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Research Article Free access | 10.1172/JCI2389

A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.

J C Tardiff, S M Factor, B D Tompkins, T E Hewett, B M Palmer, R L Moore, S Schwartz, J Robbins, and L A Leinwand

Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

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Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

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Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

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Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

Find articles by Hewett, T. in: JCI | PubMed | Google Scholar

Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

Find articles by Palmer, B. in: JCI | PubMed | Google Scholar

Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

Find articles by Moore, R. in: JCI | PubMed | Google Scholar

Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

Find articles by Schwartz, S. in: JCI | PubMed | Google Scholar

Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

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Department of Medicine, Cardiology Division, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

Find articles by Leinwand, L. in: JCI | PubMed | Google Scholar

Published June 15, 1998 - More info

Published in Volume 101, Issue 12 on June 15, 1998
J Clin Invest. 1998;101(12):2800–2811. https://doi.org/10.1172/JCI2389.
© 1998 The American Society for Clinical Investigation
Published June 15, 1998 - Version history
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Abstract

Mutations in multiple cardiac sarcomeric proteins including myosin heavy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients with mutations in these two genes have quite distinct clinical characteristics. Those with MyHC mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the disease, we have created transgenic mice expressing a truncated mouse cTnT allele analogous to one found in FHC patients. Mice expressing truncated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunction. Animals that express higher levels of transgene protein die within 24 h of birth. Transgenic mouse hearts demonstrate myocellular disarray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertrophy, but, also, frequent sudden death.

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