Cellular dysfunction of LQT5-minK mutants: abnormalities of I-Ks, I-Kr andtrafficking in long QT syndrome

Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of hu man long QT syndrome. MinK assembles with KvLQT1 to produce the slow delaye d rectifier K+ current I-KS and may assemble with HERG to modulate the rapi d delayed rectifier I-Kr. We used electrophysiological and immunocytochemic al methods to compare the cellular phenotypes of wild-type minK and four LQ T5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 c ells. We found that three mutants, V47F, W87R and D76N, were expressed at t he cell surface, while one mutant, L51H, was not. Coexpression of V47F and W87R with KvLQT1 produced I-Ks currents having altered gating and reduced a mplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 cu rrent rather than I-Ks and coexpression with D76N suppressed KvLQT1 current . V47F increased HERG current but to a lesser extent than WT-minK, while L5 1H and W87R had no effect and D76N suppressed HERG current markedly, Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel, We conclude that minK is a co-factor in the expression of both I-Ks and I-Kr and propose tha t clinical manifestations of LQT5 may be complicated by differing effects o f minK mutations on KvLQT1 and HERG.