Abstract 2574: A Novel Gain-of-function KCNJ2 Mutation Associated With Short QT Syndrome Impairs Inward Rectification of Kir 2.1 Currents
Background: Short QT syndrome is a recently recognized disorder associated with atrial fibrillation (AF) and sudden death due to ventricular arrhythmias. Mutations in several ion channel genes have been linked to short QT syndrome, however, the mechanism in detail remains unclear.
Methods & Results: We studied an 8-year-old girl with a marked short QT interval (QTc 0.28) suffering from paroxysmal AF. During the right heart catheterization, paroxysmal supraventricular tachycardia and ventricular fibrillation were induced. Mutational analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional assays displayed no functional Kir2.1 currents when expressed M301K alone. However, coexpression of wild-type and M301K exhibited significant larger outward currents than wild-type alone at more than −40 mV (P<0.01, Figure A⇓). These results suggest a gain-of-function type modulation of Kir2.1 due to the decreased inward rectification. Immunocytochemistry revealed normal trafficking for mutant channels. Furthermore, we analyzed the functional significance of the charge of an amino acid at M301 (neutral) by changing the residue. M301R (positive) exhibited decreased inward rectification similar to M301K (positive) (Figure B⇓), whereas M301A (neutral) showed no significant difference with wild-type (Figure C⇓).
Conclusions: We identified a novel KCNJ2 mutation associated with short QT syndrome. Though M301K alone displayed no Kir2.1 currents, coexpression of WT and M301K greatly decreased the inward rectification which is a novel mechanism predisposing short QT syndrome. These functional changes were associated with the charge of an amino acid residue at M301.