Copyright © 2005, European Society of Cardiology
Dominant-negative IKs suppression by KCNQ1-
F339 potassium channels linked to Romano–Ward syndrome
aUniversitätsklinik Heidelberg, Innere Medizin III, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
bUniversitätsklinik Heidelberg, Kinderheilkunde II, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany
cMax-Planck-Institut für medizinische Forschung, Abteilung Zellphysiologie, Jahnstraβe 29, 69120 Heidelberg, Germany
* Corresponding author. Tel.: +49 6221 5638687; fax: +49 6221 564662. Email address: Joerg_Zehelein{at}med.uni-heidelberg.de
Objective: Hereditary long QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged QT intervals and an increased risk for ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano–Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange–Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to cardiac arrhythmias. In this study, we investigate and discuss dominant-negative IKs current reduction by a KCNQ1 deletion mutation identified in a RWS family.
Methods: Single-strand conformation polymorphism analysis and direct sequencing were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were heterologously expressed in Xenopus oocytes, and potassium currents were recorded using the two-microelectrode voltage clamp technique.
Results: A heterozygous deletion of three nucleotides (CTT) identified in the KCNQ1 gene caused the loss of a single phenylalanine residue at position 339 (KCNQ1-
F339). Electrophysiological measurements in the presence and absence of the regulatory β-subunit KCNE1 revealed that mutant and wild type forms of an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger dominant-negative current reduction than the mutant form of the full-length KCNQ1 subunit (isoform 1).
Conclusion: This study highlights the functional relevance of the truncated KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in long QT syndrome. In the RWS family presented here, the autosomal-dominant trait is caused by multiple dominant-negative effects provoked by heteromultimeric channels formed by wild type and mutant KCNQ1-isoforms in combination with KCNE1.
KEYWORDS Arrhythmia (mechanisms); Ion channels; K-channel; KCNQ1; Long QT syndrome
Abbreviations: IKs, slowly activating component of IK • iso1, isoform 1 • iso2, isoform 2 • JLNS, Jervell and Lange–Nielsen syndrome • LQTS, long QT syndrome • RWS, Romano–Ward syndrome V1/2 half-maximal activation voltage • WT, wild type
1 These authors contributed equally to this work.
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