Affinage

SCN5A

Sodium channel protein type 5 subunit alpha · UniProt Q14524

Length
2016 aa
Mass
226.9 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCN5A encodes Nav1.5, the principal voltage-gated sodium channel α-subunit of the heart, responsible for the rapid depolarization upstroke of the cardiac action potential and essential for normal impulse conduction. Cardiac SCN5A expression is transcriptionally controlled by TBX5, GATA4/GATA5, BMAL1 (circadian clock), Foxo1, and Wnt/β-catenin signaling acting on its promoter and a critical intronic enhancer within the SCN10A locus, while post-transcriptionally it is suppressed by miR-24 and stabilized by the RNA-binding protein HuR (PMID:22728936, PMID:27894866, PMID:23364267, PMID:22400069, PMID:27068063, PMID:24642470, PMID:29457789, PMID:29454929). Nav1.5 membrane density is regulated by a dystrophin–syntrophin complex at the C-terminus, lateral-membrane CASK-dependent trafficking, and FAT10-mediated protection from Nedd4-2 ubiquitination, while gain-of-function mutations that increase persistent late sodium current (INa) cause long QT syndrome type 3 and atrial fibrillation—amplified by a CaMKII–Nav1.5 positive-feedback loop—and loss-of-function mutations, most of which act through dominant-negative suppression of co-expressed wild-type channels or ER/Golgi trafficking defects, cause Brugada syndrome, cardiac conduction disease, and sudden infant death syndrome (PMID:16857961, PMID:27364017, PMID:33414395, PMID:14736542, PMID:35305865, PMID:11786529, PMID:21677263, PMID:11710892, PMID:18929244). An autoimmune mechanism involving anti-Nav1.5 autoantibodies that reduce sodium current density and reproduce Brugada-type ECG changes in vivo represents an additional, mutation-independent pathogenic pathway (PMID:39078224).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2001 High

    Establishing that SCN5A gain-of-function mutations increase persistent late INa provided the first mechanistic link between Nav1.5 dysfunction and lethal arrhythmia (SIDS), showing that even modest increases in late current are pathogenic.

    Evidence Patch clamp of A997S and R1826H mutant channels in HEK cells showing 2–3-fold increased late INa

    PMID:11710892

    Open questions at the time
    • Cellular context limited to heterologous expression; no cardiomyocyte or in vivo validation at that time
  2. 2002 High

    Demonstrating that BrS-associated mutations cause ER retention of Nav1.5 established protein trafficking failure as a distinct loss-of-function mechanism, separate from gating defects.

    Evidence Confocal imaging showing calnexin co-localization of R1232W/T1620M Nav1.5 and abolished INa in tsA201 cells

    PMID:11786529

    Open questions at the time
    • Whether trafficking-defective mutants also exert dominant-negative effects on wild-type channels was not tested
  3. 2003 High

    Discovery that the common H558R polymorphism rescues nearby loss-of-function mutations (T512I, M1766L) through intragenic complementation revealed that SCN5A genotype-phenotype relationships depend on cis-allelic context and modifier polymorphisms.

    Evidence Patch clamp and immunocytochemistry of single and double mutant constructs in HEK cells

    PMID:12454206 PMID:12569159

    Open questions at the time
    • Whether intragenic rescue occurs in native cardiomyocytes with endogenous accessory subunits was not tested
    • Structural basis for complementation unknown
  4. 2003 High

    Electrophysiological characterization of mutations in domain I–II linker (L619F) and domain IVS6 (I1768V) mapped distinct structural contributions to Nav1.5 inactivation gating—the linker controlling steady-state inactivation and IVS6 stabilizing the inactivated state.

    Evidence Patch clamp with site-directed mutagenesis in HEK cells and Xenopus oocytes

    PMID:12650885 PMID:12673799

    Open questions at the time
    • No structural data to explain how these residues interact with the inactivation gate at atomic resolution
  5. 2004 High

    A transgenic mouse expressing LQT3 mutation N1325S recapitulated human QT prolongation, spontaneous ventricular arrhythmias, and early afterdepolarizations in vivo, validating the late-INa gain-of-function mechanism and demonstrating mexiletine as a targeted therapy.

    Evidence In vivo ECG telemetry, patch clamp on isolated ventricular myocytes, mexiletine pharmacological rescue in transgenic mice

    PMID:14736542

    Open questions at the time
    • Single mutation model; generalizability to other LQT3 mutations not established
  6. 2005 High

    Demonstration that the BrS mutation L325R exerts a dominant-negative effect on co-expressed wild-type Nav1.5, with fever exacerbation, introduced dominant-negative suppression as a key pathomechanism beyond simple haploinsufficiency.

    Evidence Co-expression patch clamp at varying temperatures, pharmacological rescue with mexiletine/curcumin in HEK293 cells

    PMID:15890323 PMID:16301357

    Open questions at the time
    • Generality of dominant-negative mechanism across BrS variants not yet established at that time
  7. 2006 High

    Identification of the dystrophin–syntrophin complex as a required scaffold for Nav1.5 membrane expression established that cardiac sodium current depends on cytoskeletal anchoring at the channel C-terminus.

    Evidence Pull-down/mass spectrometry, patch clamp, and ECG in dystrophin-deficient mdx5cv mice showing 50% reduction in Nav1.5 and 29% reduction in INa

    PMID:16857961

    Open questions at the time
    • Whether dystrophin loss preferentially affects lateral versus intercalated disc Nav1.5 pools was not resolved
  8. 2008 High

    The M1875T mutation linked to familial atrial fibrillation revealed a gain-of-function mechanism (+16.4 mV inactivation shift increasing channel availability) distinct from LQT3 persistent current, showing that different biophysical defects in the same channel produce chamber-specific arrhythmias.

    Evidence Patch clamp in HEK cells expressing M1875T Nav1.5

    PMID:18929244

    Open questions at the time
    • Why the atrium is preferentially affected over the ventricle was not mechanistically explained
  9. 2010 High

    Nav1.5 was shown to be intrinsically mechanosensitive, with membrane stretch shifting activation and inactivation voltage dependence and increasing peak current, providing a biophysical basis for stretch-induced arrhythmias.

    Evidence Whole-cell and cell-attached patch clamp with graded pressure application in HEK293 cells

    PMID:21041530

    Open questions at the time
    • Whether mechanosensitivity is modulated by accessory subunits or cytoskeletal anchoring in cardiomyocytes was not tested
  10. 2011 High

    Discovery of a CaMKII–Nav1.5 positive-feedback loop (late INa activates CaMKII, which phosphorylates Nav1.5 to further increase late INa) provided a molecular amplification mechanism for arrhythmogenesis in LQT3.

    Evidence Co-immunoprecipitation, isoform-specific siRNA, CaMKII phosphorylation assays in neonatal rat ventricular myocytes and N1325S transgenic mice

    PMID:21677263

    Open questions at the time
    • Specific CaMKII phosphorylation sites on Nav1.5 responsible for current augmentation not mapped in this study
    • Whether the feedback loop operates similarly in human cardiomyocytes was not shown
  11. 2012 High

    Conditional knockout of Tbx5 from the murine ventricular conduction system identified TBX5 as a direct transcriptional activator of Scn5a via a VCS-specific enhancer, establishing the first transcription factor–Nav1.5 regulatory axis essential for fast conduction and survival.

    Evidence Cre-mediated VCS-specific Tbx5 KO in mice, in vivo enhancer-reporter assay with T-box site mutagenesis

    PMID:22728936

    Open questions at the time
    • Whether TBX5 is sufficient to restore Nav1.5 in diseased conduction tissue was not tested
  12. 2012 High

    Foxo1 was identified as a direct transcriptional repressor of SCN5A via insulin-responsive elements in its promoter, linking metabolic and oxidative stress signaling to sodium current regulation.

    Evidence ChIP showing Foxo1 occupancy at SCN5A promoter, luciferase reporter, constitutively nuclear Foxo1 and RNAi in HL-1 cardiomyocytes

    PMID:22400069

    Open questions at the time
    • In vivo cardiac-specific Foxo1 manipulation not performed
  13. 2013 High

    Demonstration that BMAL1 controls circadian Scn5a expression in cardiomyocytes, with its deletion reducing Nav1.5 and increasing arrhythmia susceptibility, established a molecular clock–cardiac conduction axis.

    Evidence Inducible cardiomyocyte-specific Bmal1 KO mice with ECG telemetry, patch clamp, and promoter transactivation assay

    PMID:23364267

    Open questions at the time
    • Whether other clock components independently regulate SCN5A or act solely through BMAL1 was not dissected
  14. 2014 High

    Identification and deletion of a cardiac enhancer within SCN10A that physically contacts the SCN5A promoter (via 4C-seq) and is required for cardiac Scn5a expression resolved how non-coding GWAS variants at SCN10A influence cardiac conduction through long-range regulation of SCN5A.

    Evidence 4C-seq chromatin conformation, BAC transgenic enhancer deletion, qPCR in human and mouse heart

    PMID:24642470

    Open questions at the time
    • The transcription factors mediating enhancer–promoter communication at this locus were not fully identified
  15. 2016 High

    Multiple transcriptional regulators converging on the SCN5A promoter were characterized: GATA4/GATA5 synergistically activate SCN5A via direct co-occupancy in human ventricle; Wnt/β-catenin–TCF4 represses SCN5A under oxidative stress; and CASK negatively regulates Nav1.5 lateral-membrane trafficking.

    Evidence ChIP/Re-ChIP in human heart for GATA4/5; ChIP for β-catenin/TCF4 with siRNA in HL-1 cells; pull-down, TIRF, biotinylation, and in vivo siRNA for CASK in cardiomyocytes

    PMID:27068063 PMID:27364017 PMID:27894866

    Open questions at the time
    • How CASK versus dystrophin–syntrophin complexes coordinately partition Nav1.5 between lateral membrane and intercalated disc is incompletely understood
  16. 2018 High

    Post-transcriptional regulation of SCN5A was defined: miR-24 suppresses SCN5A via a coding-region target modulated by a synonymous SNP, and HuR stabilizes SCN5A mRNA with therapeutic potential demonstrated by AAV9-HuR overexpression improving conduction and reducing arrhythmias post-MI.

    Evidence miRNA reporter assays and human expression quantitative analysis for miR-24; RIP and AAV9-HuR overexpression with optical mapping post-MI in mice for HuR

    PMID:29454929 PMID:29457789

    Open questions at the time
    • Whether miR-24 and HuR act on the same mRNA pool or in distinct subcellular compartments is unknown
  17. 2018 High

    BrS-associated Nav1.5 trafficking mutants were shown to additionally impair Kir2.1/2.2 channel function, revealing that Nav1.5 positively modulates IK1 and that trafficking defects reduce both INa and IK1, compounding loss of excitability.

