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

Tropomyosin. an essential component of the sarcomere, regulates muscle cont raction through Ca2+-mediated activation. Familial hypertrophic cardiomyopa thy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins. i ncluding myosin heavy and light chains, actin, troponin T and I. myosin bin ding protein C. and alpha -tropomyosin. This study developed transgenic mou se lines that encode an FHC mutation in alpha -tropomyosin; this mutation i s an amino acid substitution at codon 180 (Glu180Gly) which occurs in a tro ponin 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 c ontractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atr ial enlargement. are detected within I month. The disease-associated change s progressively increase and result in death between 4 and 5 months. Physio logical analyses of the FHC mice using echocardiography, work-performing he art analyses, and force measurements of cardiac myofibers, demonstrate dram atic functional differences in diastolic performance and increased sensitiv ity to calcium. This report demonstrates that mutations in alpha -tropomyos in can be severely disruptive of sarcomeric function, which consequently tr iggers a dramatic hypertrophic response that culminates in lethality. (C) 2 001 Academic Press.