Journal of Molecular Medicine

, 86:1197 | Cite as

Thin filament proteins mutations associated with skeletal myopathies: Defective regulation of muscle contraction



In humans, more than 140 different mutations within seven genes (ACTA1, TPM2, TPM3, TNNI2, TNNT1, TNNT3, and NEB) that encode thin filament proteins (skeletal α-actin, β-tropomyosin, γ-tropomyosin, fast skeletal muscle troponin I, slow skeletal muscle troponin T, fast skeletal muscle troponin T, and nebulin, respectively) have been identified. These mutations have been linked to muscle weakness and various congenital skeletal myopathies including nemaline myopathy, distal arthrogryposis, cap disease, actin myopathy, congenital fiber type disproportion, rod-core myopathy, intranuclear rod myopathy, and distal myopathy, with a dramatic negative impact on the quality of life. In this review, we discuss studies that use various approaches such as patient biopsy specimen samples, tissue culture systems or transgenic animal models, and that demonstrate how thin filament proteins mutations alter muscle structure and contractile function. With an enhanced understanding of the cellular and molecular mechanisms underlying muscle weakness in patients carrying such mutations, better therapy strategies can be developed to improve the quality of life.


Congenital myopathies Muscle weakness Atrophy Muscle contraction Thin filament proteins 


  1. 1.
    Schiaffino S, Reggiani C (1996) Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev 76:371–423PubMedGoogle Scholar
  2. 2.
    Gordon AM, Homsher E, Regnier M (2000) Regulation of contraction in striated muscle. Physiol Rev 80:853–924PubMedGoogle Scholar
  3. 3.
    Wang K, Wright J (1988) Architecture of the sarcomere matrix of skeletal muscle: immunoelectron microscopic evidence that suggests a set of parallel inextensible nebulin filaments anchored at the Z line. J Cell Biol 107:2199–2212PubMedCrossRefGoogle Scholar
  4. 4.
    Weber A, Pennise CR, Babcock GG, Fowler VM (1994) Tropomodulin caps the pointed ends of actin filaments. J Cell Biol 127:1627–1635PubMedCrossRefGoogle Scholar
  5. 5.
    Wang K (1996) Titin/connectin and nebulin: giant protein rulers of muscle structure and function. Adv Biophys 33:123–134PubMedCrossRefGoogle Scholar
  6. 6.
    Kostyukova AS, Tiktopulo EI, Maeda Y (2001) Folding properties of functional domains of tropomodulin. Biophys J 81:345–351PubMedGoogle Scholar
  7. 7.
    Tobacman LS (1996) Thin filament-mediated regulation of cardiac contraction. Annu Rev Physiol 58:447–481PubMedCrossRefGoogle Scholar
  8. 8.
    Hai H, Sano K, Maeda K, Maeda Y, Miki M (2002) Ca2+- and S1-induced conformational changes of reconstituted skeletal muscle thin filaments observed by fluorescence energy transfer spectroscopy: structural evidence for three States of thin filament. J Biochem 131:407–418PubMedGoogle Scholar
  9. 9.
    Craig R, Lehman W (2001) Crossbridge and tropomyosin positions observed in native, interacting thick and thin filaments. J Mol Biol 311:1027–1036PubMedCrossRefGoogle Scholar
  10. 10.
    McKillop DF, Geeves MA (1993) Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament. Biophys J 65:693–701PubMedGoogle Scholar
  11. 11.
    Goebel HH, Brockman K, Bonnemann CG, Warlo IA, Hanefeld F, Labeit S, Durling HJ, Laing NG (2006) Patient with actin aggregate myopathy and not formerly identified ACTA1 mutation is heterozygous for the Gly15Arg mutation of ACTA1, which has previously been associated with actinopathy. J Child Neurol 21:545PubMedGoogle Scholar
  12. 12.
    Sparrow JC, Nowak KJ, Durling HJ, Beggs AH, Wallgren-Pettersson C, Romero N, Nonaka I, Laing NG (2003) Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord 13:519–531PubMedCrossRefGoogle Scholar
  13. 13.
    Agrawal PB, Strickland CD, Midgett C, Morales A, Newburger DE, Poulos MA, Tomczak KK, Ryan MM, Iannaccone ST, Crawford TO, Laing NG, Beggs AH (2004) Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol 56:86–96PubMedCrossRefGoogle Scholar
  14. 14.
