Abstract 13566: Biophysical Properties of Na Channel in the S5-S6 High Risk LQT3 Mutations of the Long QT Syndrome
SCN5A mutations cause a gain of function in the cardiac voltage-gated sodium channel (Nav1.5) leading to type 3 long-QT syndrome (LQT3) and higher risk of sudden cardiac death. From the multicenter Japanese LQT registry, we have previously reported that mutations in the segment S5 through S6 (S5-S6) serving as the pore-forming module of the sodium channel were associated with greater arrhythmic events in the LQT3 patients. However, biophysical properties of LQT3 between the S5-S6 and non S5-S6 mutations are still unclear.
Methods: In 126 LQT3 patients from 72 proband-based families with genetically confirmed SCN5A mutations, 38 distinct mutations were indentified (33 missense, 3 deletion, and 2 frameshift) including nine S5-S6 mutations and 29 other mutations. Whole-cell currents through wild-type (WT) Nav1.5 and novel S5-S6 mutant (Q371E, V411M, A1428S, I1762del, L1772V) channels expressed in CHO cell were recorded using patch clamp.
Results: Persistent (late) Na current was larger in all S5-S6 mutant (0.34-1.79% for peak Na current) compared with WT (0.14%) (p<0.05), but the degree of increase was similar to those of non S5-S6 mutant channels previously reported. The steady state inactivation was shifted positively in S5-S6 mutant (V411M, I1762del, L1772V) compared with WT which was completely opposite from non S5-S6 mutant previously reported, whereas no difference was observed in the activation between the S5-S6 mutant and WT. Recovery from inactivation was also faster in some S5-S6 (I1762del, L1772V) mutants compared with WT. Therefore, S5-S6 mutant channel showed increased 'window' current as well as larger late Na current during ramp repolarization pulse.
Conclusion: Biophysical properties of the S5-S6 LQT3 mutant channel were significantly different from those of non S5-S6 mutants, which may contribute to mutation site-specific difference in arrhythmic risk of the LQT3 form of the long-QT syndrome.
- © 2012 by American Heart Association, Inc.