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

Briar R. Ertz-Berger, Huamei He, Candice Dowell, Stephen M. Factor, Todd E. Haim, Sara Nunez, Steven D. Schwartz, Joanne S. Ingwall, Jil C. Tardiff

Research output: Contribution to journalArticle

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18219-18224
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number50
DOIs
StatePublished - Dec 13 2005

Keywords

  • Contractility
  • Familial hypertrophic cardiomyopathy
  • Molecular dynamics
  • Thin filament

ASJC Scopus subject areas

  • General

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