    Nowak KJ, Sewry CA, Navarro C, Squier W, Reina C, Ricoy JR, Jayawant SS, Childs AM, Dobbie JA, Appleton RE, Mountford RC, Walker KR, Clement S, Barois A, Muntoni F, Romero NB, Laing NG (2007) Nemaline myopathy caused by absence of alpha-skeletal muscle actin. Ann Neurol 61:175–184PubMedCrossRefGoogle Scholar
  15. 15.
    Hutchinson DO, Charlton A, Laing NG, Ilkovski B, North KN (2006) Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred. Neuromuscul Disord 16:113–121PubMedCrossRefGoogle Scholar
  16. 16.
    Laing NG, Clarke NF, Dye DE, Liyanage K, Walker KR, Kobayashi Y, Shimakawa S, Hagiwara T, Ouvrier R, Sparrow JC, Nishino I, North KN, Nonaka I (2004) Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol 56:689–694PubMedCrossRefGoogle Scholar
  17. 17.
    Ohlsson M, Tajsharghi H, Darin N, Kyllerman M, Oldfors A (2004) Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord 14:471–475PubMedCrossRefGoogle Scholar
  18. 18.
    Kaindl AM, Ruschendorf F, Krause S, Goebel HH, Koehler K, Becker C, Pongratz D, Muller-Hocker J, Nurnberg P, Stoltenburg-Didinger G, Lochmuller H, Huebner A (2004) Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet 41:842–848PubMedCrossRefGoogle Scholar
  19. 19.
    Tajsharghi H, Kimber E, Holmgren D, Tulinius M, Oldfors A (2007) Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation. Neurology 68:772–775PubMedCrossRefGoogle Scholar
  20. 20.
    Tajsharghi H, Ohlsson M, Lindberg C, Oldfors A (2007) Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-Tropomyosin gene (TPM2). Arch Neurol 64:1334–1338PubMedCrossRefGoogle Scholar
  21. 21.
    Sung SS, Brassington AM, Grannatt K, Rutherford A, Whitby FG, Krakowiak PA, Jorde LB, Carey JC, Bamshad M (2003) Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet 72:681–690PubMedCrossRefGoogle Scholar
  22. 22.
    Donner K, Ollikainen M, Ridanpaa M, Christen HJ, Goebel HH, de Visser M, Pelin K, Wallgren-Pettersson C (2002) Mutations in the beta-tropomyosin (TPM2) gene—a rare cause of nemaline myopathy. Neuromuscul Disord 12:151–158PubMedCrossRefGoogle Scholar
  23. 23.
    Lehtokari VL, Ceuterick-de Groote C, de Jonghe P, Marttila M, Laing NG, Pelin K, Wallgren-Pettersson C (2007) Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2. Neuromuscul Disord 17:433–442PubMedCrossRefGoogle Scholar
  24. 24.
    Lehtokari VL, Pelin K, Donner K, Voit T, Rudnik-Schoneborn S, Stoetter M, Talim B, Topaloglu H, Laing NG, Wallgren-Pettersson C (2008) Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin. Eur J Hum Genet in pressGoogle Scholar
  25. 25.
    Laing NG, Wilton SD, Akkari PA, Dorosz S, Boundy K, Kneebone C, Blumbergs P, White S, Watkins H, Love DR et al (1995) A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy NEM1. Nat Genet 10:249PubMedGoogle Scholar
  26. 26.
    Tan P, Briner J, Boltshauser E, Davis MR, Wilton SD, North K, Wallgren-Pettersson C, Laing NG (1999) Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy. Neuromuscul Disord 9:573–579PubMedCrossRefGoogle Scholar
  27. 27.
    Clarke NF, Kolski H, Dye DE, Lim E, Smith RL, Patel R, Fahey MC, Bellance R, Romero NB, Johnson ES, Labarre-Vila A, Monnier N, Laing NG, North KN (2008) Mutations in TPM3 are a common cause of congenital fiber type disproportion. Ann Neurol 63:329–337PubMedCrossRefGoogle Scholar
  28. 28.
    Penisson-Besnier I, Monnier N, Toutain A, Dubas F, Laing N (2007) A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: a clinical and pathological study. Neuromuscul Disord 17:330–337PubMedCrossRefGoogle Scholar
  29. 29.
