T65P (LQT2)

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COMMENTS ON IN VITRO DATA
The mutation T65P located in the PAS domain of HERG causes defective protein that cannot be processed to the plasma membrane. The defect in the folding was restored by decreasing the cell incubation temperature (27°C) and pharmacologically by cisapride and E-4031. When trafficking was restored, the kinetics of the mutated channel resembled that of wild-type channels although the rate of activation, deactivation, and recovery from inactivation were accelerated. Since there is no evidence for the formation of heterotetramers by co-expression of wild-type with mutant subunits at 37 degrees C, the clinical symptoms may be explained by haploinsufficiency.