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Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na+ Channel
From the Experimental and Molecular Cardiology Group (M.W.V., C.B., A.B., A.A.M.W.) and Department of Clinical Genetics (C.B.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Anesthesiology and Pharmacology (P.C.V., J.R.B.), Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Jeffrey R. Balser, MD, PhD, 23rd and Pierce Avenues, Room 560, MRB II, Vanderbilt University School of Medicine, Nashville, TN 37212. E-mail jeff.balser{at}mcmail.vanderbilt.edu
Abstract—The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinct, life-threatening rhythm disorders linked to autosomal dominant mutations in SCN5A, the gene encoding the human cardiac Na+ channel. It is believed that these two syndromes result from opposite molecular effects: LQT3 mutations induce a gain of function, whereas Brugada syndrome mutations reduce Na+ channel function. Paradoxically, an inherited C-terminal SCN5A mutation causes affected individuals to manifest electrocardiographic features of both syndromes: QT-interval prolongation (LQT3) at slow heart rates and distinctive ST-segment elevations (Brugada syndrome) with exercise. In the present study, we show that the insertion of the amino acid 1795insD has opposite effects on two distinct kinetic components of Na+ channel gating (fast and slow inactivation) that render unique, simultaneous effects on cardiac excitability. The mutation disrupts fast inactivation, causing sustained Na+ current throughout the action potential plateau and prolonging cardiac repolarization at slow heart rates. At the same time, 1795insD augments slow inactivation, delaying recovery of Na+ channel availability between stimuli and reducing the Na+ current at rapid heart rates. Our findings reveal a novel molecular mechanism for the Brugada syndrome and identify a new dual mechanism whereby single SCN5A mutations may evoke multiple cardiac arrhythmia syndromes by influencing diverse components of Na+ channel gating function. The full text of this article is available at http://www.circresaha.org.
Key Words: Na+ channel • inactivation • long-QT syndrome • Brugada syndrome
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