    Shrimpton AE, Hoo JJ (2006) A TNNI2 mutation in a family with distal arthrogryposis type 2B. Eur J Med Genet 49:201–206PubMedCrossRefGoogle Scholar
  30. 30.
    Jiang M, Zhao X, Han W, Bian C, Li X, Wang G, Ao Y, Li Y, Yi D, Zhe Y, Lo WH, Zhang X, Li J (2006) A novel deletion in TNNI2 causes distal arthrogryposis in a large Chinese family with marked variability of expression. Hum Genet 120:238–242PubMedCrossRefGoogle Scholar
  31. 31.
    Kimber E, Tajsharghi H, Kroksmark AK, Oldfors A, Tulinius M (2006) A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis. Neurology 67:597–601PubMedCrossRefGoogle Scholar
  32. 32.
    Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, Schaffer AA, Francomano CA, Biesecker LG (2000) A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet 67:814–821PubMedCrossRefGoogle Scholar
  33. 33.
    Sung SS, Brassington AM, Krakowiak PA, Carey JC, Jorde LB, Bamshad M (2003) Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Am J Hum Genet 73:212–214PubMedCrossRefGoogle Scholar
  34. 34.
    Lehtokari VL, Pelin K, Sandbacka M, Ranta S, Donner K, Muntoni F, Sewry C, Angelini C, Bushby K, Van den Bergh P, Iannaccone S, Laing NG, Wallgren-Pettersson C (2006) Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Hum Mutat 27:946–956PubMedCrossRefGoogle Scholar
  35. 35.
    Wallgren-Pettersson C, Lehtokari VL, Kalimo H, Paetau A, Nuutinen E, Hackman P, Sewry C, Pelin K, Udd B (2007) Distal myopathy caused by homozygous missense mutations in the nebulin gene. Brain 130:1465–1476PubMedCrossRefGoogle Scholar
  36. 36.
    Pelin K, Hilpela P, Donner K, Sewry C, Akkari PA, Wilton SD, Wattanasirichaigoon D, Bang ML, Centner T, Hanefeld F, Odent S, Fardeau M, Urtizberea JA, Muntoni F, Dubowitz V, Beggs AH, Laing NG, Labeit S, de la Chapelle A, Wallgren-Pettersson C (1999) Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A 96:2305–2310PubMedCrossRefGoogle Scholar
  37. 37.
    Pelin K, Donner K, Holmberg M, Jungbluth H, Muntoni F, Wallgren-Pettersson C (2002) Nebulin mutations in autosomal recessive nemaline myopathy: an update. Neuromuscul Disord 12:680–686PubMedCrossRefGoogle Scholar
  38. 38.
    Sanoudou D, Beggs AH (2001) Clinical and genetic heterogeneity in nemaline myopathy—a disease of skeletal muscle thin filaments. Trends Mol Med 7:362–368PubMedCrossRefGoogle Scholar
  39. 39.
    North KN, Laing NG, Wallgren-Pettersson C (1997) Nemaline myopathy: current concepts. The ENMC International Consortium and Nemaline Myopathy. J Med Genet 34:705–713PubMedGoogle Scholar
  40. 40.
    Yamaguchi M, Robson RM, Stromer MH, Dahl DS, Oda T (1978) Actin filaments form the backbone of nemaline myopathy rods. Nature 271:265–267PubMedCrossRefGoogle Scholar
  41. 41.
    Jockusch BM, Veldman H, Griffiths GW, van Oost BA, Jennekens FG (1980) Immunofluorescence microscopy of a myopathy. alpha-Actinin is a major constituent of nemaline rods. Exp Cell Res 127:409–420PubMedCrossRefGoogle Scholar
  42. 42.
    Schroder R, Reimann J, Salmikangas P, Clemen CS, Hayashi YK, Nonaka I, Arahata K, Carpen O (2003) Beyond LGMD1A: myotilin is a component of central core lesions and nemaline rods. Neuromuscul Disord 13:451–455PubMedCrossRefGoogle Scholar
  43. 43.
    Muller-Hocker J, Schafer S, Mendel B, Lochmuller H, Pongratz D (2000) Nemaline cardiomyopathy in a young adult: an ultraimmunohistochemical study and review of the literature. Ultrastruct Pathol 24:407–416PubMedCrossRefGoogle Scholar
  44. 44.
