Heritable Long QT Syndrome (LQTS) is genetically heterogeneous. The KCNE1 protein forms the accessory subunit of slow delayed rectifier current (IKs) potassium channels through interaction with KCNQ1; KCNE1 mutations are responsible for the LQT5 variant of LQTS (Moss and Kass, 2005). There is evidence that KCNE1 can additionally interact with hERG (which carries the rapid delayed rectifier K+ current, IKr; (McDonald et al, 1997); clinically relevant KCNE1 variants can influence hERG current (IhERG) magnitude (e.g. Ohno et al, 2007; Du et al, 2013). The T58P/L59P KCNE1 double-mutant occurs in Jervell and Lange-Nielsen syndrome (JLNS); it has been reported to impair assembly with KCNQ1 and causes a severe attenuation of IKs, through disruption of an interaction site located in the transmembrane region of KCNE1 (Harmer et al, 2010). This study was undertaken to investigate whether or not the T58P/L59P double mutant can influence IhERG modulation by KCNE1. Whole-cell patch-clamp measurements of IhERG were made at 37°C from HEK293 cells stably expressing hERG that were transiently co-transfected with wild-type (WT) or mutant KCNE1 together with Green Fluorescent Protein (GFP) as a transfection marker. With a conventional voltage-step protocol, IhERG end-pulse density at +20 mV was measured as 30.18±4.88pA/pF (mean±SEM; n=11) with WT KCNE1 and this was increased to 87.94±17.32pA/pF (n=8) for T58P/L59P KCNE1 (p<0.005; unpaired t test). IhERG tail density, observed at -40 mV following step depolarisation to +20 mV, was 58.64± 7.56pA/pF (n=11) for WT KCNE1 and 157.92±32.68pA/pF (n=8) for T58P/L59P KCNE1 (p<0.005; unpaired t test). Under ventricular action potential (AP) clamp, maximal IhERG density during AP repolarisation was also greater for T58P/L59P KCNE1, without a significant voltage shift of peak current during the AP command. IhERG was also compared with WT and T58P/L59P KCNE1 using 2s depolarizing voltage steps from −80 mV to potentials between −40 mV and +60 mV. Mean current-voltage (I-V) relations demonstrated marked elevation of the IhERG tail density for T58P/L59P KCNE1 (Two way ANOVA, p<0.01 compared to WT KCNE1). In separate experiments, WT or T58P/L59P KCNE1 was co-expressed with KCNQ1 and, as demonstrated previously (Harmer et al, 2010), T58P/L59P KCNE1 markedly suppressed the measured current. Collectively, the results of these experiments provide evidence that the KCNE1 transmembrane segment T58P/L59P double-mutant, which causes severe attenuation of IKs, can markedly augment IhERG. This finding both provides further evidence for differential modulation of IKr by WT and variant KCNE1 and suggests that the nature of the interaction(s) with KCNE1 may differ between hERG and KCNQ1.