© 1999 American Heart Association, Inc.
Original Contribution |
Mouse Model of a Familial Hypertrophic Cardiomyopathy Mutation in 
-Tropomyosin Manifests Cardiac Dysfunction
From the Department of Molecular Genetics, Biochemistry and Microbiology (M.M., K.P., P.R., D.F.W.), Department of Internal Medicine, Division of Cardiology (B.H.), Department of Pharmacology and Cell Biophysics (I.L.G.), Department of Pathology and Laboratory Medicine (G.P.B.), University of Cincinnati College of Medicine, Cincinnati, Ohio; and the Department of Physiology and Biophysics (B.W., C.E., R.J.S.), University of Illinois, College of Medicine, Chicago. The current affiliation for M.M. is the Department of Medical Physiology, Texas A&M University Health Science Center, College Station, Tex.
Correspondence to David F. Wieczorek, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524. E-mail david.wieczorek{at}uc.edu
Abstract—To investigate the
functional consequences of a tropomyosin (TM) mutation associated with
familial hypertrophic cardiomyopathy (FHC), we
generated transgenic mice that express mutant 
-TM in the adult
heart. The missense mutation, which results in the substitution of
asparagine for aspartic acid at amino acid position 175, occurs in a
troponin T binding region of TM. S1 nuclease mapping and Western blot
analyses demonstrate that increased expression of the -TM
175 transgene in different lines causes a concomitant decrease in
levels of endogenous -TM mRNA and protein expression. In
vivo physiological analyses show a severe
impairment of both contractility and relaxation in
hearts of the FHC mice, with a significant change in left
ventricular fractional shortening. Myofilaments that
contain -TM 175 demonstrate an increased activation of the thin
filament through enhanced Ca2+ sensitivity of steady-state
force. Histological analyses show patchy areas
of mild ventricular myocyte disorganization and
hypertrophy, with occasional thrombi formation in the left
atria. Thus, the FHC -TM transgenic mouse can serve as a model
system for the examination of pathological and
physiological alterations imparted through aberrant
TM isoforms.
Key Words: tropomyosin • cardiomyopathy • troponin • hypertrophy
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