A familial hypertrophic cardiomyopathy α-tropomyosin mutation causes severe cardiac hypertrophy and death in mice

Tropomyosin. an essential component of the sarcomere, regulates muscle contraction through Ca2+-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 wildtype 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 I 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. (C) 2001 Academic Press.