scholarly journals Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome

1999 ◽  
Vol 44 (3) ◽  
pp. 507-517 ◽  
Author(s):  
M Rook
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Gene Mutations ◽  
Channel Kinetics ◽  
Cardiac Sodium Channel ◽  
Scn5a Gene

P1597Two novel mutations in SCN5A gene cause enhanced inactivation and lead to Brugada syndrome

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Zaytseva ◽  
A V Karpushev ◽  
A V Karpushev ◽  
Y Fomicheva ◽  
Y Fomicheva ◽  
...  
Keyword(s):  
Steady State ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Slow Inactivation ◽  
Fast Inactivation ◽  
Novel Mutations ◽  
Patch Clamp Technique ◽  
Inactivation Curve ◽  
Voltage Gated ◽  
Cardiac Sodium Channel

Abstract Background Mutations in gene SCN5A, encoding cardiac potential-dependent sodium channel Nav1.5, are associated with various arrhythmogenic disorders among which the Brugada syndrome (BrS) and the Long QT syndrome (LQT) are the best characterized. BrS1 is associated with sodium channel dysfunction, which can be reflected by decreased current, impaired activation and enhanced inactivation. We found two novel mutations in our patients with BrS and explored their effect on fast and slow inactivation of cardiac sodium channel. Purpose The aim of this study was to investigate the effect of BrS (Y739D, L1582P) mutations on different inactivation processes in in vitro model. Methods Y739D and L1582P substitutions were introduced in SCN5A cDNA using site-directed mutagenesis. Sodium currents were recorded at room temperature in transfected HEK293-T cells using patch-clamp technique with holding potential −100 mV. In order to access the fast steady-state inactivation curve we used double-pulse protocol with 10 ms prepulses. To analyze voltage-dependence of slow inactivation we used two-pulse protocol with 10s prepulse, 20ms test pulse and 25ms interpulse at −100mV to allow recovery from fast inactivation. Electrophysiological measurements are presented as mean ±SEM. Results Y739D mutation affects highly conserved tyrosine 739 among voltage-gated sodium and calcium channels in the segment IIS2. Mutation L1582P located in the loop IVS4-S5, and leucine in this position is not conserved among voltage-gated channels superfamily. We have shown that Y739D leads to significant changes in both fast and slow inactivation, whereas L1582P enhanced slow inactivation only. Steady-state fast inactivation for Y739D was shifted on 8.9 mV towards more negative potentials compare with that for WT, while L1582P did not enhanced fast inactivation (V1/2 WT: −62.8±1.7 mV; Y739D: −71.7±2.3 mV; L1582P: −58.7±1.4 mV). Slow inactivation was increased for both substitutions (INa (+20mV)/INa (−100mV) WT: 0.45±0.03; Y739D: 0,34±0.09: L1582P: 0.38±0.04). Steady-state fast inactivation Conclusions Both mutations, observed in patients with Brugada syndrome, influence on the slow inactivation process. Enhanced fast inactivation was shown only for Y739D mutant. The more dramatic alterations in sodium channel biophysical characteristics are likely linked with mutated residue conservativity. Acknowledgement/Funding RSF #17-15-01292

Differential effects of cardiac sodium channel mutations on initiation of ventricular arrhythmias in patients with Brugada syndrome

Heart Rhythm ◽  
2009 ◽  
Vol 6 (4) ◽  
pp. 487-492 ◽  
Author(s):  
Hiroshi Morita ◽  
Satoshi Nagase ◽  
Daiji Miura ◽  
Aya Miura ◽  
Shigeki Hiramatsu ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Ventricular Arrhythmias ◽  
Differential Effects ◽  
Cardiac Sodium Channel

scholarly journals A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill

2004 ◽  
Vol 255 (1) ◽  
pp. 137-142 ◽  
Author(s):  
N. Takehara ◽  
N. Makita ◽  
J. Kawabe ◽  
N. Sato ◽  
Y. Kawamura ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Cardiac Sodium Channel ◽  
Channel Mutation ◽  
Sodium Channel Mutation

scholarly journals Compound heterozygous SCN5A gene mutations in asymptomatic Brugada syndrome child

2012 ◽  
Vol 2 (1) ◽  
pp. 11 ◽  
Author(s):  
Elena Sommariva ◽  
Matteo Vatta ◽  
Yutao Xi ◽  
Simone Sala ◽  
Tomohiko Ai ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Scn5a Gene ◽  
Syndrome Child

Abstract 5346: Regulation of Cardiac Na + Current by Pyridine Nucleotides: A Possible Explanation of Glycerol-3-Phosphate Dehydrogenase-Linked Brugada Syndrome

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shamarendra Sanyal ◽  
Iman S Gurung ◽  
Arnold E Pfahnl ◽  
Lijuan L Shang ◽  
Shahriar Iravanian ◽  
...  
Keyword(s):  
Mouse Model ◽  
Brugada Syndrome ◽  
Fluorescent Microscopy ◽  
Gene Mutations ◽  
Oxidase Inhibitor ◽  
Pyridine Nucleotides ◽  
Programmed Electrical Stimulation ◽  
Amino Acid Homology ◽  
Cardiac Sodium Channel ◽  
Glycerol 3 Phosphate Dehydrogenase

