A Dominant Negative Isoform of the Long QT Syndrome 1 Gene Product

• Published in: The Journal of biological chemistry Vol. 273; no. 12; pp. 6837 - 6843
• Main Authors: Demolombe, S, Baró, I, Péréon, Y, Bliek, J, Mohammad-Panah, R, Pollard, H, Morid, S, Mannens, M, Wilde, A, Barhanin, J, Charpentier, F, Escande, D
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 20.03.1998
• Subjects: Animals; Base Sequence; Cloning, Molecular; COS Cells; DNA, Complementary; Genes, Dominant; Humans; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Long QT Syndrome - genetics; Molecular Sequence Data; Myocardium - metabolism; Potassium Channels - genetics; Potassium Channels, Voltage-Gated; Sequence Homology, Nucleic Acid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.12.6837

Mutations in the KvLQT1 gene are the cause of the long QT syndrome 1. KvLQT1 gene product is associated with the regulator protein IsK to produce a component of the delayed rectifier K + current in cardiac myocytes. We identified an N-terminal truncated isoform of the KvLQT1 gene product, referred to as isoform 2. In RNase protection assays, isoform 2 represented 28.1 ± 0.6% of the total KvLQT1 expression in the human adult ventricle. COS-7 cells injected intranuclearly with KvLQT1 isoform 1 cDNA exhibited a fast-activating K + current, whereas those injected with a KvLQT1 isoform 1 plus IsK cDNA showed a slow-activating K + current. Cells injected with KvLQT1 isoform 2 plasmid showed no detectable K + current. Those injected with a 1/1 isoform 2/isoform 1 ratio showed no detectable K + current. Those injected with 1/5 and 2/5 ratios showed a K + current with markedly reduced amplitude. Coexpression of the IsK regulator consistently reduced the dominant negative effects of isoform 2. Our results indicate that KvLQT1 isoform 2 exerts a pronounced negative dominance on isoform 1 channels and that the cardiac KvLQT1 K + channel complex is composed of at least three different proteins as follows: isoform 1, isoform 2, and IsK.