Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction.
To investigate the functional consequences of a tropomyosin (TM) mutation associated with familial hypertrophic cardiomyopathy (FHC), we generated transgenic mice that express mutant alpha-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 alpha-TM 175 transgene in different lines causes a concomitant decrease in levels of endogenous alpha-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 alpha-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 alpha-TM transgenic mouse can serve as a model system for the examination of pathological and physiological alterations imparted through aberrant TM isoforms.
Muthuchamy
M
M
Department of Molecular Genetics, Division of Cardiology, University of Cincinnati College of Medicine, OH 45267-0524, USA.
Pieples
K
K
Rethinasamy
P
P
Hoit
B
B
Grupp
I L
IL
Boivin
G P
GP
Wolska
B
B
Evans
C
C
Solaro
R J
RJ
Wieczorek
D F
DF
D000818:Animals; D002118:Calcium / Q000502:physiology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000473:pathology; D014335:Tropomyosin / Q000235:genetics*
D014335:Tropomyosin; D002118:Calcium