A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
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.
Prabhakar
R
R
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA.
Boivin
G P
GP
Grupp
I L
IL
Hoit
B
B
Arteaga
G
G
Solaro
R J
RJ
Wieczorek
D F
DF
D000367:Age Factors; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012313:RNA / Q000378:metabolism; D013997:Time Factors; D014335:Tropomyosin / Q000235:genetics*
D000596:Amino Acids; D014335:Tropomyosin; D012313:RNA; D002118:Calcium