J Mol Cell Cardiol 33, 1815–1828 (2001) doi:10.1006/jmcc.2001.1445, available online at http://www.idealibrary.com on A Familial Hypertrophic Cardiomyopathy -Tropomyosin Mutation Causes Severe Cardiac Hypertrophy and Death in Mice Rethinasamy Prabhakar 1 , Greg P. Boivin 2 , Ingrid L. Grupp 3 , Brian Hoit 4 , Grace Arteaga 5 , R. John Solaro 5 and David F. Wieczorek 1 1 Department of Molecular Genetics, Biochemistry and Microbiology, 2 Department of Pathology and Laboratory Medicine, and 3 Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, 4 Division of Cardiology, University Hospitals, 11100 Euclid Avenue, Cleveland, OH 44106-5038, and 5 Department of Physiology and Biophysics, University of Illinois, College of Medicine, Chicago (Received 26 April 2001, accepted in revised form 17 July 2001) R. P, G. P. B, I. L. G, B. H, G. A, R. J. S  D. F. W. A Familial Hypertrophic Cardiomyopathy -Tropomyosin Mutation Causes Severe Cardiac Hypertrophy and Death in Mice. Journal of Molecular and Cellular Cardiology (2001) 33, 1815–1828. Tropomyosin, an essential component of the sarcomere, regulates muscle contraction through Ca 2+ -mediated activation. Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins, including myosin heavy and light chains, actin, troponin T and I, myosin binding protein C, and -tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in -tropomyosin; this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region. Non-transgenic and control mice expressing wild- type -tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous -tropomyosin without altering the expression of other contractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atrial enlargement, are detected within 1 month. The disease-associated changes progressively increase and result in death between 4 and 5 months. Physiological analyses of the FHC mice using echocardiography, work-performing heart analyses, and force measurements of cardiac myofibers, demonstrate dramatic functional differences in diastolic performance and increased sensitivity to calcium. This report demonstrates that mutations in -tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality.  2001 Academic Press K W: Tropomyosin; Familial hypertrophic cardiomyopathy; Transgenic mice; Cardiac hypertrophy; Sarcomeric function. molecules form coiled-coil dimers that wrap around Introduction and stabilize filamentous actin. With increases in cytosolic calcium concentration, troponin C binds Tropomyosin (TM) is an essential muscle contractile protein that plays an integral role in regulating with calcium and, through its association with troponin T and I, mediates a change in the TM contractile activity through its interactions with actin and the troponin complex. Tropomyosin position on actin. Movement of TM and troponin I Please address all correspondence to: David F. Wieczorek, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA. 0022–2828/01/101815+14 $35.00/0  2001 Academic Press