A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease.
OBJECTIVE
Loss of Na(+) channel function has been implicated in idiopathic ventricular fibrillation (IVF) and Brugada syndrome. We have studied the biophysical properties of an IVF mutation (S1710L) that exhibited an unusual clinical phenotype: rate-dependent bundle branch block without manifestation of Brugada-type ECG pattern.


METHODS
The mutant S1710L channels were expressed in mammalian cells and their gating properties, studied using whole-cell patch clamp techniques, were compared with wild-type (WT) and a Brugada syndrome mutant channel T1620M.


RESULTS
The S1710L channel exhibited significantly faster macroscopic current decay than WT or T1620M. In addition, S1710L showed a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation than in WT or T1620M. In addition to the alterations in fast inactivation most commonly observed in Brugada syndrome mutations, S1710L exhibited marked enhancement in slow inactivation and a large positive shift of activation that potentially decreases conduction velocity.


CONCLUSIONS
These functional abnormalities may be responsible for the overlapping clinical phenotypes associated with Brugada syndrome and the cardiac conduction defect, a novel cardiac Na(+) channelopathy.
Shirai
Nobumasa
N
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-8638, Japan.
Makita
Naomasa
N
Sasaki
Koji
K
Yokoi
Hisataka
H
Sakuma
Ichiro
I
Sakurada
Harumizu
H
Akai
Jun
J
Kimura
Akinori
A
Hiraoka
Masayasu
M
Kitabatake
Akira
A
D000704:Analysis of Variance; D001145:Arrhythmias, Cardiac; D002037:Bundle-Branch Block / Q000378:metabolism*; D002460:Cell Line; D004562:Electrocardiography; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013577:Syndrome
D015222:Sodium Channels