Biophysical Characterization of a Novel KCNJ2 Mutation Associated with Andersen-Tawil Syndrome and CPVT Mimicry

Abstract

Mutations in KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1), have been identified in Andersen-Tawil syndrome (ATS). ATS is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we identified a young female presenting with frequent ventricular extrasystoles and non-sustained polymorphic ventricular tachycardia (VT), bi-directional VT, syncope, and mild QTc prolongation. The proband displayed dysmorphic features including micrognatia, clinodactylia and syndactyly. The patient's symptoms continued following administration of propranolol, but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p R260P) in KCNJ2. Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild type human KCNJ2 cDNA (WT-KCNJ2) yielded robust IK1, but no measurable current in cells expressing the R260P mutant. Co-expression of WT and R260P-KCNJ2 (heterozygous expression) yielded a markedly reduced inward IK1 compared with WT alone (-36.5±9.8 pA/pF vs. -143.5±11.4 pA/pF, n=8, p>0.001, respectively at -90 mV) indicating a strong dominant negative effect of the mutant. The outward component of IK1 measured at -50 mV was also markedly reduced with the heterozygous expression vs. WT (0.52±5.5 pA/pF vs. 23.4±6.7 pA/pF, n=8, p>0.001, respectively). Conclusion: We report a novel KCNJ2 mutation associated with classical phenotypic features of Andersen-Tawil syndrome and CPVT mimicry. The R260P mutation produced a strong dominant negative effect leading to marked suppression of the inward rectifier potassium current.