N.S. : non statistically significant compared to WT ; N.A.: not available

COMMENTS and CLINICAL PHENOTYPE
L1825P was identified in a 70-years-old woman admitted to the hospital for recurrent syncope. Previous ECGs were within normal limits but severe QT interval prolongation (QTc 594 ms), ventricular arrhythmias (Torsades de Pointes-like) developed after the patient was treated with Cisapride (5mg/d) for bowel transit dysfunction. ECG normalized after Cisapride withdrawal.

L1825P significantly slowed inactivation, and caused severe abnormalities of activation that "potentially result in greater reduction in Na+ channel available during excitation". However, prominent late sustained current is compatible with QT interval prolongation. Overall the authors hypothesized that "the contribution to persistent NA+ current of L1825P to the cardiac action potential duration may be relatively small because the persistent current is offset by the concomitant loss of function phenotype.

Interestingly several biophysical properties of 1825P mutants channels (prominent late current, negative shift of steady state inactivation and decreased current density) are similar to those observed for 1795insD mutation identified in a family with overlapping Brugada syndrome and LQT3 phenotype by Bezzina et al. To explain the difference in clinical manifestations the authors state that ".....this may be attributed to alteration in the kinetics of intermediate inactivation that was not present in 1825P channels.

This mutant was also characterized by Liu et al in 2005, whp found significantly reduced peak INa (WT: 209±36 versus LP: 23±3 pA/pF, P<0.05) and demonstrate a trafficking defect. Interestingly incubating transfected cells with cisapride partially rescued misprocessing. As a result, "late" sodium current increased with cisapride.Based on these findings the authors concluded that cisapride caused torsade de pointes not only by blocking IKr but also by rescuing cell surface expression of this mutant channel, further exaggerating the LQT3 phenotype. .