title: Mutations in the hminK gene cause long QT syndrome and suppress IKs function.
abstract: Ion-channel beta-subunits are ancillary proteins that co-assemble with alpha-subunits to modulate the gating kinetics and enhance stability of multimeric channel complexes. Despite their functional importance, dysfunction of potassium-channel beta-subunits has not been associated with disease. Recent physiological studies suggest that KCNE1 encodes beta-subunits (hminK) that co-assemble with KvLQT1 alpha-subunits to form the slowly activating delayed rectifier K+ (IKs) channel. Because KVLQT1 mutations cause arrhythmia susceptibility in the long QT syndrome (LQT), we hypothesized that mutations in KCNE1 also cause this disorder. Here, we define KCNE1 missense mutations in affected members of two LQT families. Both mutations (S74L, D76N) reduced IKs by shifting the voltage dependence of activation and accelerating channel deactivation. D76N hminK also had a strong dominant-negative effect. The functional consequences of these mutations would be delayed cardiac repolarization and an increased risk of arrhythmia. This is the first description of KCNE1 as an LQT gene and confirms that hminK is an integral protein of the IKs channel.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City 84112, USA.
authors.forename: I
authors.initials: I
authors.lastname: Splawski
authors.forename: M
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: M H
authors.initials: MH
authors.lastname: Lehmann
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: M T
authors.initials: MT
authors.lastname: Keating
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004594:Electrophysiology / Q000379:methods; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000502:physiology; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014981:Xenopus
chemical_list: D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; C059983:potassium channel protein I(sk)