© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy
aDepartment of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
bMRC/US Centre for Molecular and Cellular Biology, University of Stellenbosch Medical School, Tygerberg, South Africa
* Corresponding author. Tel.: +44-1856-22-0257; fax: +44-1865-76-8844 hugh.watkins{at}cardiov.ox.ac.uk
Hypertrophic cardiomyopathy (HCM) is one of the most frequently occurring inherited cardiac disorders, affecting up to 1 in 500 of the population. Molecular genetic analysis has shown that HCM is a disease of the sarcomere, caused by mutations in certain contractile protein genes. To date seven disease-associated genes have been identified, those encoding β-myosin heavy chain, both regulatory and essential myosin light chains, myosin binding protein-C, cardiac troponin T, cardiac troponin I and 
-tropomyosin. Here we review the analyses of how these mutations affect the in vitro contractile protein function and the hypotheses derived to explain the development of the disease state.
KEYWORDS Contractile proteins; Heart muscle; Cardiomyopathy; Hypertrophy; Mutation
1 These authors contributed equally to this work.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Marston, O. Copeland, A. Jacques, K. Livesey, V. Tsang, W. J. McKenna, S. Jalilzadeh, S. Carballo, C. Redwood, and H. Watkins Evidence From Human Myectomy Samples That MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy Through Haploinsufficiency Circ. Res., July 31, 2009; 105(3): 219 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Esposito, F De Cobelli, G Perseghin, M Pieroni, E Belloni, R Mellone, T Canu, F Gentinetta, P Scifo, C Chimenti, et al. Impaired left ventricular energy metabolism in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging Heart, February 1, 2009; 95(3): 228 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H Watkins, H Ashrafian, and W J McKenna The genetics of hypertrophic cardiomyopathy: Teare redux Heart, October 1, 2008; 94(10): 1264 - 1268. [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Jacques, N. Briceno, A. E. Messer, C. E. Gallon, S. Jalilzadeh, E. Garcia, G. Kikonda-Kanda, J. Goddard, S. E. Harding, H. Watkins, et al. The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy Cardiovasc Res, August 1, 2008; 79(3): 481 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C Gaze and P. O Collinson Multiple molecular forms of circulating cardiac troponin: analytical and clinical significance Ann Clin Biochem, July 1, 2008; 45(4): 349 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Du, J. Liu, H.-Z. Feng, M. M. Hossain, N. Gobara, C. Zhang, Y. Li, P.-Y. Jean-Charles, J.-P. Jin, and X.-P. Huang Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2604 - H2613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Gillis, C. R. Marshall, and G. F. Tibbits Functional and evolutionary relationships of troponin C Physiol Genomics, December 19, 2007; 32(1): 16 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, J. Du, C. Zhang, J. W. Walker, and X. Huang Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1273 - H1281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ashrafian and H. Watkins Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications: Cardiomyopathies: Therapeutics Based on Molecular Phenotype J. Am. Coll. Cardiol., March 27, 2007; 49(12): 1251 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Adamcova, M. Sterba, T. Simunek, A. Potacova, O. Popelova, and V. Gersl Myocardial regulatory proteins and heart failure Eur J Heart Fail, June 1, 2006; 8(4): 333 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. M. Hernandez, D. Szczesna-Cordary, B. C. Knollmann, T. Miller, M. Bell, J. Zhao, S. G. Sirenko, Z. Diaz, G. Guzman, Y. Xu, et al. F110I and R278C Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy Affect Muscle Contraction in Transgenic Mice and Reconstituted Human Cardiac Fibers J. Biol. Chem., November 4, 2005; 280(44): 37183 - 37194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Gillis, B. Liang, F. Chung, and G. F. Tibbits Increasing mammalian cardiomyocyte contractility with residues identified in trout troponin C Physiol Genomics, June 16, 2005; 22(1): 1 - 7. