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

Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertro phic cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit m ild or no ventricular hypertrophy, yet demonstrate a high frequency of earl y 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 induc tion of atrial natriuretic factor and beta-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocyt es from R92Q mice have increased basal sarcomeric activation, impaired rela xation, and shorter sarcomere lengths. Isolated working heart data are cons istent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with FHC. These mice represent the first d isease model to exhibit hypercontractility, as well as a unique model syste m for exploring the cellular pathogenesis of FHC. The distinct phenotypes o f mice with different TnT alleles suggest that the clinical heterogeneity o f FHC is at least partially due to allele-specific mechanisms.