A Novel <i>KCNJ2</i> Nonsense Mutation, S369X, Impedes Trafficking and Causes a Limited Form of Andersen-Tawil Syndrome

<jats:sec> <jats:title>Background—</jats:title> <jats:p> Mutations in <jats:italic>KCNJ2</jats:italic> , a gene encoding the inward rectifier K <jats:sup>+</jats:sup> channel Kir2.1, are associated with Andersen-Tawil syndrome (ATS), which is characterized by (1) ventricular tachyarrhythmias associated with QT (QU)-interval prolongation, (2) periodic paralysis, and (3) dysmorphic features. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> We identified a novel <jats:italic>KCNJ2</jats:italic> mutation, S369X, in a 13-year-old boy with prominent QU-interval prolongation and mild periodic paralysis. The mutation results in the truncation at the middle of the cytoplasmic C-terminal domain that eliminates the endoplasmic reticulum (ER)-to-Golgi export signal. Current recordings from Chinese hamster ovary cells transfected with <jats:italic>KCNJ2</jats:italic> -S369X exhibited significantly smaller K <jats:sup>+</jats:sup> currents compared with <jats:italic>KCNJ2</jats:italic> wild type (WT) (1 μg each) (−84±14 versus −542±46 picoamperes per picofarad [pA/pF]; −140 mV; <jats:italic>P</jats:italic> <0.0001). Coexpression of the WT and S369X subunits did not show a dominant-negative suppression effect but yielded larger currents than those of WT+S369X (−724±98 pA/pF>−[84+542] pA/pF; 1 μg each; −140 mV). Confocal microscopy analysis showed that the fluorescent protein-tagged S369X subunits were predominantly retained in the ER when expressed alone; however, the expression of S369X subunits to the plasma membrane was partially restored when coexpressed with WT. Fluorescence resonance energy transfer analysis demonstrated direct protein-protein interactions between WT and S369X subunits in the intracellular compartment. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>The S369X mutation causes a loss of the ER export motif. However, the trafficking deficiency can be partially rescued by directly assembling with the WT protein, resulting in a limited restoration of plasma membrane localization and channel function. This alleviation may explain why our patient presented with a relatively mild ATS phenotype.</jats:p> </jats:sec>