{"gene":"KCNAB3","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1998,"finding":"Human Kvβ3.1 (encoded by KCNA3B/KCNAB3) coexpressed with Kv1.5 α-subunit in CHO cells generates a novel A-type (very fast-inactivating) outward potassium current upon depolarization, demonstrating that Kvβ3.1 confers fast inactivation on the Kv1.5 channel.","method":"Heterologous coexpression in Chinese hamster ovary (CHO) cells; electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological reconstitution in heterologous cells with defined subunit coexpression, single lab but clear functional readout","pmids":["9857044"],"is_preprint":false},{"year":2017,"finding":"KVβ3 (AKR6A9/KCNAB3) transcript is expressed in murine coronary arteries, and in situ proximity ligation assays confirm protein-protein interactions between KV1.5 and KVβ proteins in coronary arterial myocytes; however, the predominant functional partners at the sarcolemma were KVβ1 and KVβ2, not KVβ3.","method":"RT-qPCR, Western blot, in situ proximity ligation assay, confocal microscopy, membrane fractionation","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal methods (PLA, fractionation, confocal) but KCNAB3/KVβ3 protein not detected at protein level and functional role not directly established for KVβ3 specifically; single lab","pmids":["28342889"],"is_preprint":false},{"year":2020,"finding":"A novel missense mutation H258R in KCNAB3 (p.H258R, c.773A>G) was identified in a GEFS+ family; functional verification in HEK293 cells co-expressing Kvβ3(H258R) and Kv1.1 showed accelerated inactivation of potassium channels and reduced potassium current, increasing predicted neuronal excitability.","method":"Whole-exome sequencing, Sanger validation, electrophysiology (patch clamp) in HEK293 cells co-expressing mutant Kvβ3 and Kv1.1","journal":"Brain and behavior","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — electrophysiological functional assay in heterologous cells with defined mutation, single lab, no mutagenesis rescue control reported","pmids":["32990398"],"is_preprint":false},{"year":2022,"finding":"Introduction of the human KCNAB3 H258R mutation into mouse KCNAB3 via CRISPR/Cas9 knock-in reduced total potassium currents in hippocampal CA1 pyramidal neurons (except at maximum voltage +80 mV), confirming the mutation impairs native neuronal Kv channel function in the mammalian brain.","method":"CRISPR/Cas9 knock-in mouse model; patch clamp electrophysiology of hippocampal CA1 pyramidal cells","journal":"Translational pediatrics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo knock-in model with patch clamp, single lab, limited voltage range effect, no pharmacological or molecular rescue","pmids":["36345448"],"is_preprint":false}],"current_model":"KCNAB3 encodes the auxiliary Kvβ3 subunit that associates with Kv1-family α-subunits (demonstrated with Kv1.5 and Kv1.1) and confers fast (A-type) inactivation on these voltage-gated potassium channels; a disease-linked missense mutation (H258R) accelerates inactivation and reduces neuronal potassium current, linking KCNAB3 dysfunction to genetic epilepsy with febrile seizures plus."},"narrative":{"mechanistic_narrative":"KCNAB3 encodes Kvβ3, an auxiliary subunit that associates with Kv1-family voltage-gated potassium channel α-subunits and confers fast (A-type) inactivation: coexpression of Kvβ3.1 with the Kv1.5 α-subunit in CHO cells generates a novel, very fast-inactivating outward potassium current upon depolarization [PMID:9857044]. A disease-linked missense mutation, H258R, identified in a family with genetic epilepsy with febrile seizures plus, accelerates channel inactivation and reduces potassium current when the mutant Kvβ3 is co-expressed with Kv1.1 in HEK293 cells [PMID:32990398], and a CRISPR/Cas9 knock-in of this mutation into mouse Kcnab3 reduces native potassium currents in hippocampal CA1 pyramidal neurons, establishing that KCNAB3 dysfunction impairs neuronal Kv channel function in the mammalian brain [PMID:36345448]. Beyond these findings on subunit assembly, inactivation gating, and the H258R epilepsy link, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":1998,"claim":"Established that Kvβ3 is not merely a binding partner but a functional modulator that imposes a distinct gating behavior on Kv1 channels, answering what Kvβ3 does to channel function.","evidence":"Heterologous coexpression of Kvβ3.1 with Kv1.5 in CHO cells with electrophysiology","pmids":["9857044"],"confidence":"High","gaps":["Tested only with Kv1.5; range of Kv1 α-partners not mapped","Structural basis of inactivation conferral not defined","No native-tissue confirmation of the Kvβ3/Kv1.5 pairing"]},{"year":2017,"claim":"Addressed whether Kvβ3 is a physiologically relevant Kv1.5 partner in vascular smooth muscle, finding it expressed at transcript level but not the predominant sarcolemmal partner.","evidence":"RT-qPCR, in situ proximity ligation assay, membrane fractionation and confocal microscopy in murine coronary arterial myocytes","pmids":["28342889"],"confidence":"Medium","gaps":["Kvβ3 protein not detected at the protein level","No direct functional role established for Kvβ3 in this tissue","Kvβ1 and Kvβ2 dominate, leaving Kvβ3's native context unresolved"]},{"year":2020,"claim":"Connected KCNAB3 to human disease by showing a GEFS+-associated H258R mutation alters channel gating, linking a specific variant to a heritable epilepsy phenotype.","evidence":"Whole-exome sequencing and patch clamp of mutant Kvβ3(H258R) co-expressed with Kv1.1 in HEK293 cells","pmids":["32990398"],"confidence":"Medium","gaps":["Single family, single lab; no mutagenesis rescue control","Mechanism by which H258R accelerates inactivation not defined at the structural level","Tested with Kv1.1 only"]},{"year":2022,"claim":"Tested whether the H258R effect holds in native mammalian neurons, confirming the mutation reduces potassium currents in hippocampal CA1 pyramidal cells in vivo.","evidence":"CRISPR/Cas9 H258R knock-in mouse with patch clamp of hippocampal CA1 pyramidal neurons","pmids":["36345448"],"confidence":"Medium","gaps":["Effect limited across voltage range (no change at +80 mV)","No pharmacological or molecular rescue","Behavioral/seizure phenotype link to the current change not established here"]},{"year":null,"claim":"The full repertoire of native Kv1 α-partners for Kvβ3 across tissues and the structural/biochemical mechanism by which Kvβ3 (and the H258R variant) accelerates inactivation remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the Kvβ3/Kv1 complex","Native neuronal α-subunit partners not directly identified","Mechanistic basis of inactivation gating by Kvβ3 unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["KCNA5","KCNA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43448","full_name":"Voltage-gated potassium channel subunit beta-3","aliases":["K(+) channel subunit beta-3","Kv-beta-3"],"length_aa":404,"mass_kda":43.7,"function":"Regulatory subunit of the voltage-gated potassium (Kv) channels composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunit (PubMed:9857044). The beta-3/KCNAB3 subunit may mediate closure of potassium channels (By similarity). Increases inactivation of Kv1.5/KCNA5 alpha subunit-containing channels (PubMed:9857044). May display nicotinamide adenine dinucleotide phosphate (NADPH)-dependent aldoketoreductase activity (By similarity). The binding of oxidized and reduced NADP(H) cofactors may be required for the regulation of potassium channel activity (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43448/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNAB3","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/KCNAB3","total_profiled":1310},"omim":[{"mim_id":"613776","title":"CHROMOSOME 17p13.1 DELETION SYNDROME","url":"https://www.omim.org/entry/613776"},{"mim_id":"607738","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SHAB-RELATED SUBFAMILY, MEMBER 2; KCNB2","url":"https://www.omim.org/entry/607738"},{"mim_id":"604111","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, BETA MEMBER 3; KCNAB3","url":"https://www.omim.org/entry/604111"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":34.2},{"tissue":"endometrium 1","ntpm":14.3}],"url":"https://www.proteinatlas.org/search/KCNAB3"},"hgnc":{"alias_symbol":["AKR6A9","KCNA3B"],"prev_symbol":[]},"alphafold":{"accession":"O43448","domains":[{"cath_id":"3.20.20.100","chopping":"72-395","consensus_level":"high","plddt":93.4391,"start":72,"end":395}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43448","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43448-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43448-F1-predicted_aligned_error_v6.png","plddt_mean":84.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNAB3","jax_strain_url":"https://www.jax.org/strain/search?query=KCNAB3"},"sequence":{"accession":"O43448","fasta_url":"https://rest.uniprot.org/uniprotkb/O43448.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43448/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43448"}},"corpus_meta":[{"pmid":"9857044","id":"PMC_9857044","title":"Coexpression of the KCNA3B gene product with Kv1.5 leads to a novel A-type potassium channel.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9857044","citation_count":60,"is_preprint":false},{"pmid":"26690652","id":"PMC_26690652","title":"DNA methylation markers for oral pre-cancer progression: A critical review.","date":"2015","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26690652","citation_count":50,"is_preprint":false},{"pmid":"29933125","id":"PMC_29933125","title":"Tracking age-correlated DNA methylation markers in the young.","date":"2018","source":"Forensic science international. