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Hum Mutat. 2020 Jan 12. doi: 10.1002/humu.23981. [Epub ahead of print]

A Novel Gain-of-function Mutation in SCN5A Responsible for Multifocal Ectopic Purkinje-related Premature Contractions.

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Sorbonne Université, Paris, F-75013, France.
INSERM, UMR_S1166, Hôpital Pitié-Salpêtrière, Paris, F-75013, France.
Institute of Cardiometabolism and Nutrition, ICAN, Paris, F-75013, France.
Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Cardiologie, Paris, France.
Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département d'Imagerie Cardiovasculaire, Paris, France.
Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Biochimie métabolique, Cardiogénétique, Paris, France.


Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy. Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and dilated cardiomyopathy. After failure of anti-arrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit-sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Nav 1.5-A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current, when compared to wild-type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC-associated Nav 1.5 mutations revealed a common electrophysiological pattern of abnormal voltage-dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for hyperexcitability of the fascicular-Purkinje system observed in patients with MEPPC. This article is protected by copyright. All rights reserved.


SCN5A ; Purkinje; dilated cardiomyopathy; electrophysiology; gain-of-function mutation; polymorphic premature ventricular complexes


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