Recently, glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene mutations have been shown to reduce cardiac Na + current and cause Brugada Syndrome (BrS). The glycerol-3-phosphate dehydrogenase (GPD) family of genes is involved in nicotinamide adenine dinucleotides (NAD)-dependent energy metabolism, and GDP1-L has >80% amino acid homology with GPD. Therefore, we tested whether mutations in GPD1-L could be acting through NAD (H) to alter Na + current. Human embryonic kidney (HEK) cells stably expressing the human cardiac sodium channel (SCN5A) were used to assess the effects of wild-type (WT) and mutant (MT) GPD1-L on cellular NAD(H) and the effects of NAD(H) on Na + current. A mouse model of BrS was used to assess the effect of reduced NAD + on arrhythmic risk. MT GPD1-L raised cellular NADH level by 4.3 fold (p<0.01) and reduced Na + current by 69.9% (p<0.01). Extracellular NADH (300 μM) raised cellular NADH by 5.3 fold and decreased whole cell peak conductance by 71.4% (p<0.001). Extracellular NAD + (300 μM) raised conductance by 30.3% (p< 0.001). Fluorescent microscopy showed parallel changes in membrane-associated, GFP-tagged Na + channels. Intracellular application of NADH or NAD + resulted in an immediate change in Na + current of −55.5% (p < 0.01) and +66.6% (p < 0.01), respectively. External NAD + could prevent the reduction in Na + current caused by MT GPD1-L. Apocynin (100 μM), an NAD(P)H oxidase inhibitor, or the reducing agent, dithiothreitol (DTT), prevented the NADH-induced reduction in Na + current (p < 0.01). Application of 100 μM NAD + to a mouse model of BrS reduced the programmed electrical stimulation induced ventricular tachycardia. GPD1-L mutations may cause BrS through alterations in cellular NAD(H), and NAD + might represent a novel treatment for BrS.

scholarly journals Cardiac sodium channel, its mutations and their spectrum of arrhythmia phenotypes

2016 ◽  
Vol 26 (3) ◽  
pp. 281 ◽  
Author(s):  
Andrés Ricardo Pérez-Riera ◽  
Rodrigo Daminello Raimundo ◽  
Rodrigo Akira Watanabe ◽  
José Luiz Figueiredo ◽  
Luiz Carlos de Abreu
Keyword(s):  
Sodium Channel ◽  
Cardiac Muscle ◽  
Heart Function ◽  
Heart Diseases ◽  
Cardiac Conduction ◽  
Activation Process ◽  
Α Subunit ◽  
Cardiac Sodium Channel ◽  
Wide Range ◽  
Scn5a Gene

The mechanisms of cellular excitability and propagation of electrical signals in the cardiac muscle are very important functionally and pathologically. The heart is constituted by three types of muscle: atrial, ventricular, and specialized excitatory and conducting fi bers. From a physiological and pathophysiological point of view, the conformational states of the sodium channel during heart function constitute a signifi cant aspect for the diagnosis and treatment of heart diseases. Functional states of the sodium channel (closed, open, and inactivated) and their structure help to understand the cardiac regulation processes. There are areas in the cardiac muscle with anatomical and functional differentiation that present automatism, thus subjecting the rest of the fi bers to their own rhythm. The rate of these (pacemaker) areas could be altered by modifi cations in ions, temperature and especially, the autonomic system. Excitability is a property of the myocardium to react when stimulated. Another electrical property is conductivity, which is characterized by a conduction and activation process, where the action potential, by the all-or-nothing law, travels throughout the heart. Heart relaxation also stands out as an active process, dependent on the energetic output and on specificion and enzymatic actions, with the role of sodium channel being outstanding in the functional process. In the gene mutation aspects that encode the rapid sodium channel (SCN5A gene), this channel is responsible for several phenotypes, such as Brugada syndrome, idiopathic ventricular fibrillation, dilated cardiomyopathy, early repolarization syndrome, familial atrial fibrillation, variant 3 of long QT syndrome, multifocal ectopic ventricular contractions originating in Purkinje arborizations, progressive cardiac conduction defect (Lenègre disease), sudden infant death syndrome, sick sinus syndrome, sudden unexplained nocturnal death syndrome, among other sodium channel alterations with clinical overlapping. Finally, it seems appropriate to consider the “sodium channel syndrome” (mutations in the gene of the α subunit of the sodium channel, SCN5A gene) as a single clinical entity that may manifest in a wide range of phenotypes, to thus have a better insight on these cardiac syndromes and potential outcomes for their clinical treatment.

scholarly journals Lidocaine-Induced Brugada Syndrome Phenotype Linked to a Novel Double Mutation in the Cardiac Sodium Channel

2008 ◽  
Vol 103 (4) ◽  
pp. 396-404 ◽  
Author(s):  
Hector M. Barajas-Martínez ◽  
Dan Hu ◽  
Jonathan M. Cordeiro ◽  
Yuesheng Wu ◽  
Richard J. Kovacs ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Double Mutation ◽  
Cardiac Sodium Channel

scholarly journals Epidural Analgesia with Ropivacaine during Labour in a Patient with a SCN5A Gene Mutation

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
A. L. M. J. van der Knijff-van Dortmont ◽  
M. Dirckx ◽  
J. J. Duvekot ◽  
J. W. Roos-Hesselink ◽  
A. Gonzalez Candel ◽  
...  
Keyword(s):  
Case Report ◽  
Adverse Events ◽  
Epidural Analgesia ◽  
Brugada Syndrome ◽  
Low Dose ◽  
Gene Mutations ◽  
Pregnant Patient ◽  
Cardiac Conduction ◽  
Conduction Disturbances ◽  
Scn5a Gene

SCN5A gene mutations can lead to ion channel defects which can cause cardiac conduction disturbances. In the presence of specific ECG characteristics, this mutation is called Brugada syndrome. Many drugs are associated with adverse events, making anesthesia in patients with SCN5A gene mutations or Brugada syndrome challenging. In this case report, we describe a pregnant patient with this mutation who received epidural analgesia using low dose ropivacaine and sufentanil during labour.

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