Novel mechanism associated with an inherited cardiac arrhythmia - Defective protein trafficking by the mutant HERG (G601S) potassium channel

Background-The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval tha t leads to arrhythmia. Mutations in the human ether-a-go-go-related gene (N ERC), which encodes the rapidly activating component of the delayed rectifi er current (I-Kr), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediati ng LQT2 are varied and include mutant subunits that form channels with alte red kinetic properties or nonfunctional mutant subunits, We recently report ed a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. Methods and Results-To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type chan nels but exhibited no change in kinetic properties or dominant-negative sup pression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent pro tein tagging and Western blot analyses were performed. These showed deficie nt protein trafficking of the G601S mutant to the plasma membrane. Conclusions-Our results from both the Xenopus oocyte and HEK293 cell expres sion systems and green fluorescent protein tagging and Western blot analyse s support the conclusion that the G601S mutant is a hypomorphic mutation, r esulting in a reduced current amplitude. Thus, it represents a novel mechan ism underlying LQT2.