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| Title: | KCNQ1 MUTATION CAUSING DOMINANT-NEGATIVE SUPPRESSION DUE TO DEFECTIVE CHANNEL TRAFFICKING UNDERLIES CARDIAC ARREST IN A PATIENT WITH LONG QT SYNDROME | |
| DOI No: | 10.1142/9789812702234_0078 | |
| Source: | ADVANCES IN ELECTROCARDIOLOGY 2004 (pp 288-292) | |
| Author(s): | YOSHIYASU AIZAWA
Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan LONG-MEI WU Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan KAZUO UEDA Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan Molecular Pathogenesis, Medical Research, Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan SEIKO KAWANO Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan YUJI HIRANO Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan AKINORI KIMURA Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan Molecular Pathogenesis, Medical Research, Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan YOSHIFUSA AIZAWA Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata-shi, Niigata 951-8510, Japan MASAYASU HIRAOKA Department of Cardiovascular Disease, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan |
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| Abstract: | Long-QT syndrome is caused by mutations in 7 defined genes that mostly encode K+ and Na+ channels, and the underlying mechanisms are variable among different gene mutations. A 13-year-old girl with a history of cardiopulmonary arrest was referred to our institute for genetic analysis. Her QT interval at rest was prolonged (QTc=0.52sec) and it further prolonged with exercise (maximum QTc=0.62sec).PCR-SSCP and DNA sequence analysis identified a novel frameshift mutation Ala178fs/105 in KCNQ1, resulting in premature stop codon that eliminates the portions of S3-S6 and C-terminus of the channel. We examined electrophysiological properties using heterologous expression system in COS-7 cells. Whole-cell patch-clamp technique demonstrated that the WT-KCNQ1 with KCNE1 produced normal IKs current, while no current was observed in cells expressing A178fs/105 mutant and KCNE1. Co-expression of WT- and A178fs/105-KCNQ1 along with KCNE1 suppressed the current with a dominant-negative manner. Next we examined the subcellular localization of WT and/or A178fs/105 mutant channel using confocal laser microscopy which revealed trafficking deficiency of A178fs/105 mutant. Co-expression of GFP-tagged WT- with A178fs/105-KCNQ1 also induced the intracellular retention of the channel protein. We conclude that the A178fs/105 mutation causing dominant-negative suppression due to trafficking defect is an underlying mechanism for fatal arrhythmias of this patient. | |
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