title: Two distinct congenital arrhythmias evoked by a multidysfunctional Na(+) channel.
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.
authors.affiliation: Experimental and Molecular Cardiology Group, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: M W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: P C
authors.initials: PC
authors.lastname: Viswanathan
authors.forename: C
authors.initials: C
authors.lastname: Bezzina
authors.forename: A
authors.initials: A
authors.lastname: Baartscheer
authors.forename: A A
authors.initials: AA
authors.lastname: Wilde
authors.forename: J R
authors.initials: JR
authors.lastname: Balser
mesh_terms: D001145:Arrhythmias, Cardiac / Q000151:congenital* / Q000235:genetics*; D004562:Electrocardiography; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D008133:Long QT Syndrome; D008564:Membrane Potentials / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D015222:Sodium Channels / Q000502:physiology*
chemical_list: D015222:Sodium Channels