Misprocessing as a mechanism for phenotypic variability in LQT3

Abstract

Variable penetrance is well-recognized in monogenic arrhythmia syndromes. We report here experiments using the cardiac Na channel SCN5A mutation L1825P (LP) to identify a novel underlying mechanism. Although LP displays persistent late INa typical of LQT3, the reported clinical phenotype is mild. As shown in the Figure, peak INa generated by LP (in CHO cells) is reduced, and far fewer cells display any current (3/22 vs 9/12 for wild-type [wt]). As one test of the idea that LP may not traffic normally to the cell surface, cells were grown in the presence of channel blockers (quinidine [Q] or lidocaine [L], 100 μM); this intervention can increase cell surface expression of misprocessed channels.