NDLI: Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice

Content Provider	PubMed Central
Author	Ertz-berger, Briar R. He, Huamei Dowell, Candice Factor, Stephen M. Haim, Todd E. Nunez, Sara Schwartz, Steven D. Ingwall, Joanne S. Tardiff, Jil C.
Copyright Year	2005
Abstract	Cardiac troponin T (cTnT) is a central component of the regulatory thin filament. Mutations in cTnT have been linked to severe forms of familial hypertrophic cardiomyopathy. A mutational “hotspot” that leads to distinct clinical phenotypes has been identified at codon 92. Although the basic functional and structural roles of cTnT in modulating contractility are relatively well understood, the mechanisms that link point mutations in cTnT to the development of this complex cardiomyopathy are unknown. To address this question, we have taken a highly interdisciplinary approach by first determining the effects of the residue 92 mutations on the molecular flexibility and stability of cTnT by means of molecular dynamics simulations. To test whether the predicted alterations in thin filament structure could lead to distinct cardiomyopathies in vivo, we developed transgenic mouse models expressing either the Arg-92-Trp or Arg-92-Leu cTnT proteins in the heart. Characterization of these models at the cellular and whole-heart levels has revealed mutation-specific early alterations in transcriptional activation that result in distinct pathways of ventricular remodeling and contractile performance. Thus, our computational and experimental results show that changes in thin filament structure caused by single amino acid substitutions lead to differences in the biophysical properties of cTnT and alter disease pathogenesis.
Related Links	http://dx.doi.org/10.1073/pnas.0509181102
Ending Page	18224
Page Count	6
Starting Page	18219
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	50
Volume Number	102
Language	English
Publisher	National Academy of Sciences
Publisher Date	2005-12-13
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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