SCN5A

Official Full Name

sodium voltage-gated channel alpha subunit 5

Organism

Homo sapiens

GeneID

6331

Background

The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

Synonyms

HB1; HB2; HH1; IVF; VF1; HBBD; ICCD; LQT3; SSS1; CDCD2; CMD1E; CMPD2; PFHB1; Nav1.5;

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Detailed Information

The voltage-gated cardiac sodium channel is responsible for the rapid upstroke of the cardiac action potential and plays an important role in the initiation, propagation and maintenance of normal cardiac rhythm. The channel consists of a transmembrane pore-forming α-subunit (Na_v1.5), a modulatory β-subunit (Na_vβ1) and ancillary regulatory proteins. The Na_v1.5 is encoded by the SCN5A gene. Genetic variation in SCN5A is one of the causes of various inherited arrhythmia syndromes, including Brugada syndrome, paroxysmal ventricular fibrillation, Long-QT syndrome type 3, progressive familial heart block, atrial fibrillation, atrial standstill and sick sinus syndrome.

Biological Functions of HIF1A

The Na_v1.5 encoded by the SCN5A gene is the leading element in heart tissue and plays an important role in the excitability of cardiomyocytes. Na_v1.5 channels mediate the inward sodium current (I_Na) and induce fast depolarization, thus initiating the excitation-contraction coupling cascades in the cells. I_Na mediated by Na_v1.5 can be divided into peak and late sodium currents (I_Na-P and I_Na-L). The SCN5A gene is mainly expressed in cardiomyocytes and follows a circadian pattern of expression. There is some evidence demonstrating that sodium channels can participate in a variety of effector functions and may have a non-canonical role in non-excitable cells. At present, more than 20 proteins are known to interact with the Na_v1.5 alpha subunit in the lateral membrane or intercalated disks. This interaction leads to the regulation of expression and activity of the sodium channel through trafficking, targeting, and fixation of Na_v1.5 subunits to specific cellular compartments, post-translational protein processing, and via regulation of the biophysical properties of the sodium channel. In most of the experimental studies, Na_v1.5 was considered as a target for interacting proteins, but it may play a role in direct regulation or reciprocal co-interaction.

Figure 1. Topology of Na_v1.5 and its interaction with various regulatory proteins. (Zaklyazminskaya E, et al., 2016)

SCN5A Mutations and Cardiac Disorders

SCN5A gene mutations impair Na_v1.5 function, thus changing the magnitude and duration of I_Na-P and I_Na_-L, leading to different types of fatal arrhythmias. SCN5A mutations are responsible for various types of cardiac disorders, including long QT syndrome 3 (LQT3), cardiac conduction disease (CCD), Brudaga syndrome (BrS), atrial fibrillation (AF), sick sinus syndrome (SSS), progressive cardiac conduction defect (PCCD), multifocal ectopic Purkinje-related premature contraction (MEPPC), dilated cardiomyopathy (DCM), and the onset of a variety of non-cardiac diseases, including myotonic dystrophy, bowel syndrome, pain, epilepsy, and ataxia.

SCN5A mutations lead to the dysfunction of Na_v1.5 due to defective protein trafficking, targeting, post-translational protein processing, fixation to specific cellular compartments, the modulation of biophysical properties and many unclear mechanisms. Genotype and phenotype differ significantly, as the phenotypic characterization ranges from asymptomatic phenotypes to sudden cardiac death (SCD) in individuals that carry the same mutations. Besides, specific SCN5A mutations cause an individual phenotype or compound phenotypes, suggesting that a complex pathogenesis underlies SCN5A mutations. Based on the studies of heterologous expression systems, these mutations may induce arrhythmias through loss-of-function or gain-of-function effects (or both). Loss-of-function effects include loss of Na_v1.5 expression, the decrease of I_Na density, slower recovery from inactivation and/or enhanced slow inactivation. Na_v1.5 loss-of-function may promote arrhythmogenesis through reentry. Gain-of-function effects are realized by changes in kinetics, which leads to larger persistent Na+ current, larger window current or shift of window current towards more negative potentials. Na_v1.5 gain-of-function may enhance automaticity during repolarization or diastole, thereby resulting in the occurrence of premature extrasystoles.

References:

Tan R B, et al. A homozygous SCN5A mutation associated with atrial standstill and sudden death. Pacing and Clinical Electrophysiology, 2018, 41(8): 1036-1042.
Han D, et al. Dysfunctional Na_v1. 5 channels due to SCN5A mutations. Experimental Biology and Medicine, 2018, 243(10): 852-863.
Amin A S. SCN5A-related dilated cardiomyopathy: what do we know?. Heart Rhythm, 2014, 11(8): 1454-1455.
Glazer A M, et al. High-throughput reclassification of SCN5A variants. The American Journal of Human Genetics, 2020.
Zaklyazminskaya E, Dzemeshkevich S. The role of mutations in the SCN5A gene in cardiomyopathies. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2016, 1863(7): 1799-1805.

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