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PMID:9354802

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Citation

Splawski, I, Tristani-Firouzi, M, Lehmann, MH, Sanguinetti, MC and Keating, MT (1997) Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat. Genet. 17:338-40

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.

Links

PubMed Online version:10.1038/ng1197-338

Keywords

Amino Acid Sequence; Animals; Electrophysiology/methods; Female; Humans; Long QT Syndrome/genetics; Male; Molecular Sequence Data; Mutation; Oocytes/physiology; Pedigree; Polymorphism, Single-Stranded Conformational; Potassium Channels/genetics; Potassium Channels/metabolism; Potassium Channels, Voltage-Gated; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Xenopus

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:KCNE1

contributes_to

GO:0005251: delayed rectifier potassium channel activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KCNE1

involved_in

GO:0060307: regulation of ventricular cardiac muscle cell membrane repolarization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KCNE1

involved_in

GO:0071805: potassium ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KCNE1

involved_in

GO:0086005: ventricular cardiac muscle cell action potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KCNE1

contributes_to

GO:1902282: voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KCNE1

involved_in

GO:0098915: membrane repolarization during ventricular cardiac muscle cell action potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KCNQ1

involved_in

GO:0071805: potassium ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KCNQ1

contributes_to

GO:0005251: delayed rectifier potassium channel activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

See also

References

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