title: Long-QT syndrome-associated missense mutations in the pore helix of the HERG potassium channel.
abstract: BACKGROUND
  Mutations in the human ether-à-go-go-related gene (HERG) cause chromosome 7-linked long-QT syndrome (LQTS), an inherited disorder of cardiac repolarization that predisposes affected individuals to arrhythmia and sudden death.
  
  
  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 heterologously expressed in Xenopus oocytes alone or in combination with wild-type HERG subunits. Two-microelectrode voltage-clamp techniques were used to record currents, and a single oocyte chemiluminescence assay was used to assay surface expression of epitope-tagged subunits. When expressed alone, V612L and T613M HERG subunits did not induce detectable currents, and L615V induced very small currents. Coexpression of mutant and wild-type HERG subunits caused a dominant-negative effect that varied for each mutation.
  
  
  CONCLUSIONS
  These findings define the physiological consequences of mutations in HERG that cause LQTS and indicate the importance of the pore helix of HERG for normal channel function.
authors.affiliation: Department of Medicine, Division of Cardiology, University of Utah, Salt Lake City 84112, USA.
authors.forename: F D
authors.initials: FD
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: M T
authors.initials: MT
authors.lastname: Keating
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D009865:Oocytes; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014982:Xenopus laevis
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; D018075:RNA, Complementary; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG