title: Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia.
abstract: Long QT syndrome (LQT) is an autosomal dominant disorder that can cause sudden death from cardiac arrhythmias. We recently discovered that mutations in HERG, a K+-channel gene, cause chromosome 7-linked LQT. Heterologous expression of HERG in Xenopus oocytes revealed that HERG current was similar to a well-characterized cardiac delayed rectifier K+ current, IKr, and led to the hypothesis that mutations in HERG reduced IKr, causing prolonged myocellular action potentials. To define the mechanism of LQT, we injected oocytes with mutant HERG complementary RNAs, either singly or in combination with wild-type complementary RNA. Some mutations caused loss of function, whereas others caused dominant negative suppression of HERG function. These mutations are predicted to cause a spectrum of diminished IKr and delayed ventricular repolarization, consistent with the prolonged QT interval observed in individuals with LQT.
authors.affiliation: Cardiology Division, Department of Human Genetics, Howard Hughes Medical Institute, University of Utah Health Sciences Center, Salt Lake City 84112, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: M E
authors.initials: ME
authors.lastname: Curran
authors.forename: P S
authors.initials: PS
authors.lastname: Spector
authors.forename: M T
authors.initials: MT
authors.lastname: Keating
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins; D002897:Chromosomes, Human, Pair 7; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005799:Genes, Dominant; D006321:Heart / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000503:physiopathology; D008564:Membrane Potentials; D009865:Oocytes; D017354:Point Mutation; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; 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; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG