S (2011) Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circ Cardiovasc Genet 4(4):367–374. doi:10.1161/CIRCGENETICS.110.959270

    Article  PubMed  CAS  Google Scholar 

  • Rajan S, Ahmed RP, Jagatheesan G, Petrashevskaya N, Boivin GP, Urboniene D, Arteaga GM, Wolska BM, Solaro RJ, Liggett SB, Wieczorek DF (2007) Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity. Circ Res 101(2):205–214. doi:10.1161/CIRCRESAHA.107.148379

    Article  PubMed  CAS  Google Scholar 

  • Regitz-Zagrosek V, Erdmann J, Wellnhofer E, Raible J, Fleck E (2000) Novel mutation in the alpha-tropomyosin gene and transition from hypertrophic to hypocontractile dilated cardiomyopathy. Circulation 102(17):E112–E116

    Article  PubMed  CAS  Google Scholar 

  • Ribolow H, Barany M (1977) Phosphorylation of tropomyosin in live frog muscle. Arch Biochem Biophys 179(2):718–720

    Article  PubMed  CAS  Google Scholar 

  • Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M (2003) Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107(17):2227–2232. doi:10.1161/01.CIR.0000066323.15244.54

    Article  PubMed  Google Scholar 

  • Robinson P, Griffiths PJ, Watkins H, Redwood CS (2007) Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. Circ Res 101(12):1266–1273. doi:10.1161/CIRCRESAHA.107.156380

    Article  PubMed  CAS  Google Scholar 

  • Rysev NA, Karpicheva OE, Redwood CS, Borovikov YS (2012) The effect of the Asp175Asn and Glu180Gly TPM1 mutations on actin-myosin interaction during the ATPase cycle. Biochim Biophys Acta 1824(2):366–373. doi:10.1016/j.bbapap.2011.11.004

    Article  PubMed  CAS  Google Scholar 

  • Schober T, Huke S, Venkataraman R, Gryshchenko O, Kryshtal D, Hwang HS, Baudenbacher FJ, Knollmann BC (2012) Myofilament Ca sensitization increases cytosolic Ca binding affinity, alters intracellular Ca homeostasis, and causes pause-dependent Ca-triggered arrhythmia. Circ Res 111(2):170–179. doi:10.1161/CIRCRESAHA.112.270041

    Article  PubMed  CAS  Google Scholar 

  • Schulz EM, Wieczorek DF (2013) Tropomyosin de-phosphorylation in the heart: what are the consequences? J Muscle Res Cell Motil. doi:10.1007/s10974-013-9348-7

    PubMed  Google Scholar 

  • Schulz EM, Correll RN, Sheikh HN, Lofrano-Alves MS, Engel PL, Newman G, Schultz Jel J, Molkentin JD, Wolska BM, Solaro RJ, Wieczorek DF (2012) Tropomyosin dephosphorylation results in compensated cardiac hypertrophy. J Biol Chem 287(53):44478–44489. doi:10.1074/jbc.M112.402040

    Article  PubMed  CAS  Google Scholar 

  • Schulz EM, Wilder T, Chowdhury SA, Sheikh HN, Wolska BM, Solaro RJ, Wieczorek DF (2013) Decreasing tropomyosin phosphorylation rescues tropomyosin induced familial hypertrophic cardiomyopathy. J Biol Chem. doi:10.1074/jbc.M113.466466

    Google Scholar 

  • Sequeira V, Wijnker PJ, Nijenkamp LL, Kuster DW, Najafi A, Witjas-Paalberends ER, Regan JA, Boontje N, Ten Cate FJ, Germans T, Carrier L, Sadayappan S, van Slegtenhorst MA, Zaremba R, Foster DB, Murphy AM, Poggesi C, Dos Remedios C, Stienen GJ, Ho CY, Michels M, van der Velden J (2013) Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations. Circ Res 112(11):1491–1505. doi:10.1161/CIRCRESAHA.111.300436

