A new SCN5A mutation responsible for Multifocal Ectopic Purkinje-Related Premature Contractions

Abstract

Recently, SCN5A mutations have been associated with Multifocal Ectopic Purkinje-Related Premature Contractions (MEPPC), a cardiac syndrome associating polymorphic ventricular arrhythmia with dilated cardiomyopathy. A new SCN5A mutation was identified in a young woman presenting with polymorphic PVCs and dilated cardiomyopathy since the age of 12. Radiofrequency catheter ablation showed at least three exit sites of purkinje-PVCs. A treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs. A new heterozygous missense mutation was identified in exon 5 of SCN5A (c.611C > A, pAla204Glu) in the DI-S3 domain. We investigated the functional consequences of NaV1.5-A204E expressed in HEK cells by recording the sodium current using the whole-cell configuration of the patch clamp technique. The NaV1.5-A204E mutant channels exhibited a significant leftward shift of the activation curve of 8 mV (V0.5 of activation = −42.9 ± 1.3 mV in A204E transfected cells ( n = 24) compared to −34.8 ± 1.9 mV in cells transfected with the wild-type (WT) channel ( n = 20), P < 0.001), leading to a large, hyperpolarized window current that predicts aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. We did not observe any difference in the sodium current density, nor persistent sodium current in NaV1.5-A204E transfected cells, when compared to WT cells. This profile of channel dysfunction shares features with other MEPCC-associated SCN5A mutations and overlapped that of congenital long QT syndrome LQT3. The functional consequences of this new SCN5A mutation associated with MEPPC revealed a pattern of abnormal voltage dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of the syndrome. These features of the mutant sodium channel are likely to be responsible for hyperexcitability of the fascicular-Purkinje system.