Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias

• Published in: The EMBO journal 1997-09, Vol.16 (17), p.5472-5479
• Main Authors: Chouabe, Christophe, Neyroud, Nathalie, Guicheney, Pascale, Lazdunski, Michel, Romey, Georges, Barhanin, Jacques
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cardiology and cardiovascular system; Cloning, Molecular; COS Cells; delayed-rectifier; DNA, Complementary; DNA, Complementary - genetics; dominant-negative; Electrophysiology; Human health and pathology; Humans; IKs; IsK; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Life Sciences; long QT; Long QT Syndrome; Long QT Syndrome - genetics; MinK; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Phenotype; Potassium Channels; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Voltage-Gated; Recombinant Proteins; Recombinant Proteins - metabolism; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Tissue Distribution
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/16.17.5472

Mutations in the delayed rectifier K + channel subunit KvLQT1 have been identified as responsible for both Romano–Ward (RW) and Jervell and Lange‐Nielsen (JLN) inherited long QT syndromes. We report the molecular cloning of a human KvLQT1 isoform that is expressed in several human tissues including heart. Expression studies revealed that the association of KvLQT1 with another subunit, IsK, reconstitutes a channel responsible for the I Ks current involved in ventricular myocyte repolarization. Six RW and two JLN mutated KvLQT1 subunits were produced and co‐expressed with IsK in COS cells. All the mutants, except R555C, fail to produce functional homomeric channels and reduce the K + current when co‐expressed with the wild‐type subunit. Thus, in both syndromes, the main effect of the mutations is a dominant‐negative suppression of KvLQT1 function. The JLN mutations have a smaller dominant‐negative effect, in agreement with the fact that the disease is recessive. The R555C subunit forms a functional channel when expressed with IsK, but with altered gating properties. The voltage dependence of the activation is strongly shifted to more positive values, and deactivation kinetics are accelerated. This finding indicates the functional importance of a small positively charged cytoplasmic region of the KvLQT structure where two RW and one JLN mutations have been found to take place.