    Evidence Co-expression in cell lines, rat cardiomyocytes, hiPSC-CMs, and SCN5A haploinsufficient mice; patch clamp

    PMID:30232268

    Open questions at the time
    • The molecular interface between Nav1.5 and Kir2.x that mediates positive modulation is not structurally defined
  18. 2019 High

    K219T-LMNA was shown to epigenetically silence SCN5A by recruiting PRC2 (SUZ12) and depositing H3K27me3 at its promoter, establishing a laminopathy-driven mechanism for sodium channel downregulation correctable by CRISPR/Cas9.

    Evidence ChIP for Lamin A/C and H3K27me3 at SCN5A promoter, patch clamp, and CRISPR correction in K219T-LMNA iPSC-CMs

    PMID:31118417

    Open questions at the time
    • Whether other LMNA mutations use the same PRC2-dependent mechanism to suppress SCN5A is not established
  19. 2019 High

    Genome editing of a conserved enhancer cluster downstream of SCN5A confirmed that multiple enhancer elements within the SCN5A–SCN10A locus cooperatively control chromatin architecture over >0.5 Mb and are selectively required for cardiac Scn5a expression and normal conduction.

    Evidence CRISPR-based enhancer deletions in mice with cardiac expression and ECG analysis

    PMID:31666509

    Open questions at the time
    • How the individual enhancers communicate with each other and with the SCN5A promoter in 3D chromatin space is incompletely resolved
  20. 2021 High

    FAT10 was identified as a novel Nav1.5 stabilizer that prevents Nedd4-2-mediated ubiquitination by binding Nav1.5 C-terminal lysines, with cardiac-specific Fat10 KO reducing peak INa and increasing arrhythmia susceptibility post-MI.

    Evidence Co-IP, ubiquitination assays, conditional cardiac Fat10 KO mice with patch clamp and post-MI arrhythmia phenotyping

    PMID:33414395

    Open questions at the time
    • Whether FAT10 competes with ubiquitin at specific lysines or blocks Nedd4-2 access allosterically is unresolved
  21. 2022 High

    Systematic co-expression of 50 SCN5A loss-of-function variants with wild-type showed that dominant-negative effects (not haploinsufficiency) are the predominant mechanism for most BrS-associated missense mutations, with a 2.7-fold higher disease burden for dominant-negative variants, redefining the genetic architecture of Brugada syndrome.

    Evidence Automated patch clamp with heterozygous WT + mutant co-expression in HEK293T cells; clinical BrS burden comparison

    PMID:35305865

    Open questions at the time
    • Structural mechanism by which mutant subunits poison wild-type channel complexes is not resolved
  22. 2022 High

    TBX5 variants were shown to cause either BrS (via failure to activate SCN5A promoter) or LQTS (via failure to repress CaMKIIδ/βIV-spectrin, augmenting late INa), demonstrating that a single upstream transcription factor can produce opposing arrhythmia syndromes through distinct transcriptional targets.

    Evidence Luciferase reporter, hiPSC-CMs, HL-1 cells, mouse cardiomyocytes, patch clamp, ranolazine pharmacology

    PMID:33576403

    Open questions at the time
    • Complete set of TBX5 direct targets relevant to cardiac electrophysiology not defined
  23. 2024 High

    Anti-Nav1.5 autoantibodies were identified in 90% of BrS patients, and injection of patient plasma into wild-type mice reproduced BrS-like ECG changes, establishing a mutation-independent autoimmune pathogenic mechanism.

    Evidence Western blot/IP screening of patient sera, patch clamp in HEK293A cells treated with patient IgG, in vivo plasma injection in WT mice with ECG