    Michele DE, Metzger JM (2000) Physiological consequences of tropomyosin mutations associated with cardiac and skeletal myopathies. J Mol Med 78:543–553PubMedCrossRefGoogle Scholar
  45. 45.
    Corbett MA, Robinson CS, Dunglison GF, Yang N, Joya JE, Stewart AW, Schnell C, Gunning PW, North KN, Hardeman EC (2001) A mutation in alpha-tropomyosin(slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy. Hum Mol Genet 10:317–328PubMedCrossRefGoogle Scholar
  46. 46.
    Crawford K, Flick R, Close L, Shelly D, Paul R, Bove K, Kumar A, Lessard J (2002) Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period. Mol Cell Biol 22:5887–5896PubMedCrossRefGoogle Scholar
  47. 47.
    Sanoudou D, Haslett JN, Kho AT, Guo S, Gazda HT, Greenberg SA, Lidov HG, Kohane IS, Kunkel LM, Beggs AH (2003) Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle. Proc Natl Acad Sci U S A 100:4666–4671PubMedCrossRefGoogle Scholar
  48. 48.
    Marston S, Mirza M, Abdulrazzak H, Sewry C (2004) Functional characterisation of a mutant actin (Met132Val) from a patient with nemaline myopathy. Neuromuscul Disord 14:167–174PubMedCrossRefGoogle Scholar
  49. 49.
    D’Amico A, Graziano C, Pacileo G, Petrini S, Nowak KJ, Boldrini R, Jacques A, Feng JJ, Porfirio B, Sewry CA, Santorelli FM, Limongelli G, Bertini E, Laing N, Marston SB (2006) Fatal hypertrophic cardiomyopathy and nemaline myopathy associated with ACTA1 K336E mutation. Neuromuscul Disord 16:548–552PubMedCrossRefGoogle Scholar
  50. 50.
    Ochala J, Li M, Ohlsson M, Oldfors A, Larsson L (2008) Defective regulation of contractile function in muscle fibres carrying an E41K beta-tropomyosin mutation. J Physiol in pressGoogle Scholar
  51. 51.
    Corbett MA, Akkari PA, Domazetovska A, Cooper ST, North KN, Laing NG, Gunning PW, Hardeman EC (2005) An alphaTropomyosin mutation alters dimer preference in nemaline myopathy. Ann Neurol 57:42–49PubMedCrossRefGoogle Scholar
  52. 52.
    Michele DE, Albayya FP, Metzger JM (1999) A nemaline myopathy mutation in alpha-tropomyosin causes defective regulation of striated muscle force production. J Clin Invest 104:1575–1581PubMedCrossRefGoogle Scholar
  53. 53.
    McLachlan AD, Stewart M (1975) Tropomyosin coiled-coil interactions: evidence for an unstaggered structure. J Mol Biol 98:293–304PubMedCrossRefGoogle Scholar
  54. 54.
    Brown JH, Kim KH, Jun G, Greenfield NJ, Dominguez R, Volkmann N, Hitchcock-DeGregori SE, Cohen C (2001) Deciphering the design of the tropomyosin molecule. Proc Natl Acad Sci U S A 98:8496–8501PubMedCrossRefGoogle Scholar
  55. 55.
    Singh A, Hitchcock-DeGregori SE (2003) Local destabilization of the tropomyosin coiled coil gives the molecular flexibility required for actin binding. Biochemistry 42:14114–14121PubMedCrossRefGoogle Scholar
  56. 56.
    Singh A, Hitchcock-DeGregori SE (2006) Dual requirement for flexibility and specificity for binding of the coiled-coil tropomyosin to its target, actin. Structure 14:43–50PubMedCrossRefGoogle Scholar
  57. 57.
    Cammarato A, Craig R, Sparrow JC, Lehman W (2005) E93K charge reversal on actin perturbs steric regulation of thin filaments. J Mol Biol 347:889–894PubMedCrossRefGoogle Scholar
  58. 58.
    Moraczewska J, Greenfield NJ, Liu Y, Hitchcock-DeGregori SE (2000) Alteration of tropomyosin function and folding by a nemaline myopathy-causing mutation. Biophys J 79:3217–3225PubMedCrossRefGoogle Scholar
  59. 59.
    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 280:28498–28506PubMedCrossRefGoogle Scholar
  60. 60.
