Összes szerző

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Gaál Szabolcs

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Gaál Szabolcs
Characterization of a novel mutation in Brugada Syndrome

Aug 30 - szerda

08:45 – 09:00

Membránok és membránfehérjék biofizikája

E20

Characterization of a novel mutation in Brugada Syndrome

Szabolcs Gaál^1,2, Beáta Arnódi-Mészáros¹, István Balogh³, Bálint L. Bálint⁴, Zoltán Csanádi², György Panyi¹, and Tibor G Szántó¹

¹ University of Debrecen, Department of Biophysics and Cell Biology, Debrecen, Hungary

² University of Debrecen, Department of Cardiology and Cardiac Surgery, Debrecen, Hungary

³ University of Debrecen, Department of Human Genetics, Debrecen, Hungary

⁴ University of Debrecen. Faculty of Medicine. Department of Biochemistry and Molecular Biology. Genomic Medicine and Bioinformatic Core Facility, Debrecen, Hungary

Voltage-gated sodium channels (Na_V) play a key role in the initiation and propagation of cardiac action potential essential for the rhythmic beating of the heart. Therefore, alterations of the sodium current (I_Na) in cardiomyocytes can lead to diseases responsible for cardiac arrhythmias, such as Brugada Syndrome (BrS) that has an increased risk for sudden cardiac death due to ventricular fibrillation. The major disease gene for BrS is SCN5A encoding the primary alpha-subunit of the cardiac Na_V1.5 channel. Exploring SCN5A mutations in patients with inherited arrhythmogenic syndromes is critical for the deeper understanding the pathogenesis of BrS.

Accordingly, we aimed at fully characterizing the biophysical properties of Na_V1.5 containing a novel heterozygous mutation of R893C localized in the P-loop of domain II identified in a patient with BrS. We subsequently compared the main gating parameters of R893C channels to wild-type Na_V1.5 channels (WT). The mutation was introduced by site-directed mutagenesis. The channels were transiently expressed in CHO cells and I_Na was measured using the standard whole cell patch-clamp technique.

We found that the peak current density is substantially reduced by the R893C mutation compared to WT channels. We also observed slower activation kinetics of I_Na current in R893C channels, although the mutation had no significant effect on the steady-state activation. All observations confirmed the loss-of-function of R893C channels. Pharmacological studies revealed that the reducing agent Dithiothreitol might restore the normal function of Na_V1.5 containing R893C by reducing the cysteine bridges that may be responsible for the loss of conduction.

Our conclusion is that the analysed mutation in the SCN5A gene result in biophysical changes in the Na_V1.5 current and thus, may be responsible for BrS. Understanding the structure-function relationship of Na_V1.5 will shed new light on exploiting new therapeutic drugs for SCN5A channelopathies.