    PMID:39078224

    Open questions at the time
    • Epitope(s) recognized by the autoantibodies on Nav1.5 not mapped
    • Whether autoantibodies are pathogenic drivers or secondary phenomena in BrS requires longitudinal studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the high-resolution structural basis for dominant-negative poisoning of WT by mutant Nav1.5 subunits; the mechanism by which Nav1.5 positively modulates Kir2.x channels; how intercalated disc versus lateral membrane Nav1.5 pools are differentially regulated; and whether anti-Nav1.5 autoantibodies are primary drivers or secondary markers in Brugada syndrome.
  • No cryo-EM structure of full-length human Nav1.5 in complex with trafficking partners or mutant subunits
  • Molecular interface for Nav1.5–Kir2.x interaction undefined
  • Relative contributions of autoimmune versus genetic mechanisms in genotype-negative BrS unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-112316 Neuronal System 5 R-HSA-9609507 Protein localization 5 R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4 R-HSA-162582 Signal Transduction 2
Partners
CAMK2DCASKDMDELAVL1SNTA1SNTB1TCAPUBD
Complex memberships
Dystrophin-syntrophin complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Nav1.5 C-terminus PDZ domain-binding motif (last three residues Ser-Ile-Val) associates with dystrophin via α- and β-syntrophin proteins; disruption of this motif abolishes the interaction. In dystrophin-deficient mdx5cv mice, Nav1.5 protein is reduced by 50% and sodium current is reduced by 29%, establishing that the dystrophin-syntrophin complex is required for proper expression and membrane function of Nav1.5. Pull-down with Nav1.5 C-terminus fusion proteins + mass spectrometry, Western blot, patch-clamp in isolated cardiomyocytes, ECG in mdx5cv mice Circulation research High 16857961
2002 The SCN5A double mutant R1232W/T1620M associated with Brugada syndrome fails to traffic to the plasma membrane and is retained in the endoplasmic reticulum (co-localized with calnexin), resulting in abolition of functional sodium current. A positively charged residue at position 1232 (arginine or lysine) is required for proper transport of Nav1.5. Whole-cell patch clamp, immunofluorescence/confocal microscopy with FLAG-tagged constructs, site-directed mutagenesis in tsA201 cells Circulation research High 11786529
2001 Two SIDS-associated SCN5A missense mutations (A997S and R1826H) produce channels with slower current decay and a 2–3-fold increase in late (persistent) sodium current, establishing a gain-of-function arrhythmogenic mechanism for some SIDS cases. Mutagenesis, transient transfection in HEK cells, whole-cell patch clamp JAMA High 11710892
2003 The common SCN5A polymorphism H558R in the I-II interdomain cytoplasmic linker can mitigate the in vitro loss-of-function effects of the nearby T512I mutation on sodium channel gating, demonstrating intragenic complementation between a polymorphism and a mutation on the same allele. Whole-cell patch clamp in heterologous expression, site-directed mutagenesis The Journal of clinical investigation High 12569159
2003 The common SCN5A polymorphism H558R rescues the trafficking defect and restores normal sodium current of the LQT3 mutation M1766L; M1766L alone causes ER retention and markedly reduced current, while M1766L on the H558R background shows normal surface trafficking and persistent late current, demonstrating intragenic complementation. Voltage clamp, immunocytochemistry for surface trafficking, site-directed mutagenesis in HEK cells Physiological genomics High 12454206
2005 The Brugada-associated SCN5A mutation L325R produces misfolded Nav1.5 channels that can be partially rescued by mexiletine or curcumin; L325R channels also exert a dominant-negative effect on co-expressed wild-type channels, suggesting this mechanism underlies fever-exacerbated Brugada syndrome. Patch clamp at various temperatures, Western blot, co-expression experiments, cardiac action potential modeling in HEK293 cells Cardiovascular research High 15890323
2005 The LQT3-associated SCN5A mutation L1825P is a misprocessed channel retained at the cell surface at only ~9% of wild-type levels; cisapride rescues surface expression to ~30% of wild-type while simultaneously increasing late sodium current, establishing a novel drug-induced arrhythmia mechanism via rescue of a trafficking-defective channel. Whole-cell patch clamp, confocal imaging with epitope-tagged constructs, cell-counting assays in CHO cells Circulation High 16301357
2004 Transgenic mice expressing the LQT3 SCN5A mutation N1325S exhibit prolonged QT intervals, spontaneous polymorphic ventricular tachycardia and fibrillation, early afterdepolarizations, and a persistent late sodium current with slow recovery from inactivation; mexiletine suppresses these arrhythmias by blocking late INa and enhancing recovery from inactivation. Transgenic mouse model, in vivo ECG telemetry, patch clamp on isolated ventricular myocytes, pharmacological intervention with mexiletine Cardiovascular research High 14736542
2011 Nav1.5-dependent persistent Na+ influx (late INa) activates CaMKII, which in turn phosphorylates Nav1.5, further promoting Na+ influx in a positive feedback loop. CaMKII co-immunoprecipitates with Nav1.5, and knockdown of Nav1.5 (but not Nav1.1 or Nav1.2) prevents ATX-II-induced CaMKII phosphorylation. Co-immunoprecipitation, siRNA knockdown of specific Nav isoforms, CaMKII autophosphorylation assays, patch clamp, pharmacological inhibition in neonatal rat ventricular myocytes and N1325S transgenic mice American journal of physiology. Cell physiology High 21677263
2008 Telethonin (encoded by TCAP) physically interacts with Nav1.5 (co-immunoprecipitation) and co-localizes with Nav1.5 in gastrointestinal smooth muscle. A telethonin mutation found in a patient with intestinal pseudo-obstruction doubles the Nav1.5 window current when co-expressed in HEK293 cells, identifying telethonin as a Nav1.5-interacting protein that modulates channel activation kinetics. Co-immunoprecipitation, immunolocalization, whole-cell patch clamp with co-expression in HEK293 cells The Journal of biological chemistry High 18408010
2016 The lateral-membrane MAGUK protein CASK directly interacts with the C-terminus of Nav1.5 (pull-down) and negatively regulates Nav1.5 surface expression specifically at the lateral membrane of cardiomyocytes. CASK silencing increases INa by enhancing Nav1.5 trafficking to the lateral membrane without affecting mRNA levels; this is prevented by the trafficking inhibitor brefeldin-A. Pull-down, whole-cell patch clamp, TIRF microscopy, biotinylation assays, in vivo siRNA knockdown, immunostaining in cardiac myocytes Circulation research High 27364017
