Action potential abnormalities due to loss- or gain-of-function mutations in KCNJ2

Andersen-Tawil syndrome type 1 (ATS1) and short QT syndrome type 3 (SQT3) are associated with loss-of-function and gain-of-function mutations in the KCNJ2 gene, respectively. This gene encodes the Kir2.1 protein, which is the most abundant member of the Kir2.x family in the Kir2.x tetramers that constitute the channels that conduct the cardiac inward rectifier potassium current (I_K1). The effects of ATS1 and SQT3 related mutations in KeNJ2 on the electrophysiological characteristics of human ventricular cells were assessed in computer simulations using the updated ten Tusscher et al. human ventricular cell model. The model I_K1 was replaced with either wild-type or heterozygous mutant Kir2.1 current. In ATS1 simulations, the action potential was only modestly prolonged and calcium-driven spontaneous action potentials could be observed. The resting membrane potential was depolarized by 7 m V, thereby reducing sodium channel availability and thus contributing to a noticeable decrease in conduction velocity. In SQT3 simulations, effects on resting membrane potential and conduction velocity were relatively small. However, action potentials with a markedly shortened duration, increasing the susceptibility to tachyarrhythmias, could be elicited.