Dataset Information

Characterization of an N-terminal Na_v1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

ABSTRACT:

Background

Alterations in the SCN5A gene encoding the cardiac sodium channel Na_v1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A?>?G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the functional impact of the variant to clarify the medical relevance.

Methods

Mutant as well as wild type GFP tagged Na_v1.5 channels were expressed in HEK293 cells. We performed functional characterization experiments using patch-clamp technique.

Results

Electrophysiological measurements indicated, that the detected missense variant alters Nav1.5 channel functionality leading to a gain-of-function effect. Cells expressing S106G channels show an increase in Na_v1.5 current over the entire voltage window.

Conclusion

The results support the assumption that the detected sequence aberration alters Na_v1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.

SUBMITTER: Scheiper-Welling S

PROVIDER: S-EPMC7678220 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

Characterization of an N-terminal Na<sub>v</sub>1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

Scheiper-Welling Stefanie S Zuccolini Paolo P Rauh Oliver O Beckmann Britt-Maria BM Geisen Christof C Moroni Anna A Thiel Gerhard G Kauferstein Silke S

BMC medical genetics 20201119 1

<h4>Background</h4>Alterations in the SCN5A gene encoding the cardiac sodium channel Na<sub>v</sub>1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A > G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the function ...[more]

PMID: 33213388

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Project description:Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7-10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7-10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently, in vitro study also demonstrated that FGF21 administration was able to shorten action potential duration (APD) in hydrogen peroxide-treated AC16 cells. Mechanically, FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac sodium current (I Na) and inward rectifier potassium (I k1) in AC16 cells induced by hydrogen peroxide. Moreover, the restorative effect of FGF21 on NaV1.5 and Kir2.1 was eliminated when FGF receptors were inhibited. Collectively, FGF21 has the potential role of ameliorating transmembrane ion channels remodeling through the NaV1.5/Kir2.1 pathway by FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic therapy in clinics.

Dataset Information

Characterization of an N-terminal Na_v1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

Background

Methods

Results

Conclusion

Publications

Characterization of an N-terminal Na<sub>v</sub>1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Characterization of an N-terminal Nav1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

Background

Methods

Results

Conclusion

Publications

Characterization of an N-terminal Na<sub>v</sub>1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Characterization of an N-terminal Na_v1.5 channel variant - a potential risk factor for arrhythmias and sudden death?