R. Prabhakar et al., A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice, J MOL CEL C, 33(10), 2001, pp. 1815-1828
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.