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sanoudou, E. Vafiadaki, D. A. Arvanitis, E. Kranias, and A. Kontrogianni-Konstantopoulos Array lessons from the heart: focus on the genome and transcriptome of cardiomyopathies Physiol Genomics, April 14, 2005; 21(2): 131 - 143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Kirschner, E. Becker, M. Antognozzi, H.-P. Kubis, A. Francino, F. Navarro-Lopez, N. Bit-Avragim, A. Perrot, M. M. Mirrakhimov, K.-J. Osterziel, et al. Hypertrophic cardiomyopathy-related {beta}-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1242 - H1251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Flashman, C. Redwood, J. Moolman-Smook, and H. Watkins Cardiac Myosin Binding Protein C: Its Role in Physiology and Disease Circ. Res., May 28, 2004; 94(10): 1279 - 1289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Coutu, C. N. Bennett, E. G. Favre, S. M. Day, and J. M. Metzger Parvalbumin Corrects Slowed Relaxation in Adult Cardiac Myocytes Expressing Hypertrophic Cardiomyopathy-Linked {alpha}-Tropomyosin Mutations Circ. Res., May 14, 2004; 94(9): 1235 - 1241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Nongthomba, S. Clark, M. Cummins, M. Ansari, M. Stark, and J. C. Sparrow Troponin I is required for myofibrillogenesis and sarcomere formation in Drosophila flight muscle J. Cell Sci., May 1, 2004; 117(9): 1795 - 1805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Olsson, B. M. Palmer, B. L. Stauffer, L. A. Leinwand, and R. L. Moore Morphological and Functional Alterations in Ventricular Myocytes From Male Transgenic Mice With Hypertrophic Cardiomyopathy Circ. Res., February 6, 2004; 94(2): 201 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Woo, H Rakowski, J C Liew, M-S Zhao, C-C Liew, T G Parker, M Zeller, E D Wigle, and M J Sole Mutations of the {beta} myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis Heart, October 1, 2003; 89(10): 1179 - 1185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kohler, Y. Chen, B. Brenner, A. M. Gordon, T. Kraft, D. A. Martyn, M. Regnier, A. J. Rivera, C.-K. Wang, and P. B. Chase Familial hypertrophic cardiomyopathy mutations in troponin I (K183{Delta}, G203S, K206Q) enhance filament sliding Physiol Genomics, July 7, 2003; 14(2): 117 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Crilley, E. A. Boehm, E. Blair, B. Rajagopalan, A. M. Blamire, P. Styles, W. J. McKenna, I. Ostman-Smith, K. Clarke, and H. Watkins Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1776 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Nongthomba, M. Cummins, S. Clark, J. O. Vigoreaux, and J. C. Sparrow Suppression of Muscle Hypercontraction by Mutations in the Myosin Heavy Chain Gene of Drosophila melanogaster Genetics, May 1, 2003; 164(1): 209 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Watkins Genetic Clues to Disease Pathways in Hypertrophic and Dilated Cardiomyopathies Circulation, March 18, 2003; 107(10): 1344 - 1346. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Seidman Genetic Causes of Inherited Cardiac Hypertrophy: Robert L. Frye Lecture Mayo Clin. Proc., December 1, 2002; 77(12): 1315 - 1319. [Abstract] [PDF]
|
|
|
|
|
|
P. Robinson, M. Mirza, A. Knott, H. Abdulrazzak, R. Willott, S. Marston, H. Watkins, and C. Redwood Alterations in Thin Filament Regulation Induced by a Human Cardiac Troponin T Mutant That Causes Dilated Cardiomyopathy Are Distinct from Those Induced by Troponin T Mutants That Cause Hypertrophic Cardiomyopathy J. Biol. Chem., October 18, 2002; 277(43): 40710 - 40716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Moolman-Smook, E. Flashman, W. de Lange, Z. Li, V. Corfield, C. Redwood, and H. Watkins Identification of Novel Interactions Between Domains of Myosin Binding Protein-C That Are Modulated by Hypertrophic Cardiomyopathy Missense Mutations Circ. Res., October 18, 2002; 91(8): 704 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, M. X. Li, and B. D. Sykes Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin I147-163 and Bepridil J. Biol. Chem., August 16, 2002; 277(34): 31124 - 31133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Michele, C. A. Gomez, K. E. Hong, M. V. Westfall, and J. M. Metzger Cardiac Dysfunction in Hypertrophic Cardiomyopathy Mutant Tropomyosin Mice Is Transgene-Dependent, Hypertrophy-Independent, and Improved by {beta}-Blockade Circ. Res., August 9, 2002; 91(3): 255 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Olson, M. L. Karst, F. G. Whitby, and D. J. Driscoll Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology Circulation, May 21, 2002; 105(20): 2337 - 2340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Biesiadecki and J.-P. Jin Exon Skipping in Cardiac Troponin T of Turkeys with Inherited Dilated Cardiomyopathy J. Biol. Chem., May 17, 2002; 277(21): 18459 - 18468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Blair, C. Redwood, M. de Jesus Oliveira, J.C. Moolman-Smook, P. Brink, V.A. Corfield, I. Ostman-Smith, and H. Watkins Mutations of the Light Meromyosin Domain of the {beta}-Myosin Heavy Chain Rod in Hypertrophic Cardiomyopathy Circ. Res., February 22, 2002; 90(3): 263 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shimizu, H. Ino, M. Yamaguchi, H. Terai, K. Hayashi, K. Nakajima, J. Taki, and H. Mabuchi Heterogeneity of Cardiac Sympathetic Nerve Activity and Systolic Dysfunction in Patients with Hypertrophic Cardiomyopathy J. Nucl. Med., January 1, 2002; 43(1): 15 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.J. Janse and J.M.T. De Bakker Arrhythmia substrate and management in hypertrophic cardiomyopathy: from molecules to implantable card ioverter-defibrillators Eur. Heart J. Suppl., October 1, 2001; 3(suppl_L): L15 - L20. [Abstract] [PDF]
|
|
|
|
|
|
H. Watkins Hypertrophic cardiomyopathy: from molecular and genetic mechanisms to clinical management Eur. Heart J. Suppl., October 1, 2001; 3(suppl_L): L43 - L50. [Abstract] [PDF]
|
|
|
|
 |
|
 S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, A.J. Camm, R. Cappato, S.M. Cobbe, C. Di Mario, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology Eur. Heart J., August 2, 2001; 22(16): 1374 - 1450. [PDF]
|
|
|
|
 |
|
 E. Blair, C. Redwood, H. Ashrafian, M. Oliveira, J. Broxholme, B. Kerr, A. Salmon, I. Ostman-Smith, and H. Watkins Mutations in the {{gamma}}2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis Hum. Mol. Genet., May 1, 2001; 10(11): 1215 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Naimi, A. Harrison, M. Cummins, U. Nongthomba, S. Clark, I. Canal, A. Ferrus, and J. C. Sparrow A Tropomyosin-2 Mutation Suppresses a Troponin I Myopathy in Drosophila Mol. Biol. Cell, May 1, 2001; 12(5): 1529 - 1539. [Abstract] [Full Text]
|
|
|
|
 |
|
 O. M. Hernandez, P. R. Housmans, and J. D. Potter Plasticity in Skeletal, Cardiac, and Smooth Muscle: Invited Review: Pathophysiology of cardiac muscle contraction and relaxation as a result of alterations in thin filament regulation J Appl Physiol, March 1, 2001; 90(3): 1125 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Olsson, B. M. Palmer, L. A. Leinwand, and R. L. Moore Gender and aging in a transgenic mouse model of hypertrophic cardiomyopathy Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1136 - H1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kokado, M. Shimizu, H. Yoshio, H. Ino, K. Okeie, Y. Emoto, T. Matsuyama, M. Yamaguchi, T. Yasuda, N. Fujino, et al. Clinical Features of Hypertrophic Cardiomyopathy Caused by a Lys183 Deletion Mutation in the Cardiac Troponin I Gene Circulation, August 8, 2000; 102(6): 663 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Redwood, K. Lohmann, W. Bing, G. M. Esposito, K. Elliott, H. Abdulrazzak, A. Knott, I. Purcell, S. Marston, and H. Watkins Investigation of a Truncated Cardiac Troponin T That Causes Familial Hypertrophic Cardiomyopathy : Ca2+ Regulatory Properties of Reconstituted Thin Filaments Depend on the Ratio of Mutant to Wild-Type Protein Circ. Res., June 9, 2000; 86(11): 1146 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Watkins Sudden Death in Hypertrophic Cardiomyopathy N. Engl. J. Med., February 10, 2000; 342(6): 422 - 424. [Full Text]
|
|
|
|
|
|
K. Elliott, H. Watkins, and C. S. Redwood Altered Regulatory Properties of Human Cardiac Troponin I Mutants That Cause Hypertrophic Cardiomyopathy J. Biol. Chem., July 14, 2000; 275(29): 22069 - 22074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Blair, C. Redwood, M. de Jesus Oliveira, J.C. Moolman-Smook, P. Brink, V.A. Corfield, I. Ostman-Smith, and H. Watkins Mutations of the Light Meromyosin Domain of the {beta}-Myosin Heavy Chain Rod in Hypertrophic Cardiomyopathy Circ. Res., February 22, 2002; 90(3): 263 - 269. [Abstract] [Full Text] [PDF]
|
|