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Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.

Author(s): Andrea Vincent, Karen M Curran, T J VanRaay, Yin Wang, T Connors, T J VanRaay, G M Landes, Sheila M. Keating, Katherine W Timothy, Qingxi Shen, I Splawski, Mark Atkinson, J A Toubin, Charlotte Burn, Jasper Koning, J M Millholland, Melissa A. Moss, Stefan Kubicek, Andrew Dimond

Publication date: 1995-12-31

Journal: Nature genetics

Keywords: Amino Acid Sequence, Base Sequence, Chromosomes, Human, Pair 11, Cloning, Molecular, Female, Genetic Linkage, Humans, Long QT Syndrome, genetics, Male, Molecular Sequence Data, Pedigree, Point Mutation, Polymorphism, Single-Stranded Conformational, Potassium Channels, Sequence Alignment, Sequence Deletion, Sequence Homology, Amino Acid

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Abstract

Genetic factors contribute to the risk of sudden death from cardiac arrhythmias. Here, positional cloning methods establish KVLQT1 as the chromosome 11-linked LQT1 gene responsible for the most common inherited cardiac arrhythmia. KVLQT1 is strongly expressed in the heart and encodes a protein with structural features of a voltage-gated potassium channel. KVLQT1 mutations are present in affected members of 16 arrhythmia families, including one intragenic deletion and ten different missense mutations. These data define KVLQT1 as a novel cardiac potassium channel gene and show that mutations in this gene cause susceptibility to ventricular tachyarrhythmias and sudden death.

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SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.

Q. Wang, J. Shen, I Splawski … (1995)

Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.

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Determination of the subunit stoichiometry of a voltage-activated potassium channel.

R MacKinnon (1991)

The voltage-activated K+, Na+ and Ca2+ channels are responsible for the generation and propagation of electrical signals in cell membranes. The K+ channels are multimeric membrane proteins formed by the aggregation of an unknown number of independent subunits. By studying the interaction of a scorpion toxin with coexpressed wild-type and toxin-insensitive mutant Shaker K+ channels, the subunit stoichiometry can be determined. The Shaker K+ channel is found to have a tetrameric structure. This is consistent with the sequence relationship between a K+ channel and each of the four internally homologous repeats of Na+ and Ca2+ channels.