title: Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel.
abstract: BACKGROUND
  The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go-related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (IKr), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work.
  
  
  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 channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane.
  
  
  CONCLUSIONS
  Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.
authors.affiliation: Department of Pediatric Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Furutani
authors.forename: M C
authors.initials: MC
authors.lastname: Trudeau
authors.forename: N
authors.initials: N
authors.lastname: Hagiwara
authors.forename: A
authors.initials: A
authors.lastname: Seki
authors.forename: Q
authors.initials: Q
authors.lastname: Gong
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.forename: S
authors.initials: S
authors.lastname: Imamura
authors.forename: H
authors.initials: H
authors.lastname: Nagashima
authors.forename: H
authors.initials: H
authors.lastname: Kasanuki
authors.forename: A
authors.initials: A
authors.lastname: Takao
authors.forename: K
authors.initials: K
authors.lastname: Momma
authors.forename: C T
authors.initials: CT
authors.lastname: January
authors.forename: G A
authors.initials: GA
authors.lastname: Robertson
authors.forename: R
authors.initials: R
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D001692:Biological Transport; D015153:Blotting, Western; D027682:Cation Transport Proteins; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006801:Humans; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000096:biosynthesis; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014981:Xenopus
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG