| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2000 American Heart Association, Inc.
Integrative Physiology |
Transgenic Modeling of a Cardiac Troponin I Mutation Linked to Familial Hypertrophic Cardiomyopathy
From the Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Children’s Hospital Research Foundation, Cincinnati, Ohio.
Correspondence to J. Robbins, PhD, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.robbins{at}chmcc.org
Abstract—Multiple
mutations in cardiac troponin I (cTnI) have been associated with
familial hypertrophic cardiomyopathy. Two mutations are located in the
cTnI inhibitory domain, a highly negatively charged region that
alternately binds to either actin or troponin C, depending on the
intracellular concentration of calcium. This region is critical to the
inhibition of actin-myosin crossbridge formation when intracellular
calcium is low. We modeled one of the inhibitory domain mutations,
arginine145
glycine (TnI146Gly in the
mouse sequence), by cardiac-specific expression of the mutated protein
in transgenic mice. Multiple lines were generated with varying degrees
of expression to establish a dose relationship; the severity of
phenotype could be correlated directly with transgene expression
levels. Transgenic mice overexpressing wild-type cTnI were generated as
controls and analyzed in parallel with the
TnI146Gly animals. The control mice showed
no abnormalities, indicating that the phenotype of
TnI146Gly was not simply an artifact of
transgenesis. In contrast, TnI146Gly mice
showed cardiomyocyte disarray and interstitial fibrosis and suffered
premature death. The functional alterations that seem to be responsible
for the development of cardiac disease include increased skinned fiber
sensitivity to calcium and, at the whole organ level,
hypercontractility with diastolic dysfunction. Severely affected lines
develop a pathology similar to human familial hypertrophic
cardiomyopathy but within a dramatically shortened time frame. These
data establish the causality of this mutation for cardiac disease,
provide an animal model for understanding the resultant pathogenic
structure-function relationships, and highlight the differences in
phenotype severity of the troponin mutations between human and mouse
hearts.
Key Words: hypertrophic cardiomyopathy mouse cardiac troponin I sarcomere
This article has been cited by other articles:
 |
|
 |
|
  S. Morimoto Expanded Spectrum of Gene Causing Both Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy Circ. Res., August 14, 2009; 105(4): 313 - 315. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lange, B. Kaynak, U. B. Forster, M. Tonjes, J. J. Fischer, C. Grimm, J. Schlesinger, S. Just, I. Dunkel, T. Krueger, et al. Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex Genes & Dev., September 1, 2008; 22(17): 2370 - 2384. [Abstract] [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]
|
|
|
|
 |
|
 Y. Wen, J. R. Pinto, A. V. Gomes, Y. Xu, Y. Wang, Y. Wang, J. D. Potter, and W. G. L. Kerrick Functional Consequences of the Human Cardiac Troponin I Hypertrophic Cardiomyopathy Mutation R145G in Transgenic Mice J. Biol. Chem., July 18, 2008; 283(29): 20484 - 20494. [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. Tsoutsman, M. Kelly, D. C.H. Ng, J.-E. Tan, E. Tu, L. Lam, M. A. Bogoyevitch, C. E. Seidman, J.G. Seidman, and C. Semsarian Severe Heart Failure and Early Mortality in a Double-Mutation Mouse Model of Familial Hypertrophic Cardiomyopathy Circulation, April 8, 2008; 117(14): 1820 - 1831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sadayappan, N. Finley, J. W. Howarth, H. Osinska, R. Klevitsky, J. N. Lorenz, P. R. Rosevear, and J. Robbins Role of the acidic N' region of cardiac troponin I in regulating myocardial function FASEB J, April 1, 2008; 22(4): 1246 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Morimoto Sarcomeric proteins and inherited cardiomyopathies Cardiovasc Res, March 1, 2008; 77(4): 659 - 666. [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]
|
|
|
|
 |
|
 T. Kubo, J. R. Gimeno, A. Bahl, U. Steffensen, M. Steffensen, E. Osman, R. Thaman, J. Mogensen, P. M. Elliott, Y. Doi, et al. Prevalence, Clinical Significance, and Genetic Basis of Hypertrophic Cardiomyopathy With Restrictive Phenotype J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2419 - 2426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Davis, H. Wen, T. Edwards, and J. M. Metzger Thin Filament Disinhibition by Restrictive Cardiomyopathy Mutant R193H Troponin I Induces Ca2+-Independent Mechanical Tone and Acute Myocyte Remodeling Circ. Res., May 25, 2007; 100(10): 1494 - 1502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, M. W. Ashford, J. Chen, M. P. Watkins, T. A. Williams, S. A. Wickline, and X. Yu MR tagging demonstrates quantitative differences in regional ventricular wall motion in mice, rats, and men Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2515 - H2521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kobayashi and R. J. Solaro Increased Ca2+ Affinity of Cardiac Thin Filaments Reconstituted with Cardiomyopathy-related Mutant Cardiac Troponin I J. Biol. Chem., May 12, 2006; 281(19): 13471 - 13477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Gomes, J. Liang, and J. D. Potter Mutations in Human Cardiac Troponin I That Are Associated with Restrictive Cardiomyopathy Affect Basal ATPase Activity and the Calcium Sensitivity of Force Development J. Biol. Chem., September 2, 2005; 280(35): 30909 - 30915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Szczesna-Cordary, G. Guzman, J. Zhao, O. Hernandez, J. Wei, and Z. Diaz-Perez The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice J. Cell Sci., August 15, 2005; 118(16): 3675 - 3683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.J. Marian On Mice, Rabbits, and Human Heart Failure Circulation, May 10, 2005; 111(18): 2276 - 2279. [Full Text] [PDF]
