| First Author | Prabhakar R | Year | 2001 |
| Journal | J Mol Cell Cardiol | Volume | 33 |
| Issue | 10 | Pages | 1815-28 |
| PubMed ID | 11603924 | Mgi Jnum | J:127507 |
| Mgi Id | MGI:3763833 | Doi | 10.1006/jmcc.2001.1445 |
| Citation | Prabhakar R, et al. (2001) A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol 33(10):1815-28 |
| abstractText | 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 alpha-tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in alpha-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 alpha-tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous alpha-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 alpha-tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality. |