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29933125","citation_count":41,"is_preprint":false},{"pmid":"23030542","id":"PMC_23030542","title":"Identification of novel genes involved in migraine.","date":"2012","source":"Headache","url":"https://pubmed.ncbi.nlm.nih.gov/23030542","citation_count":30,"is_preprint":false},{"pmid":"26842698","id":"PMC_26842698","title":"PreImplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids.","date":"2016","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/26842698","citation_count":26,"is_preprint":false},{"pmid":"28342889","id":"PMC_28342889","title":"Heteromeric complexes of aldo-keto reductase auxiliary KVβ subunits (AKR6A) regulate sarcolemmal localization of KV1.5 in coronary arterial myocytes.","date":"2017","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/28342889","citation_count":20,"is_preprint":false},{"pmid":"28967789","id":"PMC_28967789","title":"Exploring genome-wide DNA methylation patterns in Aicardi syndrome.","date":"2017","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/28967789","citation_count":7,"is_preprint":false},{"pmid":"32990398","id":"PMC_32990398","title":"H258R mutation in KCNAB3 gene in a family with genetic epilepsy and febrile seizures plus.","date":"2020","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/32990398","citation_count":6,"is_preprint":false},{"pmid":"39938337","id":"PMC_39938337","title":"A novel signature of cartilage aging-related immunophenotyping biomarkers in osteoarthritis.","date":"2025","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39938337","citation_count":3,"is_preprint":false},{"pmid":"38007095","id":"PMC_38007095","title":"Comprehensive analysis of circRNA-miRNA-mRNA networks in the kidney of snakehead (Channa argus) response to Nocardia seriolae challenge.","date":"2023","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38007095","citation_count":1,"is_preprint":false},{"pmid":"36345448","id":"PMC_36345448","title":"Functional characterization of a KCNAB3 genetic epilepsy with febrile seizures plus adult mouse model.","date":"2022","source":"Translational pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/36345448","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7506,"output_tokens":1150,"usd":0.019884,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7678,"output_tokens":1804,"usd":0.041745,"stage2_stop_reason":"end_turn"},"total_usd":0.061629,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human Kvβ3.1 (encoded by KCNA3B/KCNAB3) coexpressed with Kv1.5 α-subunit in CHO cells generates a novel A-type (very fast-inactivating) outward potassium current upon depolarization, demonstrating that Kvβ3.1 confers fast inactivation on the Kv1.5 channel.\",\n      \"method\": \"Heterologous coexpression in Chinese hamster ovary (CHO) cells; electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological reconstitution in heterologous cells with defined subunit coexpression, single lab but clear functional readout\",\n      \"pmids\": [\"9857044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KVβ3 (AKR6A9/KCNAB3) transcript is expressed in murine coronary arteries, and in situ proximity ligation assays confirm protein-protein interactions between KV1.5 and KVβ proteins in coronary arterial myocytes; however, the predominant functional partners at the sarcolemma were KVβ1 and KVβ2, not KVβ3.\",\n      \"method\": \"RT-qPCR, Western blot, in situ proximity ligation assay, confocal microscopy, membrane fractionation\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal methods (PLA, fractionation, confocal) but KCNAB3/KVβ3 protein not detected at protein level and functional role not directly established for KVβ3 specifically; single lab\",\n      \"pmids\": [\"28342889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A novel missense mutation H258R in KCNAB3 (p.H258R, c.773A>G) was identified in a GEFS+ family; functional verification in HEK293 cells co-expressing Kvβ3(H258R) and Kv1.1 showed accelerated inactivation of potassium channels and reduced potassium current, increasing predicted neuronal excitability.\",\n      \"method\": \"Whole-exome sequencing, Sanger validation, electrophysiology (patch clamp) in HEK293 cells co-expressing mutant Kvβ3 and Kv1.1\",\n      \"journal\": \"Brain and behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — electrophysiological functional assay in heterologous cells with defined mutation, single lab, no mutagenesis rescue control reported\",\n      \"pmids\": [\"32990398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Introduction of the human KCNAB3 H258R mutation into mouse KCNAB3 via CRISPR/Cas9 knock-in reduced total potassium currents in hippocampal CA1 pyramidal neurons (except at maximum voltage +80 mV), confirming the mutation impairs native neuronal Kv channel function in the mammalian brain.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model; patch clamp electrophysiology of hippocampal CA1 pyramidal cells\",\n      \"journal\": \"Translational pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo knock-in model with patch clamp, single lab, limited voltage range effect, no pharmacological or molecular rescue\",\n      \"pmids\": [\"36345448\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNAB3 encodes the auxiliary Kvβ3 subunit that associates with Kv1-family α-subunits (demonstrated with Kv1.5 and Kv1.1) and confers fast (A-type) inactivation on these voltage-gated potassium channels; a disease-linked missense mutation (H258R) accelerates inactivation and reduces neuronal potassium current, linking KCNAB3 dysfunction to genetic epilepsy with febrile seizures plus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNAB3 encodes Kvβ3, an auxiliary subunit that associates with Kv1-family voltage-gated potassium channel α-subunits and confers fast (A-type) inactivation: coexpression of Kvβ3.1 with the Kv1.5 α-subunit in CHO cells generates a novel, very fast-inactivating outward potassium current upon depolarization [#0]. A disease-linked missense mutation, H258R, identified in a family with genetic epilepsy with febrile seizures plus, accelerates channel inactivation and reduces potassium current when the mutant Kvβ3 is co-expressed with Kv1.1 in HEK293 cells [#2], and a CRISPR/Cas9 knock-in of this mutation into mouse Kcnab3 reduces native potassium currents in hippocampal CA1 pyramidal neurons, establishing that KCNAB3 dysfunction impairs neuronal Kv channel function in the mammalian brain [#3]. Beyond these findings on subunit assembly, inactivation gating, and the H258R epilepsy link, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that Kvβ3 is not merely a binding partner but a functional modulator that imposes a distinct gating behavior on Kv1 channels, answering what Kvβ3 does to channel function.\",\n      \"evidence\": \"Heterologous coexpression of Kvβ3.1 with Kv1.5 in CHO cells with electrophysiology\",\n      \"pmids\": [\"9857044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested only with Kv1.5; range of Kv1 α-partners not mapped\", \"Structural basis of inactivation conferral not defined\", \"No native-tissue confirmation of the Kvβ3/Kv1.5 pairing\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Addressed whether Kvβ3 is a physiologically relevant Kv1.5 partner in vascular smooth muscle, finding it expressed at transcript level but not the predominant sarcolemmal partner.\",\n      \"evidence\": \"RT-qPCR, in situ proximity ligation assay, membrane fractionation and confocal microscopy in murine coronary arterial myocytes\",\n      \"pmids\": [\"28342889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kvβ3 protein not detected at the protein level\", \"No direct functional role established for Kvβ3 in this tissue\", \"Kvβ1 and Kvβ2 dominate, leaving Kvβ3's native context unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected KCNAB3 to human disease by showing a GEFS+-associated H258R mutation alters channel gating, linking a specific variant to a heritable epilepsy phenotype.\",\n      \"evidence\": \"Whole-exome sequencing and patch clamp of mutant Kvβ3(H258R) co-expressed with Kv1.1 in HEK293 cells\",\n      \"pmids\": [\"32990398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family, single lab; no mutagenesis rescue control\", \"Mechanism by which H258R accelerates inactivation not defined at the structural level\", \"Tested with Kv1.1 only\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tested whether the H258R effect holds in native mammalian neurons, confirming the mutation reduces potassium currents in hippocampal CA1 pyramidal cells in vivo.\",\n      \"evidence\": \"CRISPR/Cas9 H258R knock-in mouse with patch clamp of hippocampal CA1 pyramidal neurons\",\n      \"pmids\": [\"36345448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect limited across voltage range (no change at +80 mV)\", \"No pharmacological or molecular rescue\", \"Behavioral/seizure phenotype link to the current change not established here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full repertoire of native Kv1 α-partners for Kvβ3 across tissues and the structural/biochemical mechanism by which Kvβ3 (and the H258R variant) accelerates inactivation remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the Kvβ3/Kv1 complex\", \"Native neuronal α-subunit partners not directly identified\", \"Mechanistic basis of inactivation gating by Kvβ3 unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KCNA5\", \"KCNA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}