M. Furutani et al., Novel mechanism associated with an inherited cardiac arrhythmia - Defective protein trafficking by the mutant HERG (G601S) potassium channel, CIRCULATION, 99(17), 1999, pp. 2290-2294
Citations number
25
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
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.