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 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
M W
MW
Experimental and Molecular Cardiology Group, Academic Medical Center, Amsterdam, The Netherlands.
Viswanathan
P C
PC
Bezzina
C
C
Baartscheer
A
A
Wilde
A A
AA
Balser
J R
JR
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*
D015222:Sodium Channels