2014 A cardiac enhancer located within the SCN10A locus (encompassing variant rs6801957) interacts with the SCN5A promoter and is essential for cardiac Scn5a expression; deletion of this enhancer in BAC transgenic mice abolishes Scn5a cardiac expression, and the rs6801957 variant modulates SCN5A transcript levels in human heart. High-resolution 4C-seq chromatin conformation analysis, BAC transgenic mouse enhancer deletion, qPCR of SCN5A transcript levels in human and mouse heart The Journal of clinical investigation High 24642470
2012 TBX5 directly drives Scn5a expression in the ventricular conduction system (VCS); deletion of Tbx5 from the mature murine VCS reduces Nav1.5 expression, causes loss of fast conduction, arrhythmias, and sudden death. A TBX5-responsive enhancer downstream of Scn5a, dependent on canonical T-box binding sites, drives VCS expression in vivo. Conditional Cre-mediated knockout in mice, ECG, in vivo enhancer reporter assay with T-box binding site mutagenesis, Western blot The Journal of clinical investigation High 22728936
2013 The cardiomyocyte molecular clock (BMAL1) controls circadian expression of Scn5a; inducible cardiomyocyte-specific Bmal1 deletion abolishes circadian Scn5a expression, reduces Nav1.5 protein and sodium current in ventricular myocytes, slows heart rate, prolongs QRS, and increases arrhythmia susceptibility. Overexpression of clock factors transactivates the Scn5a promoter in vitro. Inducible cardiomyocyte-specific Bmal1 KO mice, ECG telemetry, patch clamp, luciferase reporter assay, Western blot American journal of physiology. Cell physiology High 23364267
2019 K219T-LMNA mutation causes increased binding of Lamin A/C to the SCN5A promoter, recruits the PRC2 component SUZ12, and deposits the repressive histone mark H3K27me3 at SCN5A, resulting in downregulation of Nav1.5 expression, reduced peak sodium current, and decreased conduction velocity in iPSC-derived cardiomyocytes. CRISPR/Cas9 correction of the mutation re-establishes sodium current density and SCN5A expression. iPSC-derived cardiomyocytes from K219T-LMNA patients, ChIP for Lamin A/C and H3K27me3 at SCN5A promoter, patch clamp, CRISPR/Cas9 correction Nature communications High 31118417
2010 Nav1.5 (encoded by SCN5A) is mechanosensitive: membrane stretch produces graded hyperpolarizing shifts in both activation and inactivation V1/2 (~0.7 mV/mmHg), increases peak current by recruiting more active channels, and slows recovery from inactivation. Stretch accelerates voltage sensor movement but not gate opening or fast inactivation rate constants. Whole-cell and cell-attached patch clamp in HEK293 cells expressing Nav1.5, application of graded patch pressure The Journal of physiology High 21041530
2012 Foxo1 transcription factor directly binds insulin-responsive elements (IRE: 5'-CAAAACA-3') in the SCN5A promoter (confirmed by ChIP), and negatively regulates Nav1.5 expression; constitutively nuclear Foxo1 reduces Nav1.5 expression and INa, while Foxo1 siRNA increases Nav1.5 expression. H2O2 suppresses Nav1.5 expression by promoting Foxo1 nuclear localization, and this suppression is prevented by Foxo1 siRNA. ChIP, luciferase reporter assay, constitutively nuclear Foxo1 overexpression, RNAi knockdown, whole-cell voltage clamp in HL-1 cardiomyocytes PloS one High 22400069
2016 H2O2-activated Wnt/β-catenin signaling suppresses Nav1.5 expression; nuclear β-catenin interacts with TCF4 and both are recruited to the SCN5A promoter (ChIP), reducing its transcriptional activity. GSK-3β inhibitors phenocopy H2O2 suppression, and β-catenin siRNA prevents H2O2-mediated reduction of SCN5A promoter activity and Nav1.5 expression. Co-immunoprecipitation, ChIP, luciferase SCN5A promoter assay, GSK-3β pharmacological manipulation, siRNA, immunofluorescence, patch clamp in HL-1 cells Free radical biology & medicine High 27068063
2016 GATA4 and GATA5 co-occupy the SCN5A promoter and first intron in human left ventricle (ChIP/Re-ChIP); GATA4 and GATA5 synergistically activate the SCN5A promoter in a GATA binding-site-dependent manner. GATA4 mRNA levels are strongly and positively correlated with SCN5A transcript levels in human heart. ChIP, sequential Re-ChIP, luciferase reporter assay with promoter mutagenesis, ddPCR in fresh human left ventricle samples Journal of molecular and cellular cardiology High 27894866
2019 An evolutionarily conserved enhancer cluster downstream of SCN5A (within the SCN5A-SCN10A locus) controls the chromatin conformation of a >0.5 Mb genomic region and is selectively required for cardiac Scn5a expression, normal cardiac conduction, and normal embryonic development; genome editing deletions of individual enhancer components in mice demonstrate this requirement. Genome editing (CRISPR-based deletions) in mice, cardiac Scn5a expression analysis, ECG conduction analysis Nature communications High 31666509
2018 miR-24 potently suppresses SCN5A expression post-transcriptionally; a synonymous SNP (rs1805126) adjacent to the miR-24 binding site in the SCN5A coding sequence modulates this suppression. In mice, decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. miRNA reporter assays, human cardiac expression analysis linked to SNP genotype, mouse model with reduced Scn5a expression and ROS measurement The Journal of clinical investigation High 29457789
2018 HuR (ELAVL1) binds to and stabilizes SCN5A mRNA in cardiomyocytes; HuR is downregulated in failing hearts, and AAV9-mediated overexpression of HuR in mice after MI increases SCN5A expression, improves action potential upstroke and conduction velocity in the infarct border zone, and reduces reentrant arrhythmia risk. RNA-binding protein immunoprecipitation (RIP), AAV9 overexpression in mice post-MI, optical mapping of intact hearts, qRT-PCR Heart rhythm High 29454929
2021 FAT10 binds to lysine residues in the C-terminal fragments of Nav1.5 (co-immunoprecipitation) and prevents Nav1.5 ubiquitination by the E3 ligase Nedd4-2, thereby stabilizing Nav1.5 membrane expression. Cardiac-specific Fat10 knockout mice show reduced peak INa, augmented late INa, decreased Nav1.5 membrane expression, and increased ventricular arrhythmia/mortality after MI. Co-immunoprecipitation, conditional cardiac KO mice (Myh6-Cre × Fat10F/F), patch clamp, Western blot, immunofluorescence, ubiquitination assays Cell death & disease High 33414395
