Mutation location of HCM-causing troponin T mutations defines the degree of myofilament dysfunction in human cardiomyocytes

BackgroundThe clinical outcome of hypertrophic cardiomyopathy patients is not only determined by the disease-causing mutation but influenced a variety disease modifiers. Here, we defined role location and mutant protein dose troponin T mutations I79N, R94C R278C.Methods resultsWe myofilament function after exchange in permeabilized single human cardiomyocytes as well cardiac patient samples harboring R278C mutation. Notably, found that small sufficient for maximal effect on Ca2+-sensitivity I79N while determines magnitude this effect. While incorporation increased Ca2+-sensitivity, at low intermediate dose, it decreased high dose. All three cTnT mutants showed reduced thin filament binding affinity, which coincided with relatively (50.5 ± 5.2%) complex cardiomyocytes. In accordance, 32.2 4.0% was two 50.0 3.7% mRNA. accordance studies variability exact same mutation, observed functional cell level These differences properties could be explained amount protein.ConclusionsUsing cardiomyocytes, show TNNT2 mutation-induced changes depend location, all affinity. The specific mutation-effect translated to from patients, most likely other (post)-translational modifications. Overall, our illustrate underlies shows highly dose-dependent function.