title: Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.
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 beta-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.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Tardiff
authors.forename: T E
authors.initials: TE
authors.lastname: Hewett
authors.forename: B M
authors.initials: BM
authors.lastname: Palmer
authors.forename: C
authors.initials: C
authors.lastname: Olsson
authors.forename: S M
authors.initials: SM
authors.lastname: Factor
authors.forename: R L
authors.initials: RL
authors.lastname: Moore
authors.forename: J
authors.initials: J
authors.lastname: Robbins
authors.forename: L A
authors.initials: LA
authors.lastname: Leinwand
mesh_terms: D000483:Alleles; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D048429:Cell Size; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D020125:Mutation, Missense; D009200:Myocardial Contraction; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D012518:Sarcomeres / Q000648:ultrastructure; D020107:Troponin T / Q000235:genetics*
chemical_list: D017931:DNA Primers; D020107:Troponin T; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains