{"gene":"SCN4B","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2007,"finding":"The SCN4B-encoded β4 subunit (L179F missense mutation) co-assembles with the SCN5A-encoded Nav1.5 α-subunit and, when mutated, causes an ~8-fold increase in late sodium current compared to SCN5A alone and ~3-fold increase compared to SCN5A + wild-type β4, establishing β4 as a functional regulatory subunit of the cardiac sodium channel whose loss-of-function/gain-of-function directly alters channel gating.","method":"Site-directed mutagenesis of L179F-β4; heterologous expression in HEK293 cells stably expressing SCN5A; electrophysiological recording of late sodium current","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional assay with site-directed mutagenesis and electrophysiology in a defined heterologous system; single lab but multiple orthogonal methods (mutagenesis + patch-clamp + co-segregation)","pmids":["17592081"],"is_preprint":false},{"year":2016,"finding":"In breast cancer cells, reducing β4 (SCN4B) expression increases RhoA activity, potentiates cell migration and invasiveness via an amoeboid-mesenchymal hybrid phenotype; this effect is independent of voltage-gated sodium channel (NaV) function and is specifically prevented by overexpression of the intracellular C-terminus of β4, identifying the C-terminus as the functional domain mediating RhoA suppression and migration control.","method":"siRNA knockdown and overexpression of SCN4B/β4 and C-terminus domain in breast cancer cell lines; RhoA activity assays; invasion/migration assays; in vivo xenograft metastasis models; pharmacological NaV channel blockade controls","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, OE, domain rescue, RhoA activity assay, in vivo model, NaV-independence controls) in a single study; single lab","pmids":["27917859"],"is_preprint":false},{"year":2019,"finding":"SCN4B variants p.Gly8Ser and p.Ala145Ser significantly reduce the expression level of the Navβ4 protein, as demonstrated by Western blotting, indicating a loss-of-function mechanism for these arrhythmia-associated variants.","method":"Western blotting of variant proteins expressed in cells","journal":"Molecular genetics and genomics : MGG","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single method (Western blot), single lab, no electrophysiology or co-expression functional assay","pmids":["31020414"],"is_preprint":false},{"year":2019,"finding":"miR-424-5p directly targets SCN4B mRNA to inhibit its expression, thereby promoting colorectal cancer cell proliferation and metastasis; this was validated by direct luciferase reporter assay showing miR-424-5p binds the SCN4B 3′UTR.","method":"Bioinformatics target prediction; luciferase reporter assay; loss-of-function experiments in HT29 and SW480 cells; mouse xenograft models","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay (direct binding evidence) plus in vitro KD and in vivo xenograft; single lab","pmids":["31785995"],"is_preprint":false},{"year":2020,"finding":"miR-3175 directly targets SCN4B: knockdown of miR-3175 increased luciferase activity of an SCN4B reporter construct and increased SCN4B protein expression, while suppressing proliferation, migration, and invasion of prostate cancer cells alongside EMT marker changes (decreased N-cadherin, increased E-cadherin).","method":"Luciferase reporter assay; RT-qPCR; Western blotting; MTT, Edu, scratch, and Transwell invasion assays in prostate cancer cell lines","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by luciferase reporter plus functional rescue experiments; single lab","pmids":["32833340"],"is_preprint":false},{"year":2026,"finding":"Loss of Scn4b in wild-type mice mimics Huntington's disease (HD)-associated motor/cognitive deficits and striatal gene expression signatures; conversely, Scn4b overexpression in an HD mouse model rescues motor/cognitive deficits, HD-associated gene expression signatures, and improves striatal spiny projection neuron electrophysiological properties, establishing Scn4b as a functional modulator of SPN excitability in vivo.","method":"Scn4b knockout mice; Scn4b overexpression in HD model mice; snRNA-seq; electrophysiology of striatal SPNs; behavioral motor and cognitive testing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo methods (KO, OE, snRNA-seq, electrophysiology, behavior) in a single preprint; not yet peer-reviewed","pmids":["41959367"],"is_preprint":true},{"year":2026,"finding":"Overexpression of SCN4B in lung adenocarcinoma cell lines (A549 and H1299) suppresses EMT, as shown by upregulation of E-cadherin and downregulation of N-cadherin, Vimentin, and Snail, while also reducing cell viability, migration, and invasion and promoting apoptosis.","method":"SCN4B overexpression in LUAD cell lines; Western blotting for EMT markers; wound-healing, Transwell invasion, CCK-8 viability, and flow cytometry apoptosis assays","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with molecular marker readouts; single lab, single study","pmids":["41685607"],"is_preprint":false}],"current_model":"SCN4B encodes the Navβ4 auxiliary subunit that associates with the Nav1.5 α-subunit (SCN5A) to modulate cardiac sodium channel gating (increasing late Na⁺ current when mutated); independently of its ion channel role, the intracellular C-terminus of β4 suppresses RhoA activity to restrain cell migration and invasion, and β4 additionally inhibits epithelial-mesenchymal transition; in neurons, Scn4b maintains striatal spiny projection neuron electrophysiological properties and modulates Huntington's disease phenotypes in vivo."},"narrative":{"mechanistic_narrative":"SCN4B encodes Navβ4, a regulatory subunit of the cardiac sodium channel that also functions as a tumor-suppressive modulator of cell motility and a determinant of striatal neuron excitability [PMID:17592081, PMID:27917859]. Navβ4 co-assembles with the SCN5A-encoded Nav1.5 α-subunit, and arrhythmia-associated mutations (e.g. L179F) increase late sodium current by altering channel gating, while other variants (p.Gly8Ser, p.Ala145Ser) reduce Navβ4 protein levels, both representing channel-dysregulating loss/gain-of-function mechanisms [PMID:17592081, PMID:31020414]. Independently of ion channel activity, the intracellular C-terminus of Navβ4 suppresses RhoA activity to restrain cell migration and invasion, and Navβ4 inhibits epithelial-mesenchymal transition, shifting cells toward an epithelial state (increased E-cadherin, decreased N-cadherin, Vimentin, and Snail) [PMID:27917859, PMID:41685607]. Consistent with a tumor-suppressive role, SCN4B is silenced by oncogenic microRNAs—miR-424-5p in colorectal cancer and miR-3175 in prostate cancer—each binding the SCN4B transcript to promote proliferation and metastasis [PMID:31785995, PMID:32833340]. In the nervous system, Scn4b maintains the electrophysiological properties of striatal spiny projection neurons and modulates Huntington's disease motor, cognitive, and transcriptional phenotypes in vivo [PMID:41959367].","teleology":[{"year":2007,"claim":"Established that Navβ4 is a functional regulatory subunit of the cardiac sodium channel, answering whether SCN4B variants can directly alter channel gating and cause arrhythmia.","evidence":"Site-directed mutagenesis of L179F-β4 with heterologous co-expression with SCN5A in HEK293 cells and late sodium current recording","pmids":["17592081"],"confidence":"High","gaps":["Structural basis of β4 binding to Nav1.5 not resolved","Effect of wild-type β4 on native cardiomyocyte channels not tested in vivo"]},{"year":2016,"claim":"Revealed a non-channel function of Navβ4 by showing its intracellular C-terminus suppresses RhoA to restrain migration and invasion, decoupling its motility role from ion conduction.","evidence":"siRNA knockdown, overexpression and C-terminus domain rescue in breast cancer cells with RhoA activity assays, invasion/migration assays, xenograft metastasis models, and NaV channel blockade controls","pmids":["27917859"],"confidence":"High","gaps":["Direct molecular link between the β4 C-terminus and RhoA regulators not defined","Whether C-terminus acts as adaptor or via an intermediate protein unknown"]},{"year":2019,"claim":"Connected specific arrhythmia-associated SCN4B variants to reduced Navβ4 protein abundance, supporting a loss-of-function disease mechanism.","evidence":"Western blotting of p.Gly8Ser and p.Ala145Ser variant proteins expressed in cells","pmids":["31020414"],"confidence":"Medium","gaps":["Single method (Western blot) without electrophysiology or co-expression functional assay","Mechanism of reduced expression (stability vs translation) not determined"]},{"year":2019,"claim":"Identified SCN4B as a direct target of an oncogenic microRNA, establishing transcript-level suppression as a route to its downregulation in cancer.","evidence":"Luciferase reporter assay of the SCN4B 3'UTR with miR-424-5p plus loss-of-function and xenograft experiments in colorectal cancer cells","pmids":["31785995"],"confidence":"Medium","gaps":["Downstream effectors linking SCN4B loss to proliferation not mapped","Whether RhoA axis mediates the colorectal phenotype not tested"]},{"year":2020,"claim":"Generalized microRNA-mediated SCN4B silencing to prostate cancer and linked SCN4B restoration to EMT marker reversal.","evidence":"Luciferase reporter assay with miR-3175, RT-qPCR, Western blotting of EMT markers and proliferation/migration/invasion assays in prostate cancer cells","pmids":["32833340"],"confidence":"Medium","gaps":["Direct mechanism by which SCN4B controls EMT markers not defined","Single-lab, single-context validation"]},{"year":2026,"claim":"Demonstrated a neuronal role for Scn4b in maintaining striatal spiny projection neuron excitability and modulating Huntington's disease phenotypes in vivo.","evidence":"Scn4b knockout and HD-model overexpression mice analyzed by snRNA-seq, SPN electrophysiology, and behavioral motor/cognitive testing (preprint)","pmids":["41959367"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Molecular mechanism linking Scn4b to SPN excitability changes not resolved","Whether effect is channel-dependent or via the non-channel pathway unknown"]},{"year":2026,"claim":"Confirmed SCN4B as an EMT and proliferation suppressor in lung adenocarcinoma, reinforcing its tumor-suppressive function across cancer types.","evidence":"SCN4B overexpression in A549 and H1299 cells with EMT marker Western blots, wound-healing, Transwell, viability, and apoptosis assays","pmids":["41685607"],"confidence":"Medium","gaps":["Whether RhoA/C-terminus axis underlies the LUAD effect not tested","Single-lab, in vitro only"]},{"year":null,"claim":"The molecular link between the Navβ4 C-terminus and RhoA regulation, and whether this same pathway underlies its EMT-suppressive and neuronal roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct binding partner connecting β4 C-terminus to RhoA identified","Unclear whether neuronal phenotypes are channel-dependent","No structural model of Navβ4–Nav1.5 assembly"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,4,6]}],"complexes":["cardiac voltage-gated sodium channel (Nav1.5)"],"partners":["SCN5A","RHOA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWT1","full_name":"Sodium channel regulatory subunit beta-4","aliases":[],"length_aa":228,"mass_kda":25.0,"function":"Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na+ ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues. The accessory beta subunits participate in localization and functional modulation of the Nav channels (PubMed:24297919). Modulates the activity of SCN1A/Nav1.1 (PubMed:33712547). Modulates the activity of SCN2A/Nav1.2 (PubMed:24297919)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IWT1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCN4B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SCN4B","total_profiled":1310},"omim":[{"mim_id":"615378","title":"ATRIAL FIBRILLATION, FAMILIAL, 14; ATFB14","url":"https://www.omim.org/entry/615378"},{"mim_id":"615377","title":"ATRIAL FIBRILLATION, FAMILIAL, 13; ATFB13","url":"https://www.omim.org/entry/615377"},{"mim_id":"613120","title":"BRUGADA SYNDROME 7; BRGDA7","url":"https://www.omim.org/entry/613120"},{"mim_id":"611819","title":"LONG QT SYNDROME 10; LQT10","url":"https://www.omim.org/entry/611819"},{"mim_id":"608583","title":"ATRIAL FIBRILLATION, FAMILIAL, 1; ATFB1","url":"https://www.omim.org/entry/608583"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":28.4},{"tissue":"skeletal muscle","ntpm":28.5},{"tissue":"tongue","ntpm":53.0}],"url":"https://www.proteinatlas.org/search/SCN4B"},"hgnc":{"alias_symbol":["LQT10"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWT1","domains":[{"cath_id":"2.60.40.10","chopping":"30-151","consensus_level":"high","plddt":94.8926,"start":30,"end":151},{"cath_id":"1.20.5","chopping":"158-192","consensus_level":"medium","plddt":94.0383,"start":158,"end":192}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWT1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWT1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWT1-F1-predicted_aligned_error_v6.png","plddt_mean":83.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCN4B","jax_strain_url":"https://www.jax.org/strain/search?query=SCN4B"},"sequence":{"accession":"Q8IWT1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWT1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWT1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWT1"}},"corpus_meta":[{"pmid":"17592081","id":"PMC_17592081","title":"SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome.","date":"2007","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/17592081","citation_count":272,"is_preprint":false},{"pmid":"23604097","id":"PMC_23604097","title":"Mutations of the SCN4B-encoded sodium channel β4 subunit in familial atrial fibrillation.","date":"2013","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23604097","citation_count":58,"is_preprint":false},{"pmid":"27917859","id":"PMC_27917859","title":"SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27917859","citation_count":54,"is_preprint":false},{"pmid":"31785995","id":"PMC_31785995","title":"miR-424-5p promotes the proliferation and metastasis of colorectal cancer by directly targeting SCN4B.","date":"2019","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/31785995","citation_count":42,"is_preprint":false},{"pmid":"30821358","id":"PMC_30821358","title":"Significant association of rare variant p.Gly8Ser in cardiac sodium channel β4-subunit SCN4B with atrial fibrillation.","date":"2019","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30821358","citation_count":23,"is_preprint":false},{"pmid":"29723302","id":"PMC_29723302","title":"Preserved SCN4B expression is an independent indicator of favorable recurrence-free survival in classical papillary thyroid cancer.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29723302","citation_count":22,"is_preprint":false},{"pmid":"31020414","id":"PMC_31020414","title":"Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia.","date":"2019","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/31020414","citation_count":8,"is_preprint":false},{"pmid":"32833340","id":"PMC_32833340","title":"Silencing of microRNA-3175 represses cell proliferation and invasion in prostate cancer by targeting the potential tumor-suppressor SCN4B.","date":"2020","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32833340","citation_count":7,"is_preprint":false},{"pmid":"20730464","id":"PMC_20730464","title":"Mutational analysis of SCN2B, SCN3B and SCN4B in a large Chinese Han family with generalized tonic-clonic seizure.","date":"2010","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/20730464","citation_count":3,"is_preprint":false},{"pmid":"41959367","id":"PMC_41959367","title":"Scn4b Modulates Huntington's Disease Phenotype Severity in vivo.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41959367","citation_count":0,"is_preprint":false},{"pmid":"41685607","id":"PMC_41685607","title":"Suppressive role of SCN4B in the epithelial‑mesenchymal transition of lung adenocarcinoma.","date":"2026","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/41685607","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7763,"output_tokens":1900,"usd":0.025895,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8826,"output_tokens":2740,"usd":0.056315,"stage2_stop_reason":"end_turn"},"total_usd":0.08221,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"The SCN4B-encoded β4 subunit (L179F missense mutation) co-assembles with the SCN5A-encoded Nav1.5 α-subunit and, when mutated, causes an ~8-fold increase in late sodium current compared to SCN5A alone and ~3-fold increase compared to SCN5A + wild-type β4, establishing β4 as a functional regulatory subunit of the cardiac sodium channel whose loss-of-function/gain-of-function directly alters channel gating.\",\n      \"method\": \"Site-directed mutagenesis of L179F-β4; heterologous expression in HEK293 cells stably expressing SCN5A; electrophysiological recording of late sodium current\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro functional assay with site-directed mutagenesis and electrophysiology in a defined heterologous system; single lab but multiple orthogonal methods (mutagenesis + patch-clamp + co-segregation)\",\n      \"pmids\": [\"17592081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In breast cancer cells, reducing β4 (SCN4B) expression increases RhoA activity, potentiates cell migration and invasiveness via an amoeboid-mesenchymal hybrid phenotype; this effect is independent of voltage-gated sodium channel (NaV) function and is specifically prevented by overexpression of the intracellular C-terminus of β4, identifying the C-terminus as the functional domain mediating RhoA suppression and migration control.\",\n      \"method\": \"siRNA knockdown and overexpression of SCN4B/β4 and C-terminus domain in breast cancer cell lines; RhoA activity assays; invasion/migration assays; in vivo xenograft metastasis models; pharmacological NaV channel blockade controls\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, OE, domain rescue, RhoA activity assay, in vivo model, NaV-independence controls) in a single study; single lab\",\n      \"pmids\": [\"27917859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SCN4B variants p.Gly8Ser and p.Ala145Ser significantly reduce the expression level of the Navβ4 protein, as demonstrated by Western blotting, indicating a loss-of-function mechanism for these arrhythmia-associated variants.\",\n      \"method\": \"Western blotting of variant proteins expressed in cells\",\n      \"journal\": \"Molecular genetics and genomics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (Western blot), single lab, no electrophysiology or co-expression functional assay\",\n      \"pmids\": [\"31020414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-424-5p directly targets SCN4B mRNA to inhibit its expression, thereby promoting colorectal cancer cell proliferation and metastasis; this was validated by direct luciferase reporter assay showing miR-424-5p binds the SCN4B 3′UTR.\",\n      \"method\": \"Bioinformatics target prediction; luciferase reporter assay; loss-of-function experiments in HT29 and SW480 cells; mouse xenograft models\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay (direct binding evidence) plus in vitro KD and in vivo xenograft; single lab\",\n      \"pmids\": [\"31785995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-3175 directly targets SCN4B: knockdown of miR-3175 increased luciferase activity of an SCN4B reporter construct and increased SCN4B protein expression, while suppressing proliferation, migration, and invasion of prostate cancer cells alongside EMT marker changes (decreased N-cadherin, increased E-cadherin).\",\n      \"method\": \"Luciferase reporter assay; RT-qPCR; Western blotting; MTT, Edu, scratch, and Transwell invasion assays in prostate cancer cell lines\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by luciferase reporter plus functional rescue experiments; single lab\",\n      \"pmids\": [\"32833340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of Scn4b in wild-type mice mimics Huntington's disease (HD)-associated motor/cognitive deficits and striatal gene expression signatures; conversely, Scn4b overexpression in an HD mouse model rescues motor/cognitive deficits, HD-associated gene expression signatures, and improves striatal spiny projection neuron electrophysiological properties, establishing Scn4b as a functional modulator of SPN excitability in vivo.\",\n      \"method\": \"Scn4b knockout mice; Scn4b overexpression in HD model mice; snRNA-seq; electrophysiology of striatal SPNs; behavioral motor and cognitive testing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo methods (KO, OE, snRNA-seq, electrophysiology, behavior) in a single preprint; not yet peer-reviewed\",\n      \"pmids\": [\"41959367\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Overexpression of SCN4B in lung adenocarcinoma cell lines (A549 and H1299) suppresses EMT, as shown by upregulation of E-cadherin and downregulation of N-cadherin, Vimentin, and Snail, while also reducing cell viability, migration, and invasion and promoting apoptosis.\",\n      \"method\": \"SCN4B overexpression in LUAD cell lines; Western blotting for EMT markers; wound-healing, Transwell invasion, CCK-8 viability, and flow cytometry apoptosis assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with molecular marker readouts; single lab, single study\",\n      \"pmids\": [\"41685607\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCN4B encodes the Navβ4 auxiliary subunit that associates with the Nav1.5 α-subunit (SCN5A) to modulate cardiac sodium channel gating (increasing late Na⁺ current when mutated); independently of its ion channel role, the intracellular C-terminus of β4 suppresses RhoA activity to restrain cell migration and invasion, and β4 additionally inhibits epithelial-mesenchymal transition; in neurons, Scn4b maintains striatal spiny projection neuron electrophysiological properties and modulates Huntington's disease phenotypes in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCN4B encodes Navβ4, a regulatory subunit of the cardiac sodium channel that also functions as a tumor-suppressive modulator of cell motility and a determinant of striatal neuron excitability [#0, #1]. Navβ4 co-assembles with the SCN5A-encoded Nav1.5 α-subunit, and arrhythmia-associated mutations (e.g. L179F) increase late sodium current by altering channel gating, while other variants (p.Gly8Ser, p.Ala145Ser) reduce Navβ4 protein levels, both representing channel-dysregulating loss/gain-of-function mechanisms [#0, #2]. Independently of ion channel activity, the intracellular C-terminus of Navβ4 suppresses RhoA activity to restrain cell migration and invasion, and Navβ4 inhibits epithelial-mesenchymal transition, shifting cells toward an epithelial state (increased E-cadherin, decreased N-cadherin, Vimentin, and Snail) [#1, #6]. Consistent with a tumor-suppressive role, SCN4B is silenced by oncogenic microRNAs—miR-424-5p in colorectal cancer and miR-3175 in prostate cancer—each binding the SCN4B transcript to promote proliferation and metastasis [#3, #4]. In the nervous system, Scn4b maintains the electrophysiological properties of striatal spiny projection neurons and modulates Huntington's disease motor, cognitive, and transcriptional phenotypes in vivo [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that Navβ4 is a functional regulatory subunit of the cardiac sodium channel, answering whether SCN4B variants can directly alter channel gating and cause arrhythmia.\",\n      \"evidence\": \"Site-directed mutagenesis of L179F-β4 with heterologous co-expression with SCN5A in HEK293 cells and late sodium current recording\",\n      \"pmids\": [\"17592081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of β4 binding to Nav1.5 not resolved\",\n        \"Effect of wild-type β4 on native cardiomyocyte channels not tested in vivo\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-channel function of Navβ4 by showing its intracellular C-terminus suppresses RhoA to restrain migration and invasion, decoupling its motility role from ion conduction.\",\n      \"evidence\": \"siRNA knockdown, overexpression and C-terminus domain rescue in breast cancer cells with RhoA activity assays, invasion/migration assays, xenograft metastasis models, and NaV channel blockade controls\",\n      \"pmids\": [\"27917859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular link between the β4 C-terminus and RhoA regulators not defined\",\n        \"Whether C-terminus acts as adaptor or via an intermediate protein unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected specific arrhythmia-associated SCN4B variants to reduced Navβ4 protein abundance, supporting a loss-of-function disease mechanism.\",\n      \"evidence\": \"Western blotting of p.Gly8Ser and p.Ala145Ser variant proteins expressed in cells\",\n      \"pmids\": [\"31020414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single method (Western blot) without electrophysiology or co-expression functional assay\",\n        \"Mechanism of reduced expression (stability vs translation) not determined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SCN4B as a direct target of an oncogenic microRNA, establishing transcript-level suppression as a route to its downregulation in cancer.\",\n      \"evidence\": \"Luciferase reporter assay of the SCN4B 3'UTR with miR-424-5p plus loss-of-function and xenograft experiments in colorectal cancer cells\",\n      \"pmids\": [\"31785995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effectors linking SCN4B loss to proliferation not mapped\",\n        \"Whether RhoA axis mediates the colorectal phenotype not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generalized microRNA-mediated SCN4B silencing to prostate cancer and linked SCN4B restoration to EMT marker reversal.\",\n      \"evidence\": \"Luciferase reporter assay with miR-3175, RT-qPCR, Western blotting of EMT markers and proliferation/migration/invasion assays in prostate cancer cells\",\n      \"pmids\": [\"32833340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism by which SCN4B controls EMT markers not defined\",\n        \"Single-lab, single-context validation\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a neuronal role for Scn4b in maintaining striatal spiny projection neuron excitability and modulating Huntington's disease phenotypes in vivo.\",\n      \"evidence\": \"Scn4b knockout and HD-model overexpression mice analyzed by snRNA-seq, SPN electrophysiology, and behavioral motor/cognitive testing (preprint)\",\n      \"pmids\": [\"41959367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Molecular mechanism linking Scn4b to SPN excitability changes not resolved\",\n        \"Whether effect is channel-dependent or via the non-channel pathway unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed SCN4B as an EMT and proliferation suppressor in lung adenocarcinoma, reinforcing its tumor-suppressive function across cancer types.\",\n      \"evidence\": \"SCN4B overexpression in A549 and H1299 cells with EMT marker Western blots, wound-healing, Transwell, viability, and apoptosis assays\",\n      \"pmids\": [\"41685607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether RhoA/C-terminus axis underlies the LUAD effect not tested\",\n        \"Single-lab, in vitro only\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular link between the Navβ4 C-terminus and RhoA regulation, and whether this same pathway underlies its EMT-suppressive and neuronal roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct binding partner connecting β4 C-terminus to RhoA identified\",\n        \"Unclear whether neuronal phenotypes are channel-dependent\",\n        \"No structural model of Navβ4–Nav1.5 assembly\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 4, 6]}\n    ],\n    \"complexes\": [\n      \"cardiac voltage-gated sodium channel (Nav1.5)\"\n    ],\n    \"partners\": [\n      \"SCN5A\",\n      \"RhoA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}