Abstract 13462: Novel Mechanism of Kcnj2-Related Short Qt Syndrome
Short QT syndrome (SQT) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias in structurally normal heart. Previously we identified the first KCNJ2 mutation (D172N) associated with “gain of function” in a SQT patient, suggesting that KCNJ2 is the causative gene for type 3 SQT syntdrome (SQT3). Recently we identified two novel SQT3 mutations and functionally characterized them in HEK293 cells. The first mutation K364T was identified in two 8-years homozygous twins with short QT interval (QTc 316 ms and 310 ms) with sporadic palpitations. The second mutation E299V was found in a 11-year old boy with paroxysmal atrial fibrillation and very short QT (QTc 280 ms, figure). We transiently expressed both mutations in HEK cells. Whole-cell patch-clamp studies demonstrated that K364T mutation presents a larger outward IK1 than WT (P<0.05) at potentials between -75 mV and -55 mV therefore the biophysical properties overlap with those of the D172N mutation. Interestingly however E299V presented a loss of the rectification properties and a huge outward IK1 at potentials above -55 mV as compared to WT (P<0.01). As expected coexpression of WT and E299V to mimic the heterozygous condition yielded an intermediate phenotype between WT and Homozygous E299V (Figure, I-V curves adjusted by junction potential). The functional properties are consistent with the unique role of aminoacid E299 that has been previously reported as a critical determinant of the rectification properties of Kir2.1 In conclusion our study identifies loss of rectification as a novel mechanism for SQT3; the severity of the biophysical properties seems to be paralleled by the very marked shortening of QT interval in the affected patient.
- © 2011 by American Heart Association, Inc.