{"gene":"KCNAB3","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1998,"finding":"Human Kvβ3.1 (encoded by KCNAB3) co-assembles with Kv1.5 α-subunits to form a novel A-type potassium channel mediating very fast inactivating outward currents upon depolarization, demonstrating that Kvβ3.1 confers rapid (A-type) inactivation on Kv1.5 channels.","method":"Heterologous co-expression of Kv1.5 and Kvβ3.1 in Chinese hamster ovary (CHO) cells; electrophysiological recording","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct reconstitution in heterologous system with electrophysiological functional readout","pmids":["9857044"],"is_preprint":false},{"year":2020,"finding":"A missense mutation H258R in KCNAB3 accelerates inactivation of potassium channels and reduces potassium current, thereby increasing neuronal excitability and promoting epileptic convulsion, as established by functional verification in HEK293 cells co-expressing Kvβ3(H258R) and Kv1.1.","method":"Whole-exome sequencing to identify variant; functional expression in HEK293 cells co-expressing mutant Kvβ3(H258R) with Kv1.1; patch-clamp electrophysiology","journal":"Brain and behavior","confidence":"Medium","confidence_rationale":"Tier 2 — heterologous expression with electrophysiology, single lab, single study","pmids":["32990398"],"is_preprint":false},{"year":2022,"finding":"The KCNAB3 H258R mutation reduces total potassium currents in hippocampal CA1 pyramidal cells in a knock-in mouse model, confirming that the Kvβ3 subunit modulates native neuronal potassium channel activity in the mammalian brain.","method":"CRISPR/Cas9 knock-in mouse model carrying human H258R mutation; patch-clamp recording of pyramidal cells from hippocampal CA1 region","journal":"Translational pediatrics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo knock-in model with electrophysiology, single lab, single study","pmids":["36345448"],"is_preprint":false},{"year":2017,"finding":"KVβ3 (AKR6A9, encoded by KCNAB3) is detected at the transcript level in murine coronary arterial myocytes, where KVβ1 and KVβ2 (but not KVβ3 protein) associate with KV1.5 channels and regulate sarcolemmal localization of KV1.5, providing context for the functional role of the AKR6A subfamily of KVβ subunits in vascular tissue.","method":"RT-qPCR for transcript detection; Western blot; in situ proximity ligation assay; confocal microscopy; membrane fractionation in KVβ2-null mice","journal":"Chemico-biological interactions","confidence":"Low","confidence_rationale":"Tier 3 — KVβ3 protein not detected in the native coronary artery tissue studied; only transcript evidence for KCNAB3 in this context","pmids":["28342889"],"is_preprint":false}],"current_model":"KCNAB3 encodes the auxiliary β subunit Kvβ3, which co-assembles with Kv1-family voltage-gated K⁺ channel α-subunits (e.g., Kv1.5, Kv1.1) to confer rapid (A-type) inactivation on otherwise slowly inactivating channels, and a disease-causing H258R mutation in Kvβ3 accelerates inactivation and reduces potassium currents in both heterologous cells and hippocampal neurons in vivo, increasing neuronal excitability."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing the core function of Kvβ3: it was unknown whether Kvβ3.1 could confer A-type inactivation on Kv1 α-subunits; reconstitution with Kv1.5 demonstrated that Kvβ3.1 converts a slowly inactivating delayed-rectifier into a rapidly inactivating A-type potassium channel.","evidence":"Heterologous co-expression of Kvβ3.1 and Kv1.5 in CHO cells with electrophysiological recording","pmids":["9857044"],"confidence":"High","gaps":["No in vivo confirmation that Kvβ3 confers A-type inactivation on native Kv1 channels","Structural basis of inactivation ball-and-chain mechanism for Kvβ3 not resolved","Selectivity of Kvβ3 for different Kv1 α-subunit partners not systematically tested"]},{"year":2020,"claim":"Linking KCNAB3 to human disease: the H258R missense mutation was identified in epilepsy patients and shown to accelerate inactivation and reduce potassium current when co-expressed with Kv1.1, providing a mechanistic explanation for increased neuronal excitability.","evidence":"Whole-exome sequencing of epilepsy patients; patch-clamp electrophysiology in HEK293 cells co-expressing Kvβ3(H258R) with Kv1.1","pmids":["32990398"],"confidence":"Medium","gaps":["Single-lab finding not independently replicated","Effect of H258R on assembly stoichiometry and trafficking of Kv1 channels not examined","Whether H258R affects the oxidoreductase-related fold of the aldo-keto reductase domain is unknown"]},{"year":2022,"claim":"Validating the disease mechanism in vivo: a CRISPR knock-in mouse carrying H258R