2018 BrS-associated Nav1.5 mutations with ER trafficking defects fail to positively modulate Kir2.1/2.2 channels, thus reducing IK1 in addition to INa; Golgi trafficking-defective Nav1.5 mutants additionally exert a dominant-negative effect on Kir2.1/2.2. ER trafficking-defective Nav1.5 channels can be partially rescued by Kir2.1/2.2 through an unconventional GRASP-dependent secretory route. Overexpression of mutant Nav1.5 in expression systems, rat ventricular cardiomyocytes and hiPSC-CMs; SCN5A haploinsufficient mouse model; patch clamp; co-expression experiments JCI insight High 30232268
2022 Most SCN5A missense loss-of-function variants exert a dominant-negative effect on co-expressed wild-type Nav1.5 (32 of 35 complete LoF variants), reducing peak current below 75% of wild-type alone; individuals carrying dominant-negative LoF variants have a 2.7-fold higher Brugada syndrome burden versus putative haploinsufficient variants. Automated patch clamp in HEK293T cells with heterozygous co-expression of WT and mutant SCN5A; clinical database comparison Genetics in medicine High 35305865
2014 The SCN5A E558X nonsense mutation (modeled at orthologous position in pig) causes conduction abnormalities and increased susceptibility to ventricular fibrillation initiated by short-coupled ventricular premature beats; optical mapping during VF shows organized focal activity arising from the right ventricular free wall, establishing a large-animal mechanistic model of sodium channelopathy arrhythmia. Knock-in pig model (SCN5A E558X/+), in vivo ECG, Langendorff-perfused heart pacing, optical mapping during VF The Journal of clinical investigation High 25500882
2003 The LQT3 SCN5A mutation L619F in the domain I-II linker increases maintained (late) sodium current, shifts steady-state inactivation by +5.8 mV without shifting activation, and increases window current; this establishes a role for the I-II cytoplasmic linker in Nav1.5 inactivation gating. Whole-cell patch clamp in transiently transfected HEK cells, site-directed mutagenesis Human mutation High 12673799
2003 The LQT3 SCN5A mutation I1768V (domain IVS6 C-terminal end) destabilizes the inactivated state: mutant channels recover from inactivation 2.4-fold faster and show less slow inactivation than wild-type, without persistent late current, demonstrating a role for domain IVS6 in stabilizing Nav1.5 inactivation. Two-electrode voltage clamp in Xenopus oocytes after cRNA injection, site-directed mutagenesis Cardiovascular research High 12650885
2008 The M1875T gain-of-function SCN5A mutation associated with familial atrial fibrillation causes a +16.4 mV shift in steady-state inactivation V1/2 (increasing channel availability) without persistent late current; this is mechanistically distinct from LQT3 and is predicted to increase atrial excitability. Whole-cell patch clamp in HEK cells expressing M1875T Nav1.5 Journal of the American College of Cardiology High 18929244
2022 TBX5 variants (p.F206L and p.D111Y) differentially regulate Nav1.5: p.F206L fails to transactivate the SCN5A promoter reducing peak INa and causing Brugada syndrome phenotype; p.D111Y increases SCN5A expression but fails to repress CAMK2D and SPTBN4, causing increased CaMKIIδ and βIV-spectrin and thereby augmenting late INa (INaL), prolonging action potential duration and causing LQT syndrome phenotype. Luciferase reporter, hiPSC-CMs, HL-1 cells, mouse cardiomyocytes overexpressing Tbx5 variants, patch clamp, ranolazine pharmacology, ECG in transgenic mice Cardiovascular research High 33576403
2002 Nav1.5 protein is expressed in the mouse brain, co-localizing with neurofilaments and clustering at high density in neuronal axons, suggesting a role in CNS electrical signal propagation. Immunohistochemistry with Nav1.5-specific antibody in mouse brain sections, co-localization with neurofilament markers Neuroreport Medium 12499865
2006 Canine intracardiac neurons functionally express Nav1.5 (TTX-resistant sodium current with IC50 ~1.17 µM for TTX, inactivation kinetics consistent with Nav1.5); SCN5A expression confirmed by PCR and sequencing, suggesting intrinsic cardiac ganglia as a site of SCN5A function relevant to autonomically modulated arrhythmias. Patch clamp of dissociated intracardiac neurons, immunohistochemistry, RT-PCR with sequencing Heart rhythm Medium 16818219
2015 Nav1.5 (SCN5A) promotes breast cancer tumor growth and metastatic dissemination in vivo; stable Nav1.5 knockdown reduces tumor growth, local invasion, and liver/lung/spleen metastasis in an orthotopic model, increases apoptosis, and reduces CD44 expression, suggesting Nav1.5 activity regulates invasion via the CD44-src-cortactin axis. Stable shRNA knockdown of Nav1.5, orthotopic breast cancer xenograft model, TTX-blocked patch clamp in tumor slices confirming functional VGSC activity in vivo Oncotarget Medium 26452220
2014 Human macrophage SCN5A initiates an innate immune signaling pathway: pharmacological channel stimulation or cytoplasmic poly(I:C) (dsRNA mimic) activates the channel, leading to ADCY8 (adenylate cyclase 8) and ATF2-mediated transcription of SP100-related genes and interferon β. Intracellular poly(I:C) augments inward voltage-sensitive sodium current and inhibits outward nonselective current. Pharmacological channel activation, electrophysiology (whole-cell and intracellular poly(I:C) application), gene expression analysis in human macrophages The Journal of biological chemistry Medium 25368329
2024 Anti-Nav1.5 autoantibodies are present in 90% of Brugada syndrome patients (vs. 6% controls); these autoantibodies significantly reduce sodium current density in cellular models, and injection of BrS patient plasma induces Brugada-like ECG abnormalities in wild-type mice, establishing an immunopathogenic mechanism for BrS independent of SCN5A mutation. Western blot, immunoprecipitation, immunofluorescence screening; patch clamp in HEK293A cells; in vivo plasma injection in wild-type mice with ECG monitoring European heart journal High 39078224
2011 The SCN5A-S1103Y African American common polymorphism interacts with the SCN5A-R680H mutation to significantly increase late INa (3.4-fold when co-expressed, 3.6-fold on the same construct) in the major Q1077del splice variant background; intracellular acidosis (pH 6.7) further amplifies this interaction, providing a mechanistic basis for arrhythmic sudden death. Whole-cell patch clamp in HEK293 cells with site-directed mutagenesis; splice-variant-specific expression constructs; intracellular pH manipulation Physiological genomics High 21385947

