Long-QT syndrome-associated missense mutations in the pore helix of the HERG potassium channel

Background-Mutations in the human ether-h-go-go-related gene (HERG) cause c hromosome 7-linked long-QT syndrome (LQTS), an inherited disorder of cardia c repolarization that predisposes affected individuals to arrhythmia and su dden death. Methods and Results-Here, we characterize the physiological consequences of 3 LQTS-associated missense mutations (V612L, T613M, and L615V) located in the pore helix of the HERG channel subunit. Mutant HERG subunits were heter ologously expressed in Xenopus oocytes alone or in combination with wild-ty pe HERG subunits. Two-microelectrode voltage-clamp techniques were used to record currents, and a single oocyte chemiluminescence assay was used to as say surface expression of epitope-tagged subunits. When expressed alone, V6 12L and T613M HERG subunits did not induce detectable currents, and L615V i nduced very small currents. Coexpression of mutant and wild-type HERG subun its caused a dominant-negative effect that varied for each mutation. Conclusions-These findings define the physiological consequences of mutatio ns in HERG that cause LQTS and indicate the importance of the pore helix of HERG for normal channel function.