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  Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome

Thomas, D., Wimmer, A.-B., Karle, C. A., Licka, M., Alter, M., Khalil, M., et al. (2005). Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome. Cardiovascular Research, 67(3), 487-497. doi:10.1016/j.cardiores.2005.05.003.

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Genre: Journal Article
Alternative Title : Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome

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CardiovascRes_67_2005_487.pdf (Any fulltext), 829KB
 
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 Creators:
Thomas, Dierck, Author
Wimmer, Anna-Britt, Author
Karle, Christoph A., Author
Licka, Manuela, Author
Alter, Markus, Author
Khalil, Markus, Author
Ulmer, Herbert E., Author
Kathöfer, Sven, Author
Kiehn, J., Author
Katus, Hugo A., Author
Schoels, Wolfgang, Author
Koenen, Michael1, 2, Author           
Zehelein, Joerg1, Author           
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              

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Free keywords: Arrhythmia (mechanisms); Ion channels; K-channel; KCNQ1; Long QT syndrome
 Abstract: 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 I(Ks) 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-deltaF339). Electrophysiological measurements in the presence and absence of the regulatory beta-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.

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Language(s): eng - English
 Dates: 2005-02-272005-05-022005-08-15
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
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Title: Cardiovascular Research
  Other : Cardiovasc. Res.
Source Genre: Journal
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Publ. Info: London : Elsevier
Pages: - Volume / Issue: 67 (3) Sequence Number: - Start / End Page: 487 - 497 Identifier: ISSN: 0008-6363
CoNE: https://pure.mpg.de/cone/journals/resource/954925389222