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 961 10973849
2004 SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 346 15466643
2001 Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 319 11710892
2000 Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. Journal of the American College of Cardiology 305 10716483
2018 Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy. JACC. Clinical electrophysiology 263 29798782
2006 Cardiac sodium channel Nav1.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin. Circulation research 189 16857961
2000 The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation 185 10961955
2008 Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart rhythm 173 19251209
2003 A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. The Journal of clinical investigation 164 12569159
2008 Cardiac sodium channel overlap syndromes: different faces of SCN5A mutations. Trends in cardiovascular medicine 162 18436145
2005 Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations. Cardiovascular research 157 15890323
2011 Biology of cardiac sodium channel Nav1.5 expression. Cardiovascular research 153 21937582
2008 A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation. Journal of the American College of Cardiology 149 18929244
2014 A common genetic variant within SCN10A modulates cardiac SCN5A expression. The Journal of clinical investigation 144 24642470
2010 Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. The Journal of physiology 144 21041530
2008 SCN5A channelopathies--an update on mutations and mechanisms. Progress in biophysics and molecular biology 131 19027780
2003 A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation. Physiological genomics 128 12454206
2010 Environmental regulation of lateral root emergence in Medicago truncatula requires the HD-Zip I transcription factor HB1. The Plant cell 127 20675575
2012 R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy. Journal of the American College of Cardiology 124 22999724
2013 The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility. American journal of physiology. Cell physiology 123 23364267
2012 TBX5 drives Scn5a expression to regulate cardiac conduction system function. The Journal of clinical investigation 122 22728936
2018 SCN5A Variants: Association With Cardiac Disorders. Frontiers in physiology 111 30364184
2019 The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy. Nature communications 97 31118417
2002 Expression and intracellular localization of an SCN5A double mutant R1232W/T1620M implicated in Brugada syndrome. Circulation research 89 11786529
2011 Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. American journal of physiology. Cell physiology 86 21677263
2002 Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome. European heart journal 86 12069453
2015 Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo. Oncotarget 85 26452220
2014 Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. The Journal of clinical investigation 85 25500882
2015 Regulation of the cardiac Na+ channel NaV1.5 by post-translational modifications. Journal of molecular and cellular cardiology 82 25748040
2004 Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo. Cardiovascular research 74 14736542
2016 The role of mutations in the SCN5A gene in cardiomyopathies. Biochimica et biophysica acta 71 26916278
2021 Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome. European heart journal 68 34219138
2006 SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias. Journal of cardiovascular electrophysiology 67 16684018
2009 Inherited cardiac diseases caused by mutations in the Nav1.5 sodium channel. Journal of cardiovascular electrophysiology 66 19845816
2014 Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy. Heart rhythm 63 24815523
2007 Novel mutation in the SCN5A gene associated with arrhythmic storm development during acute myocardial infarction. Heart rhythm 58 17675083
2008 A mutation in telethonin alters Nav1.5 function. The Journal of biological chemistry 56 18408010
2018 Dysfunctional Nav1.5 channels due to SCN5A mutations. Experimental biology and medicine (Maywood, N.J.) 50 29806494
2012 Cardiac sodium channel Nav1.5 mutations and cardiac arrhythmia. Pediatric cardiology 48 22460359
2018 Systematic re-evaluation of SCN5A variants associated with Brugada syndrome. Journal of cardiovascular electrophysiology 46 30203441
2018 Colorectal cancer invasiveness in vitro: Predominant contribution of neonatal Nav1.5 under normoxia and hypoxia. Journal of cellular physiology 46 30341901
2002 Novel mutations in domain I of SCN5A cause Brugada syndrome. Molecular genetics and metabolism 44 12051963
2023 SCN5A channelopathy: arrhythmia, cardiomyopathy, epilepsy and beyond. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 43 37122208
2016 Lateral Membrane-Specific MAGUK CASK Down-Regulates NaV1.5 Channel in Cardiac Myocytes. Circulation research 43 27364017
2018 Brugada syndrome trafficking-defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels. JCI insight 42 30232268
2005 New mechanism contributing to drug-induced arrhythmia: rescue of a misprocessed LQT3 mutant. Circulation 42 16301357
2002 Localization of Nav1.5 sodium channel protein in the mouse brain. Neuroreport 40 12499865
2021 Arrhythmic Phenotypes Are a Defining Feature of Dilated Cardiomyopathy-Associated SCN5A Variants: A Systematic Review. Circulation. Genomic and precision medicine 39 34949099
2001 Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome. British journal of pharmacology 39 11156564
2018 A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality. The Journal of clinical investigation 37 29457789
2017 Anti-arrhythmic potential of the late sodium current inhibitor GS-458967 in murine Scn5a-1798insD+/- and human SCN5A-1795insD+/- iPSC-derived cardiomyocytes. Cardiovascular research 37 28430892
2012 Reactive oxygen species suppress cardiac NaV1.5 expression through Foxo1. PloS one 37 22400069
