Cardiovascular Research Advance Access originally published online on February 5, 2008
Cardiovascular Research 2008 78(3):494-504; doi:10.1093/cvr/cvn023
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Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome
1 Department of Pharmacology and Toxicology, University of Lausanne, 27, Bugnon, 1005 Lausanne, Vaud, Switzerland
2 Service of Cardiology, CHUV, Lausanne, Switzerland
3 Department of Cardiology, University Hospital, Basel, Switzerland
4 Department of Physiology, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland
* Corresponding author. Tel: +41 21 692 5364; fax: +41 21 692 5355 (H.A); Tel: +41 31 631 87 59; fax: +41 31 631 4611 (J.P.K.).E-mail addresses: hugues.abriel{at}unil.ch (H.A.); kucera{at}pyl.unibe.ch (J.P.K.)
Aims: Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Nav1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation.
Methods and results: SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Nav1.5 channels were expressed in HEK293 cells. Sodium currents (INa) were analysed using the whole-cell patch-clamp technique at 37°C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (Ito) was incorporated. A new mutation (C1850S) was identified in the Nav1.5 C-terminal domain. In HEK293 cells, mutant INa density was decreased by 62% at –20 mV. Inactivation of mutant INa was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of INa. In the simulations, the Ito density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block.
Conclusion: Our data confirm that mutations of the C-terminal domain of Nav1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant role in the pathogenesis of BrS.
KEYWORDS Brugada syndrome; Sodium channel; Genetics; Electrophysiology; Computational analysis
Time for primary review: 29 days
These authors contributed equally to this study.
These authors share the last authorship of this article.