A mouse model of familial hypertrophic cardiomyopathy caused by a alpha-tropomyosin mutation

Rethinasamy Prabhakar, Natalia Petrashevskaya, Arnold Schwartz, Bruce Aronow, Greg P Boivin, Jeffery D Molkentin, David F Wieczorek
Molecular and Cellular Biochemistry 2003, 251 (1-2): 33-42
Familial hypertrophic cardiomyopathy, a disease caused by mutations in cardiac contractile proteins, is characterized by left and/or right ventricular hypertrophy, myocyte disarray, fibrosis, and cardiac arrhythmias that may lead to premature sudden death. Five distinct point mutations within alpha-tropomyosin are associated with the development of familial hypertrophic cardiomyopathy. Two of these mutations are found within a troponin T binding site, located at amino acids 175 and 180. In this study, we analyze a transgenic mouse model for one of the mutations that occur at codon 180: a substitution of a glutamic acid for a glycine. These mice develop severe cardiac hypertrophy, substantial interstitial fibrosis, and have an increased heart weight/ body weight ratio. Results show that calcium-handling proteins associated with the sarcoplasmic reticulum exhibit decreased expression. These alterations in gene expression, coupled with the structurally-altered tropomyosin, may contribute to the demonstrated decreased physiological performance exhibited by these transgenic mice. A DNA hybridization microarray analysis of the transgenic vs. control ventricular RNAs shows that 50 transcripts are differentially expressed by more than 100% during the onset of the hypertrophic process, many of which are associated with the extracellular matrix. This study demonstrates that mutations within tropomyosin can be severely disruptive of sarcomeric function, triggering a hypertrophic response coupled with a cascade of alterations in gene expression.

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