The 1795insD mutation in SCN5A disrupts fast inactivation to prolong repolarization at slow heart rates, while augmenting slow inactivation to reduce Na+ current at rapid heart rates.
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.
Veldkamp et al. (Fri,) conducted a other in Congenital long-QT syndrome (LQT3) and Brugada syndrome. 1795insD mutation in SCN5A was evaluated on Na+ channel gating (fast and slow inactivation). The 1795insD mutation in SCN5A disrupts fast inactivation to prolong repolarization at slow heart rates, while augmenting slow inactivation to reduce Na+ current at rapid heart rates.