Two distinct congenital arrhythmias evoked by a multidysfunctional Na+ channel

The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinct, life-threatening rhythm disorder; 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.