Key result
Tbx20 p.R311C mutation decreases hERG current and prolongs action potentials in iPSC-CMs by disabling KCNH2 transcription.
Why the study?
Does the Tbx20 p.R311C mutation alter KCNH2 expression and hERG currents in human induced pluripotent stem cell-derived cardiomyocytes?
Does the Tbx20 p.R311C mutation alter KCNH2 expression and hERG currents in human induced pluripotent stem cell-derived cardiomyocytes?
Tbx20 regulates KCNH2 expression, and its p.R311C mutation causes decreased hERG current and prolonged action potentials, providing a mechanistic basis for long QT syndrome in affected patients.
Suggests Tbx20 mutation as arrhythmia mechanism; leaves open clinical translation and therapeutic targeting.
Significance Tbx20 is a transcription factor whose critical role in cardiogenesis is well-established. Here we functionally analyzed the electrophysiological effects produced by a mutation (p.R311C) in Tbx20 found in some affected individuals belonging to a family with long QT syndrome (an inherited cardiac arrhythmia due to delayed ventricular repolarization). We demonstrated that Tbx20 selectively increases the expression of KCNH2 , which encodes for the channel Kv11.1 (hERG) that generates the main ventricular repolarizing current. Conversely, the p.R311C mutation disables the Tbx20 protranscriptional activity over KCNH2 , leading to a decrease in the hERG current and a prolongation of the action potentials recorded in human induced pluripotent stem cell-derived cardiomyocytes. Therefore, we propose that Tbx20, besides its described role, regulates KCNH2 expression.
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Caballero et al. (2017) studied Long QT syndrome. Tbx20 p.R311C mutation was evaluated on KCNH2 expression and hERG current. The Tbx20 p.R311C mutation disables protranscriptional activity over KCNH2, decreasing hERG current and prolonging action potentials in human induced pluripotent stem cell-derived cardiomyocytes.
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