Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy

Jil C. Tardiff, Timothy E. Hewett, Bradley M. Palmer, Charlotte Olsson, Stephen M. Factor, Russell L. Moore, Jeffrey Robbins, Leslie A. Leinwand

Research output: Contribution to journalArticle

162 Scopus citations

Abstract

Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, we created transgenic mouse lines expressing 30%, 67%, and 92% of their total cTnT as a missense (R92Q) allele analogous to one found in FHC. Similar to a mouse FHC model expressing a truncated cTnT protein, the left ventricles of all R92Q lines are smaller than those of wild-type. In striking contrast to truncation mice, however, the R92Q hearts demonstrate significant induction of atrial natriuretic factor and β-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice have increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data are consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with FHC. These mice represent the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of FHC. The distinct phenotypes of mice with different TnT alleles suggest that the clinical heterogeneity of FHC is at least partially due to allele-specific mechanisms.

Original languageEnglish (US)
Pages (from-to)469-481
Number of pages13
JournalJournal of Clinical Investigation
Volume104
Issue number4
DOIs
StatePublished - Aug 1999

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy'. Together they form a unique fingerprint.

  • Cite this

    Tardiff, J. C., Hewett, T. E., Palmer, B. M., Olsson, C., Factor, S. M., Moore, R. L., Robbins, J., & Leinwand, L. A. (1999). Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. Journal of Clinical Investigation, 104(4), 469-481. https://doi.org/10.1172/JCI6067