Abstract | OBJECTIVE: 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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Authors | Dierk Thomas, Anna-Britt Wimmer, Christoph A Karle, Manuela Licka, Markus Alter, Markus Khalil, Herbert E Ulmer, Sven Kathöfer, Johann Kiehn, Hugo A Katus, Wolfgang Schoels, Michael Koenen, Joerg Zehelein |
Journal | Cardiovascular research
(Cardiovasc Res)
Vol. 67
Issue 3
Pg. 487-97
(Aug 15 2005)
ISSN: 0008-6363 [Print] England |
PMID | 15950200
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- KCNQ1 Potassium Channel
- KCNQ1 protein, human
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Topics |
- Adult
- Animals
- Cells, Cultured
- DNA Mutational Analysis
- Female
- Gene Deletion
- Genes, Dominant
- Heterozygote
- Humans
- Ion Channel Gating
(genetics)
- KCNQ1 Potassium Channel
(genetics)
- Male
- Middle Aged
- Myocardium
(metabolism)
- Oocytes
- Patch-Clamp Techniques
- Polymorphism, Single-Stranded Conformational
- Romano-Ward Syndrome
(genetics, metabolism)
- Transfection
- Xenopus
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