Abstract 197: Determining the Potential Role of cTnT Isoform Switching In the Development of Early Childhood Tropomyosin-Linked DCM

Abstract

An oft-noted component of sarcomeric HCM and DCM is the observation that patients within families, carrying the same primary mutation, often exhibit significant phenotypic variability. This lack of a distinct link between genotype and phenotype has greatly complicated clinical management. In a recent study of two large unrelated multigenerational families carrying the tropomyosin (Tm) mutation Asp230Asn (D230N), a striking “bimodal” distribution of severity was observed. In these families, many children (<1 year) with the mutation presented with a severe form of DCM that led to sudden, often fatal congestive heart failure, while adults developed a mild to moderate DCM in mid-life. Of note, children who survived the initial presentation often recovered significant systolic function in adolescence and young adulthood. Therefore, to better understand the mechanism of this “bimodal” phenotype, we began to investigate the potential modulating role of isoform switching by other sarcomeric components. We hypothesize that the age-dependent remodeling seen in children with D230N Tm is a result of temporal isoform switches involving a closely linked Tm binding partner cardiac Troponin T (cTnT). Initial biophysical studies (circular dichroism and regulated in vitro motility, R-IVM) show that while D230N does not alter Tm’s thermal stability it does have a profound impact on myofilament activation. Both maximal velocity of filament sliding and calcium sensitivity were decreased. Furthermore, an additive decrease was observed in these parameters for R-IVM solutions containing cTnT 1 (fetal)+D230N Tm filaments as compared to cTnT 3 (adult)+D230N. Preliminary in vivo studies utilizing our novel double transgenic Tm-D230N x cTnT 1 mice show profound changes in wall thickness and chamber dilation, as compared to age-matched non-transgenic mice and D230N Tm mice. Further studies aim to model the “bimodal” clinical phenotype seen in families with D230N Tm and assess the potential for disease reversibility using a cardiac specific inducible cTnT 1 transgenic mouse model. Our goal is to use a translational approach to better understand the mechanism by which primary mutations lead to distinct clinical phenotypes in order to improve clinical management.