|
|
|
|
|
|
A. Sanbe, J. James, V. Tuzcu, S. Nas, L. Martin, J. Gulick, H. Osinska, S. Sakthivel, R. Klevitsky, K. S. Ginsburg, et al. Transgenic Rabbit Model for Human Troponin I-Based Hypertrophic Cardiomyopathy Circulation, May 10, 2005; 111(18): 2330 - 2338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. James, L. Martin, M. Krenz, C. Quatman, F. Jones, R. Klevitsky, J. Gulick, and J. Robbins Forced Expression of {alpha}-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions Circulation, May 10, 2005; 111(18): 2339 - 2346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Kruger, S Zittrich, C Redwood, N Blaudeck, J James, J Robbins, G Pfitzer, and R Stehle Effects of the mutation R145G in human cardiac troponin I on the kinetics of the contraction-relaxation cycle in isolated cardiac myofibrils J. Physiol., April 15, 2005; 564(2): 347 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sakthivel, N. L. Finley, P. R. Rosevear, J. N. Lorenz, J. Gulick, S. Kim, P. VanBuren, L. A. Martin, and J. Robbins In Vivo and in Vitro Analysis of Cardiac Troponin I Phosphorylation J. Biol. Chem., January 7, 2005; 280(1): 703 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yan, R. L. Price, M. Nakayama, K. Ito, A. J. T. Schuldt, W. J. Manning, A. Sanbe, T. K. Borg, J. Robbins, and B. H. Lorell Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2179 - H2187. [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]
|
|
|
|
|
|
A. Hinkle and L. S. Tobacman Folding and Function of the Troponin Tail Domain. EFFECTS OF CARDIOMYOPATHIC TROPONIN T MUTATIONS J. Biol. Chem., January 3, 2003; 278(1): 506 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fatkin and R. M. Graham Molecular Mechanisms of Inherited Cardiomyopathies Physiol Rev, October 1, 2002; 82(4): 945 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Murphy Troponin I: In Sickness and In Health--and Normal Development Circ. Res., September 20, 2002; 91(6): 449 - 450. [Full Text] [PDF]
|
|
|
|
|
|
M. V. Westfall, A. R. Borton, F. P. Albayya, and J. M. Metzger Myofilament Calcium Sensitivity and Cardiac Disease: Insights From Troponin I Isoforms and Mutants Circ. Res., September 20, 2002; 91(6): 525 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Wolska, G. M. Arteaga, J. R. Pena, G. Nowak, R. M. Phillips, S. Sahai, P. P. de Tombe, A. F. Martin, E. G. Kranias, and R. J. Solaro Expression of Slow Skeletal Troponin I in Hearts of Phospholamban Knockout Mice Alters the Relaxant Effect of {beta}-Adrenergic Stimulation Circ. Res., May 3, 2002; 90(8): 882 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lang, A. V. Gomes, J. Zhao, P. R. Housmans, T. Miller, and J. D. Potter Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy J. Biol. Chem., March 29, 2002; 277(14): 11670 - 11678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. F Bueno, E. van Rooij, J. D Molkentin, P. A Doevendans, and L. J De Windt Calcineurin and hypertrophic heart disease: novel insights and remaining questions Cardiovasc Res, March 1, 2002; 53(4): 806 - 821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Morimoto, Q.-W. Lu, K. Harada, F. Takahashi-Yanaga, R. Minakami, M. Ohta, T. Sasaguri, and I. Ohtsuki Ca2+-desensitizing effect of a deletion mutation Delta K210 in cardiac troponin T that causes familial dilated cardiomyopathy PNAS, January 1, 2002; (2002) 22628899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M Wolska, K. Vijayan, G. M Arteaga, J. P Konhilas, R. M Phillips, R. Kim, T. Naya, J. M Leiden, A. F Martin, P. P de Tombe, et al. Expression of slow skeletal troponin I in adult transgenic mouse heart muscle reduces the force decline observed during acidic conditions J. Physiol., November 1, 2001; 536(3): 863 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
S. Morimoto, Q.-W. Lu, K. Harada, F. Takahashi-Yanaga, R. Minakami, M. Ohta, T. Sasaguri, and I. Ohtsuki Ca2+-desensitizing effect of a deletion mutation Delta K210 in cardiac troponin T that causes familial dilated cardiomyopathy PNAS, January 22, 2002; 99(2): 913 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Wolska, G. M. Arteaga, J. R. Pena, G. Nowak, R. M. Phillips, S. Sahai, P. P. de Tombe, A. F. Martin, E. G. Kranias, and R. J. Solaro Expression of Slow Skeletal Troponin I in Hearts of Phospholamban Knockout Mice Alters the Relaxant Effect of {beta}-Adrenergic Stimulation Circ. Res., May 3, 2002; 90(8): 882 - 888. [Abstract] [Full Text] [PDF]
|
|