confirmed that mutant Kvβ3 reduces potassium currents in hippocampal CA1 pyramidal neurons, establishing that this β-subunit modulates native neuronal potassium channel function.","evidence":"CRISPR/Cas9 knock-in mouse; patch-clamp recording from hippocampal CA1 pyramidal cells","pmids":["36345448"],"confidence":"Medium","gaps":["Single-lab study; independent replication needed","Whether the knock-in mouse exhibits spontaneous seizure phenotype not fully characterized","Contribution of Kvβ3 versus Kvβ1/Kvβ2 to native hippocampal channel complexes not resolved"]},{"year":null,"claim":"The tissue-specific expression, α-subunit selectivity, and potential aldo-keto reductase catalytic activity of Kvβ3 remain largely uncharacterized in vivo, and the structural basis for how disease mutations alter channel gating has not been determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of Kvβ3 in complex with a Kv1 α-subunit","Enzymatic activity of the aldo-keto reductase domain of Kvβ3 not demonstrated","Comprehensive tissue-level proteomics for Kvβ3 protein expression lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["KCNA5","KCNA1"],"other_free_text":[]},"mechanistic_narrative":"KCNAB3 encodes the voltage-gated potassium channel auxiliary subunit Kvβ3, which co-assembles with Kv1-family α-subunits to confer rapid A-type inactivation on otherwise slowly inactivating channels; co-expression of Kvβ3.1 with Kv1.5 in heterologous cells produces fast-inactivating outward potassium currents [PMID:9857044]. A disease-causing missense mutation (H258R) in KCNAB3 accelerates channel inactivation and reduces potassium current amplitude when co-expressed with Kv1.1 in HEK293 cells, and a CRISPR knock-in mouse model carrying H258R confirms reduced potassium currents in hippocampal CA1 pyramidal neurons with increased neuronal excitability linked to epileptic seizures [PMID:32990398, PMID:36345448]."},"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":38,"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":18,"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":6735,"output_tokens":1116,"usd":0.018472},"stage2":{"model":"claude-opus-4-6","input_tokens":4370,"output_tokens":1378,"usd":0.08445},"total_usd":0.102922,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human Kvβ3.1 (encoded by KCNAB3) co-assembles with Kv1.5 α-subunits to form a novel A-type potassium channel mediating very fast inactivating outward currents upon depolarization, demonstrating that Kvβ3.1 confers rapid (A-type) inactivation on Kv1.5 channels.\",\n      \"method\": \"Heterologous co-expression of Kv1.5 and Kvβ3.1 in Chinese hamster ovary (CHO) cells; electrophysiological recording\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct reconstitution in heterologous system with electrophysiological functional readout\",\n      \"pmids\": [\"9857044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A missense mutation H258R in KCNAB3 accelerates inactivation of potassium channels and reduces potassium current, thereby increasing neuronal excitability and promoting epileptic convulsion, as established by functional verification in HEK293 cells co-expressing Kvβ3(H258R) and Kv1.1.\",\n      \"method\": \"Whole-exome sequencing to identify variant; functional expression in HEK293 cells co-expressing mutant Kvβ3(H258R) with Kv1.1; patch-clamp electrophysiology\",\n      \"journal\": \"Brain and behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — heterologous expression with electrophysiology, single lab, single study\",\n      \"pmids\": [\"32990398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The KCNAB3 H258R mutation reduces total potassium currents in hippocampal CA1 pyramidal cells in a knock-in mouse model, confirming that the Kvβ3 subunit modulates native neuronal potassium channel activity in the mammalian brain.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model carrying human H258R mutation; patch-clamp recording of pyramidal cells from hippocampal CA1 region\",\n      \"journal\": \"Translational pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knock-in model with electrophysiology, single lab, single study\",\n      \"pmids\": [\"36345448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KVβ3 (AKR6A9, encoded by KCNAB3) is detected at the transcript level in murine coronary arterial myocytes, where KVβ1 and KVβ2 (but not KVβ3 protein) associate with KV1.5 channels and regulate sarcolemmal localization of KV1.5, providing context for the functional role of the AKR6A subfamily of KVβ subunits in vascular tissue.