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Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy
Jil C. Tardiff, … , Jeffrey Robbins, Leslie A. Leinwand
Jil C. Tardiff, … , Jeffrey Robbins, Leslie A. Leinwand
Published August 15, 1999
Citation Information: J Clin Invest. 1999;104(4):469-481. https://doi.org/10.1172/JCI6067.
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Article

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

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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.

Authors

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

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Figure 1

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R92Q-TnT and truncation-TnT map to 2 distinct functional domains. (a) Ex...
R92Q-TnT and truncation-TnT map to 2 distinct functional domains. (a) Exon composition of human cTnT, with positions of disease alleles Arg92Gln and intron 15 G→A marked above. The representative murine transgene allele is in parenthesis below. Tr-Myc represents a loss of exons 15 and 16. Functional domains are depicted by filled bars, with associated protein binding sites below. Location of translational start and stop codons are represented by ATG and TAG, respectively. (b) Constructs used to generate wild-type (WT) and Arg92Gln (R92Q) Myc-tagged murine cardiac TnT.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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