    Article  PubMed  CAS  Google Scholar 

  • Smith GA, Dixon HB, Kirschenlohr HL, Grace AA, Metcalfe JC, Vandenberg JI (2000) Ca2+ buffering in the heart: Ca2+ binding to and activation of cardiac myofibrils. Biochem J 346(Pt 2):393–402

    Article  PubMed  CAS  Google Scholar 

  • Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, Kim JB, Schmitt JP, Molkentin JD, Norris RA, Tager AM, Hoffman SR, Markwald RR, Seidman CE, Seidman JG (2010) Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-beta. J Clin Invest 120(10):3520–3529. doi:10.1172/JCI42028

    Article  PubMed  CAS  Google Scholar 

  • Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE (1994) Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 77(5):701–712

    Article  PubMed  Google Scholar 

  • Tobacman LS (1996) Thin filament-mediated regulation of cardiac contraction. Annu Rev Physiol 58:447–481. doi:10.1146/annurev.ph.58.030196.002311

    Article  PubMed  CAS  Google Scholar 

  • van de Meerakker JB, Christiaans I, Barnett P, Lekanne Deprez RH, Ilgun A, Mook OR, Mannens MM, Lam J, Wilde AA, Moorman AF, Postma AV (2013) A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding. Biochim Biophys Acta 1833(4):833–839. doi:10.1016/j.bbamcr.2012.11.003

    Article  PubMed  Google Scholar 

  • Van Driest SL, Will ML, Atkins DL, Ackerman MJ (2002) A novel TPM1 mutation in a family with hypertrophic cardiomyopathy and sudden cardiac death in childhood. Am J Cardiol 90(10):1123–1127

    Article  PubMed  Google Scholar 

  • Van Driest SL, Ellsworth EG, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ (2003) Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. Circulation 108(4):445–451. doi:10.1161/01.CIR.0000080896.52003.DF

    Article  PubMed  Google Scholar 

  • van Spaendonck-Zwarts KY, van Rijsingen IA, van den Berg MP, Lekanne Deprez RH, Post JG, van Mil AM, Asselbergs FW, Christiaans I, van Langen IM, Wilde AA, de Boer RA, Jongbloed JD, Pinto YM, van Tintelen JP (2013) Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years’ experience. Eur J Heart Fail. doi:10.1093/eurjhf/hft013

    PubMed  Google Scholar 

  • Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O’Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG et al (1995) Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 332(16):1058–1064. doi:10.1056/NEJM199504203321603

    Article  PubMed  CAS  Google Scholar 

  • Watkins H, Ashrafian H, Redwood C (2011) Inherited cardiomyopathies. N Engl J Med 364(17):1643–1656. doi:10.1056/NEJMra0902923

    Article  PubMed  CAS  Google Scholar 

  • Wernicke D, Thiel C, Duja-Isac CM, Essin KV, Spindler M, Nunez DJ, Plehm R, Wessel N, Hammes A, Edwards RJ, Lippoldt A, Zacharias U, Stromer H, Neubauer S, Davies MJ, Morano I, Thierfelder L (2004) 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 287(3):R685–R695. doi:10.1152/ajpregu.00620.2003

    Article  PubMed  CAS  Google Scholar 

  • Yamauchi-Takihara K, Nakajima-Taniguchi C, Matsui H, Fujio Y, Kunisada K, Nagata S, Kishimoto T (1996) Clinical implications of hypertrophic cardiomyopathy associated with mutations in the alpha-tropomyosin gene. Heart 76(1):63–65

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Our work has been supported by the British Heart Foundation and the European Community’s Seventh Framework Programme Grant Agreement No. 241577 (BIG-Heart).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charles Redwood.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Redwood, C., Robinson, P. Alpha-tropomyosin mutations in inherited cardiomyopathies. J Muscle Res Cell Motil 34, 285–294 (2013). https://doi.org/10.1007/s10974-013-9358-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10974-013-9358-5

Keywords

Navigation