2010 SCN5A mutation is associated with early and frequent recurrence of ventricular fibrillation in patients with Brugada syndrome. Circulation journal : official journal of the Japanese Circulation Society 37 21048329
2003 The implications of genetic mutations in the sodium channel gene (SCN5A). Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 37 14753626
2012 p.D1690N Nav1.5 rescues p.G1748D mutation gating defects in a compound heterozygous Brugada syndrome patient. Heart rhythm 36 23085483
2003 A novel mutation L619F in the cardiac Na+ channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating. Human mutation 36 12673799
2016 Activation of Wnt/β-catenin signaling by hydrogen peroxide transcriptionally inhibits NaV1.5 expression. Free radical biology & medicine 34 27068063
2012 Mouse Models of SCN5A-Related Cardiac Arrhythmias. Frontiers in physiology 34 22737129
2017 Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation. International journal of cardiology 33 28262340
2018 Disease Modifiers of Inherited SCN5A Channelopathy. Frontiers in cardiovascular medicine 32 30327767
2010 Mutation-specific effects of polymorphism H558R in SCN5A-related sick sinus syndrome. Journal of cardiovascular electrophysiology 32 20384651
2008 Mouse models of SCN5A-related cardiac arrhythmias. Progress in biophysics and molecular biology 32 19041666
2006 Functional expression of "cardiac-type" Nav1.5 sodium channel in canine intracardiac ganglia. Heart rhythm 32 16818219
1979 DNA fragments of the Mus musculus beta globin haplotypes Hbbs and Hbbd. Proceedings of the National Academy of Sciences of the United States of America 32 286321
2018 Copy number variations of SCN5A in Brugada syndrome. Heart rhythm 30 29574140
2015 The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles. Pflugers Archiv : European journal of physiology 28 26545784
2012 Concomitant Brugada-like and short QT electrocardiogram linked to SCN5A mutation. European journal of human genetics : EJHG 28 22490985
2016 Transcriptional regulation of the sodium channel gene (SCN5A) by GATA4 in human heart. Journal of molecular and cellular cardiology 26 27894866
2011 The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current. Physiological genomics 26 21385947
2022 Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome. Cardiovascular research 25 33576403
2019 An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo. Nature communications 25 31666509
2016 Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes. Journal of the American Heart Association 25 27625342
2006 Involvement of Kv1.1 and Nav1.5 in proliferation of gastric epithelial cells. Journal of cellular physiology 25 16331678
2018 HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure. Heart rhythm 24 29454929
2018 Predicting changes to INa from missense mutations in human SCN5A. Scientific reports 24 30143662
2021 Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants. Journal of the American College of Cardiology 23 34649698
2019 SCN5A variant R222Q generated abnormal changes in cardiac sodium current and action potentials in murine myocytes and Purkinje cells. Heart rhythm 23 31125670
2018 SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers. International journal of cardiology 22 29709244
2007 Solution structure of Jingzhaotoxin-III, a peptide toxin inhibiting both Nav1.5 and Kv2.1 channels. Toxicon : official journal of the International Society on Toxinology 22 17481690
2022 Dominant negative effects of SCN5A missense variants. Genetics in medicine : official journal of the American College of Medical Genetics 21 35305865
2022 Subcellular diversity of Nav1.5 in cardiomyocytes: distinct functions, mechanisms and targets. The Journal of physiology 21 36469003
2020 Intracerebral Transplantation of BDNF-overexpressing Human Neural Stem Cells (HB1.F3.BDNF) Promotes Migration, Differentiation and Functional Recovery in a Rodent Model of Huntington's Disease. Experimental neurobiology 21 32408403
2018 A homozygous SCN5A mutation associated with atrial standstill and sudden death. Pacing and clinical electrophysiology : PACE 21 29781517
2014 Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense. The Journal of biological chemistry 21 25368329
2014 Atrial Fibrillation and SCN5A Variants. Cardiac electrophysiology clinics 21 25484998
2009 Analysis of four novel variants of Nav1.5/SCN5A cloned from the brain. Neuroscience research 21 19376164
2008 New variants of Nav1.5/SCN5A encode Na+ channels in the brain. Journal of neurogenetics 19 18386309
2003 A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics. Cardiovascular research 19 12650885
2021 FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation. Cell death & disease 18 33414395
2018 Blocking the Nav1.5 channel using eicosapentaenoic acid reduces migration and proliferation of ovarian cancer cells. International journal of oncology 18 29901108
2009 Atrial arrhythmogenesis in wild-type and Scn5a+/delta murine hearts modelling LQT3 syndrome. Pflugers Archiv : European journal of physiology 18 19184093
2023 Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 17 36504385
2018 Sex-Dependent Phenotypic Variability of an SCN5A Mutation: Brugada Syndrome and Sick Sinus Syndrome. Journal of the American Heart Association 17 30371189
2017 Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function. Pacing and clinical electrophysiology : PACE 17 28370132
2015 De Novo Mutation in the SCN5A Gene Associated with Brugada Syndrome. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 17 26279430
2023 Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 16 37369559
2016 Negative-dominance phenomenon with genetic variants of the cardiac sodium channel Nav1.5. Biochimica et biophysica acta 16 26907222
2015 Arrhythmogenic Biophysical Phenotype for SCN5A Mutation S1787N Depends upon Splice Variant Background and Intracellular Acidosis. PloS one 16 25923670
2024 NaV1.5 autoantibodies in Brugada syndrome: pathogenetic implications. European heart journal 15 39078224
2007 Cardiac sodium channel Nav1.5 and its associated proteins. Archives des maladies du coeur et des vaisseaux 15 18033008