Background: Andersen Tawil Syndrome (ATS) is associated with QT prolongation, bidirectional ventricular tachycardia (BDVT) and KCNJ2 mutations.
Methods: We performed genetic screening on 3 families presenting with incessant BDVT at rest. In 2 families (A,B) affected members were asymptomatic although one patient developed tachycardia induced cardiomyopathy. QTc was normal. In the third family (C) the proband had recurrent syncope, prolonged QTc and dysmorphic features. Whole-cell current recordings were performed for KCNJ2wild type and mutants homologously and heterologously expressed in HEK 293 cells.
Results: All affected Family A members carried a novel heterozygous KCNJ2 (M307V) mutation. Expression of KCNJ2- M307V(n=19 ) showed significant loss of function (LOF) at -140 mV and -60 mV compared to WT (n=30) (current density = -189.9±14.3 and 27.5±3.3 and 25.7± 3.6and 7.3±0.9vs. pA/pF, respectively; p<0.001). KCNJ2- M307V also had a dominant negative effect when co-expressed with WT (n=29 )(-68.1± 8.6 and 9.8±1.5 pA/pF for -140 and -60 mV; p<0.001) .The proband in family B also carried a novel heterozygous KCNJ2 (V77E) mutation. Expression of KCNJ2- V77E (n=10) showed significant LOF at -140 mV and -60 mV compared to WT (current density = 18.3± 2.37and 5±0.6 pA/pF ; p2 had no effect on the outward current density in both mutations providing further proof of complete suppression of mutant Kir2.1 current.
The proband in family C was found to carry a known KCNJ2 (R67W) mutation reported to result in similar LOF however patient had also 2 CaV1.2 gene (N2091S, G490R) mutations.
Conclusions: KCNJ2 - M307V and V77E - KCNJ2- are novel KCNJ2 mutations associated with significant LOF of Kir2.1 current and incessant asymptomatic BDVT. Interactions with other mutant ionic channels probably underlie the differences in phenotypes.
