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(Circulation. 1999;99:2290-2294.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Novel Mechanism Associated With an Inherited Cardiac Arrhythmia
Defective Protein Trafficking by the Mutant HERG (G601S) Potassium Channel
From the Department of Pediatric Cardiology (M.F., A.T., K.M., R.M.), Department of Cardiology (N.H., A.S., H.N., H.K.), and Research Division (S.I.), The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo, Japan, and Department of Physiology (M.C.T., G.A.R.) and Section of Cardiology, Department of Medicine (Q.G., Z.Z., C.T.J.), University of Wisconsin, Madison, Wis.
Correspondence to Rumiko Matsuoka, MD, PhD, Department of Pediatric Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162, Japan. E-mail rumiko{at}imcir.twmu.ac.jp
Background—The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go–related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (IKr), cause chromosome 7–linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work.
Methods and Results—To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane.
Conclusions—-Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.
Key Words: genes • arrhythmia • long-QT syndrome
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|
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|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
A. Kagan, Z. Yu, G. I. Fishman, and T. V. McDonald The Dominant Negative LQT2 Mutation A561V Reduces Wild-type HERG Expression J. Biol. Chem., April 6, 2000; 275(15): 11241 - 11248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Robertson LQT2 : Amplitude Reduction and Loss of Selectivity in the Tail That Wags the HERG Channel Circ. Res., March 17, 2000; 86(5): 492 - 493. [Full Text] [PDF]
|
|
|
|
|
|
D. M Roden and J. R Balser A plethora of mechanisms in the HERG-related long QT syndrome: Genetics meets electrophysiology Cardiovasc Res, November 1, 1999; 44(2): 242 - 246. [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhou, Q. Gong, and C. T. January Correction of Defective Protein Trafficking of a Mutant HERG Potassium Channel in Human Long QT Syndrome. PHARMACOLOGICAL AND TEMPERATURE EFFECTS J. Biol. Chem., October 29, 1999; 274(44): 31123 - 31126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|