    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 282:13487–13497PubMedCrossRefGoogle Scholar
  61. 61.
    Tobacman LS, Nihli M, Butters C, Heller M, Hatch V, Craig R, Lehman W, Homsher E (2002) The troponin tail domain promotes a conformational state of the thin filament that suppresses myosin activity. J Biol Chem 277:27636–27642PubMedCrossRefGoogle Scholar
  62. 62.
    Chang AN, Harada K, Ackerman MJ, Potter JD (2005) Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin. J Biol Chem 280:34343–34349PubMedCrossRefGoogle Scholar
  63. 63.
    Clarke NF, Ilkovski B, Cooper S, Valova VA, Robinson PJ, Nonaka I, Feng JJ, Marston S, North K (2007) The pathogenesis of ACTA1-related congenital fiber type disproportion. Ann Neurol 61:552–561PubMedCrossRefGoogle Scholar
  64. 64.
    Wattanasirichaigoon D, Swoboda KJ, Takada F, Tong HQ, Lip V, Iannaccone ST, Wallgren-Pettersson C, Laing NG, Beggs AH (2002) Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy. Neurology 59:613–617PubMedGoogle Scholar
  65. 65.
    Nilsson J, Tajsharghi H (2008) beta-Tropomyosin mutations alter tropomyosin isoform composition. Eur J Neurol 15:573–578PubMedCrossRefGoogle Scholar
  66. 66.
    Palmiter KA, Kitada Y, Muthuchamy M, Wieczorek DF, Solaro RJ (1996) Exchange of beta- for alpha-tropomyosin in hearts of transgenic mice induces changes in thin filament response to Ca2+, strong cross-bridge binding, and protein phosphorylation. J Biol Chem 271:11611–11614PubMedCrossRefGoogle Scholar
  67. 67.
    Wolska BM, Keller RS, Evans CC, Palmiter KA, Phillips RM, Muthuchamy M, Oehlenschlager J, Wieczorek DF, de Tombe PP, Solaro RJ (1999) Correlation between myofilament response to Ca2+ and altered dynamics of contraction and relaxation in transgenic cardiac cells that express beta-tropomyosin. Circ Res 84:745–751PubMedGoogle Scholar
  68. 68.
    Boussouf SE, Maytum R, Jaquet K, Geeves MA (2007) Role of tropomyosin isoforms in the calcium sensitivity of striated muscle thin filaments. J Muscle Res Cell Motil 28:49–58PubMedCrossRefGoogle Scholar
  69. 69.
    Joya JE, Kee AJ, Nair-Shalliker V, Ghoddusi M, Nguyen MA, Luther P, Hardeman EC (2004) Muscle weakness in a mouse model of nemaline myopathy can be reversed with exercise and reveals a novel myofiber repair mechanism. Hum Mol Genet 13:2633–2645PubMedCrossRefGoogle Scholar
  70. 70.
    Beals RK (2005) The distal arthrogryposes: a new classification of peripheral contractures. Clin Orthop Relat Res 435:203–210PubMedCrossRefGoogle Scholar
  71. 71.
    Ochala J, Li M, Tajsharghi H, Kimber E, Tulinius M, Oldfors A, Larsson L (2007) Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres. J Physiol 581:1283–1292PubMedCrossRefGoogle Scholar
  72. 72.
    Robinson P, Lipscomb S, Preston LC, Altin E, Watkins H, Ashley CC, Redwood CS (2007) Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function. FASEB J 21:896–905PubMedCrossRefGoogle Scholar
  73. 73.
    Brenner B (1988) Effect of Ca2+ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: implications for regulation of muscle contraction. Proc Natl Acad Sci U S A 85:3265–3269PubMedCrossRefGoogle Scholar
  74. 74.
    Rarick HM, Tu XH, Solaro RJ, Martin AF (1997) The C terminus of cardiac troponin I is essential for full inhibitory activity and Ca2+ sensitivity of rat myofibrils. J Biol Chem 272:26887–26892PubMedCrossRefGoogle Scholar
  75. 75.
    Palm T, Graboski S, Hitchcock-DeGregori SE, Greenfield NJ (2001) Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region. Biophys J 81:2827–2837PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Neuroscience, Clinical NeurophysiologyUniversity HospitalUppsalaSweden

Personalised recommendations