Kv11.1 channels pass the rapid delayed rectifier current (IKr) which plays a specific role in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Mutations that cause loss of Kv11.1 channel function result in long-QT syndrome type 2 (LQTS2), one of the commonest causes of sudden cardiac death in the young. LQTS2 has a highly variable presentation ranging from sudden death in the young to mild symptomatic presentation in adulthood. We wish to investigate whether this variable presentation is mutation specific, i.e. can quantifying the extent to which a mutation perturbs the function of Kv11.1 channels, assessed in vitro, assist with stratifying the risk of clinical events in these patients.
Assessing the degree of arrhythmic risk for a LQTS2 mutation requires knowledge of both the amount of protein that reaches the membrane and the gating phenotype of the channel, as perturbations to both factors can alter the IKr phenotype. So far we have performed trafficking assays on 89 LQTS2 causing mutations in Kv11.1 channels expressed in HEK293 cells to access the expression level of these Kv11.1 mutant channels at the cell surface. Of the Kv11.1 mutants examined, 65% have less than half of the normal WT Kv11.1 channel expressed on the cell surface, whilst 12% have 50-75% of WT levels and 23% have 75-100% of WT levels. Preliminary data also suggests that reduced expression (>50% reduction) is significantly correlated with risk of cardiac events (syncope, aborted cardiac arrest or sudden death).