\",\n      \"method\": \"RT-qPCR for transcript detection; Western blot; in situ proximity ligation assay; confocal microscopy; membrane fractionation in KVβ2-null mice\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KVβ3 protein not detected in the native coronary artery tissue studied; only transcript evidence for KCNAB3 in this context\",\n      \"pmids\": [\"28342889\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNAB3 encodes the auxiliary β subunit Kvβ3, which co-assembles with Kv1-family voltage-gated K⁺ channel α-subunits (e.g., Kv1.5, Kv1.1) to confer rapid (A-type) inactivation on otherwise slowly inactivating channels, and a disease-causing H258R mutation in Kvβ3 accelerates inactivation and reduces potassium currents in both heterologous cells and hippocampal neurons in vivo, increasing neuronal excitability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KCNAB3 encodes the voltage-gated potassium channel auxiliary subunit Kvβ3, which co-assembles with Kv1-family α-subunits to confer rapid A-type inactivation on otherwise slowly inactivating channels; co-expression of Kvβ3.1 with Kv1.5 in heterologous cells produces fast-inactivating outward potassium currents [PMID:9857044]. A disease-causing missense mutation (H258R) in KCNAB3 accelerates channel inactivation and reduces potassium current amplitude when co-expressed with Kv1.1 in HEK293 cells, and a CRISPR knock-in mouse model carrying H258R confirms reduced potassium currents in hippocampal CA1 pyramidal neurons with increased neuronal excitability linked to epileptic seizures [PMID:32990398, PMID:36345448].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the core function of Kvβ3: it was unknown whether Kvβ3.1 could confer A-type inactivation on Kv1 α-subunits; reconstitution with Kv1.5 demonstrated that Kvβ3.1 converts a slowly inactivating delayed-rectifier into a rapidly inactivating A-type potassium channel.\",\n      \"evidence\": \"Heterologous co-expression of Kvβ3.1 and Kv1.5 in CHO cells with electrophysiological recording\",\n      \"pmids\": [\"9857044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo confirmation that Kvβ3 confers A-type inactivation on native Kv1 channels\",\n        \"Structural basis of inactivation ball-and-chain mechanism for Kvβ3 not resolved\",\n        \"Selectivity of Kvβ3 for different Kv1 α-subunit partners not systematically tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking KCNAB3 to human disease: the H258R missense mutation was identified in epilepsy patients and shown to accelerate inactivation and reduce potassium current when co-expressed with Kv1.1, providing a mechanistic explanation for increased neuronal excitability.\",\n      \"evidence\": \"Whole-exome sequencing of epilepsy patients; patch-clamp electrophysiology in HEK293 cells co-expressing Kvβ3(H258R) with Kv1.1\",\n      \"pmids\": [\"32990398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding not independently replicated\",\n        \"Effect of H258R on assembly stoichiometry and trafficking of Kv1 channels not examined\",\n        \"Whether H258R affects the oxidoreductase-related fold of the aldo-keto reductase domain is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Validating the disease mechanism in vivo: a CRISPR knock-in mouse carrying H258R confirmed that mutant Kvβ3 reduces potassium currents in hippocampal CA1 pyramidal neurons, establishing that this β-subunit modulates native neuronal potassium channel function.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in mouse; patch-clamp recording from hippocampal CA1 pyramidal cells\",\n      \"pmids\": [\"36345448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication needed\",\n        \"Whether the knock-in mouse exhibits spontaneous seizure phenotype not fully characterized\",\n        \"Contribution of Kvβ3 versus Kvβ1/Kvβ2 to native hippocampal channel complexes not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The tissue-specific expression, α-subunit selectivity, and potential aldo-keto reductase catalytic activity of Kvβ3 remain largely uncharacterized in vivo, and the structural basis for how disease mutations alter channel gating has not been determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of Kvβ3 in complex with a Kv1 α-subunit\",\n        \"Enzymatic activity of the aldo-keto reductase domain of Kvβ3 not demonstrated\",\n        \"Comprehensive tissue-level proteomics for Kvβ3 protein expression lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [0, 1, 2]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-112316\",\n        \"supporting_discovery_ids\": [0, 1, 2]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KCNA5\",\n      \"KCNA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}