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

• DOI: 10.1161/res.115.suppl_1.197
• Publication Date: 2021-07-03T08:46:20Z
• Authors: Melissa Lynn; Lauren Tal-Grinspan; J.P. Jin; Jil Tardiff
• Keywords: Troponin complex; Myofilament; Tropomyosin; Troponin T

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