HCM- and DCM-associated TNNT2 sarcomeric variants induce divergent nucleus remodeling in human iPSC-CMs

Sarcomeric protein variants in thick- and thin-filament genes are associated with hypertrophic (HCM) and dilated (DCM) cardiomyopathy, including TNNT2 gene, which encodes the thin-filament protein cardiac troponin T (cTnT). In patients, pathogenic variants in cTnT lead to altered cardiac contractility and high incidence of sudden cardiac death. We analyzed the morphological and functional effects of four different cTnT variants in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with their respective isogenic controls: two cell lines bearing the HCM-associated variants I79N and R92Q; and two cell lines bearing the DCM-associated variants R141W and R134G.