Dominant-negative effect of a mutant cardiac troponin T on cardiac structure and function in transgenic mice.
Hypertrophic cardiomyopathy (HCM) is a disease of sarcomeric proteins. The mechanism by which mutant sarcomeric proteins cause HCM is unknown. The leading hypothesis proposes that mutant sarcomeric proteins exert a dominant-negative effect on myocyte structure and function. To test this, we produced transgenic mice expressing low levels of normal or mutant human cardiac troponin T (cTnT). We constructed normal (cTnT-Arg92) and mutant (cTnT-Gln92) transgenes, driven by a murine cTnT promoter, and produced three normal and five mutant transgenic lines, which were identified by PCR and Southern blotting. Expression levels of the transgene proteins, detected using a specific antibody, ranged from 1 to 10% of the total cTnT pool. M-mode and Doppler echocardiography showed normal left ventricular dimensions and systolic function, but diastolic dysfunction in the mutant mice evidenced by a 50% reduction in the E/A ratio of mitral inflow velocities. Histological examination showed cardiac myocyte disarray in the mutant mice, which amounted to 1-15% of the total myocardium, and a twofold increase in the myocardial interstitial collagen content. Thus, the mutant cTnT-Gln92, responsible for human HCM, exerted a dominant-negative effect on cardiac structure and function leading to disarray, increased collagen synthesis, and diastolic dysfunction in transgenic mice.
Oberst
L
L
Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Zhao
G
G
Park
J T
JT
Brugada
R
R
Michael
L H
LH
Entman
M L
ML
Roberts
R
R
Marian
A J
AJ
D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D003094:Collagen; D003971:Diastole; D004452:Echocardiography; D015150:Echocardiography, Doppler; D005109:Extracellular Matrix / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D020107:Troponin T / Q000235:genetics*
D020107:Troponin T; D003094:Collagen