Annotated PGx Gene Information for SCN5A
Submitted by: Ping Yang and Andrew Wooldridge (PAT)
Reviewed by: Reviewed
Submitted date: Dec 21, 2006
| Gene HGNC Name: | SCN5A |
|---|---|
| Gene Common Name: | Cardiac sodium channel, alpha subunit |
| Introductory Information: | The voltage-gated sodium channel type V alpha isoform (NaV1.5) belongs to a superfamily of nine sodium channels that are gated (opened and closed) by changes in membrane potential. The encoded protein is found primarily in cardiac muscle, generates the initial fast upstroke of the action potential in most cardiac cells, and underlies fast conduction in atria and ventricles; sodium channel block prolongs QRS duration on the electrocardiogram. Unlike neuronal sodium channels, the cardiac isoform is relatively resistant to block by the pufferfish toxin tetrodotoxin. The human gene, SCN5A, was cloned by Gellens et al. [PMID: 1309946] in 1992 and localized to chromosome 3p21 by George et al. in 1995 [PMID: 7956363]. The gene consists of 28 exons (generating an mRNA of 8526 nucleotides) with an open reading frame that encodes a 2016-amino acid protein. The coding region of the gene includes four common non-synonymous polymorphisms: R34C, H558R, S1103Y, and R1193Q. One common splice variant: Q1077del [Makielski et al. PMID: 14500339] has been reported. More than 100 mutations in SCN5A have been associated with a range of congenital human arrhythmia syndromes. Loss of normal fast inactivation results in increased maintained inward plateau current, generating the long QT syndrome type 3 (LQT3) [MIM#603830]. Loss of function variants - through a variety of mechanisms - produce the Brugada syndrome [MIM#601144]. Other arrhythmias reported with SCN5A mutations include autosomal recessive sick sinus syndrome 1 (sss1) [MIM#608567], idiopathic ventricular fibrillation (IVF) [MIM#603829], sudden infant death syndrome (SIDS) [MIM#272120] and progressive familial heart block type I [MIM#113900]. The spectrum of these disease related mutations have been reported in several large scale screening studies [PMID: 15851227, 10973849]. Drugs that block sodium channels include those used for the treatment of arrhythmias as well as a small number of non-antiarrhythmics. Sodium channel blocking antiarrhythmics include quinidine, procainamide, disopyramide, flecainide, propafenone, lidocaine, mexiletine, and amiodarone. Many of these exert other important electrophysiologic, autonomic and other effects. Sodium channel blocking antiarrhythmics have been shown to increase mortality (likely due to ventricular fibrillation) in patients convalescing from myocardial infarction [PMID: 1720917, 2473403, 1377359, 6209318, 6369290]. Drugs not used as antiarrhythmics but that block sodium channels include tricyclic antidepressants, cocaine, and lithium. Administration of sodium channel blocking drugs may unmask the typical electrocardiogram of previously subclinical Brugada syndrome [PMID: 16144991]. In addition, subclinical LQT3 has been reported to be unmasked by administration of the QT-prolonging drug cisapride [PMID:12208804]. |
| Key PubMed IDs: | 7842012, 7889574, 9521325, 14523039, 15828879, 10973849, 10690282, 11234013, 11997281, 14500339, 12208804, 1720917, 2473403, 1377359, 6209318, 6369290 |
| Key Pathways: | Antiarrhythmic Drug Pathways |
| Drugs/Substrates: | quinidine, procainamide, disopyramide, flecainide, propafenone, lidocaine, mexiletine, amiodarone, tricyclic antidepressants, cocaine, and lithium . |
| Phenotypes/Diseases: | Long QT Syndrome [MIM#603830], Brugada syndrome [MIM#601144], autosomal recessive sick sinus syndrome 1 (sss1) [MIM#608567], idiopathic ventricular fibrillation (IVF) [MIM#603829], Sudden Infant Death Syndrome (SIDS) [MIM#272120] and progressive familial heart block type I [MIM#113900] |
| Important Variants: | SCN5A:R34C, SCN5A:H558R, SCN5A:S1103Y |
| Important Haplotypes: | There are no published studies yet focusing specifically on haplotype structure of this gene. HapB, a series of 6 polymorphisms (5 SNPs and an indel) with high LD has been identified in the promoter region of the gene in Asian subjects and linked to reduced promoter activity in vitro, longer QRS duration, and greater QRS prolongation after exposure to channel blocking drugs [PMID: 16415376] . |