{"gene":"KCNAB1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1996,"finding":"KCNAB1 (hKvβ1) encodes at least three splice variants (hKvβ1.1, hKvβ1.2, hKvβ1.3); coexpression of hKvβ1.1 and hKvβ1.2 with hKv1.5 α-subunits in 293 cells confers rapid inactivation on otherwise non-inactivating hKv1.5 channels, with different potencies attributed to differences in their N-terminal inactivating domains. The N-terminal inactivating domain of Kvβ1.1 and that of Kv1.4α compete for the same receptor site(s) on Kv1α subunits.","method":"Heterologous coexpression in 293 cells, patch-clamp electrophysiology, competition assay between inactivating domains","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological reconstitution with coexpression and domain competition assay, single lab but multiple orthogonal functional tests","pmids":["8938711"],"is_preprint":false},{"year":1998,"finding":"Coexpression of human Kvβ3.1 (encoded by KCNA3B, a distinct Kvβ gene) with Kv1.5 in CHO cells yields a novel A-type (fast-inactivating) outward K+ current upon depolarization. Additionally, KCNA1B (Kvβ1) gene structure was comparatively analyzed, revealing it spans ≥350 kb with 14 exons encoding the open reading frame, and Kvβ1/Kvβ2 splice variants arise from alternative use of 5′ exons.","method":"Heterologous coexpression in CHO cells, patch-clamp electrophysiology, gene structure analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct electrophysiological reconstitution in CHO cells, single lab; structural characterization of KCNA1B gene noted but functional work focuses on Kvβ3.1","pmids":["9857044"],"is_preprint":false},{"year":1996,"finding":"The human KCNA1B (Kvβ1) gene was mapped to chromosome 3q26.1 by somatic cell hybrid mapping and fluorescence in situ hybridization (FISH), corroborated by PCR screening of the CEPH YAC library.","method":"Somatic cell hybrid mapping, FISH, YAC library PCR screening","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal cytogenetic methods (somatic hybrid, FISH, YAC PCR) all confirming the same chromosomal location","pmids":["8838324"],"is_preprint":false},{"year":2003,"finding":"Kvβ1.3 (AKR6A3/KCNAB1 product) co-transfected with Kv1.5 in COS-7 cells localizes to the membrane (whereas Kvβ1.3 alone is cytoplasmic), indicating high-affinity binding between the two proteins. Kvβ1.3 confers pronounced inactivation on Kv1.5 currents. NAD⁺ (1 mM, intracellular) abolishes Kvβ1.3-induced inactivation of Kv1.5 currents, while NADPH (0.1 mM) does not, demonstrating that the pyridine nucleotide redox state (NAD⁺ vs. NADPH) bound to the Kvβ subunit controls whether it imparts inactivation, providing a potential redox-sensing mechanism linking cellular metabolic state to K+ channel activity.","method":"Transient transfection of COS-7 cells, patch-clamp electrophysiology with intracellular nucleotide dialysis, subcellular localization by immunofluorescence","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct electrophysiological reconstitution with pharmacological manipulation of cofactor, single lab, single paper","pmids":["12604247"],"is_preprint":false},{"year":2017,"finding":"In murine coronary arterial myocytes, KVβ1 (AKR6A3, product of KCNAB1) protein is detected and forms protein–protein interactions with KV1.5 channels (demonstrated by in situ proximity ligation assay). KVβ1 also interacts with KVβ2 in the same cells. KVβ2-null mice show reduced sarcolemmal KV1.5 abundance (assessed by confocal microscopy and membrane fractionation), suggesting KVβ2 is the principal chaperone for KV1.5 membrane trafficking; KVβ1 is present but does not appear to be the primary chaperone.","method":"In situ proximity ligation assay, confocal microscopy, membrane fractionation, real-time qPCR, Western blot, KVβ2 knockout mouse model","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal proximity ligation + membrane fractionation + KO mouse, single lab with multiple orthogonal methods","pmids":["28342889"],"is_preprint":false},{"year":2016,"finding":"Genetic ablation of Kvβ1.1 (KCNAB1 isoform 1) in female mice causes cardiac hypertrophy (increased heart size and area), prolonged monophasic action potentials, elevated blood pressure, and increased myosin heavy chain α (MHCα) expression. siRNA-mediated knockdown of Kvβ1 in H9C2 cells upregulates MHCα expression. Kvβ1.1 protein was shown to bind MHCα directly. Male Kvβ1.1 KO mice show prolonged QTc and APD but do not develop cardiac hypertrophy, revealing a sex-specific role.","method":"KCNAB1 knockout mouse model (female and male), ECG, monophasic action potential recordings, echocardiography, siRNA knockdown in H9C2 cells, Western blot, co-immunoprecipitation/protein binding assay for Kvβ1–MHCα interaction","journal":"Experimental physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cardiac phenotype + siRNA functional validation + protein binding assay, multiple orthogonal methods in single lab","pmids":["27038296"],"is_preprint":false},{"year":2019,"finding":"In the mouse cerebral cortex, Kcnab1 mRNA (variant 1.1) is specifically expressed in subplate (SP)/layer 6b neurons. Retrograde tracing combined with in situ hybridization demonstrated that Kcnab1-expressing neurons in L6b/SP of primary somatosensory cortex project unilaterally to primary motor cortex and do not exhibit callosal projections. Kvβ1 protein co-localizes with L6b/SP markers Ctgf (88%), Cplx3 (79%), and Nurr1 (58%), indicating molecular subdivision of these projection neurons.","method":"Retrograde neuronal tracing, in situ hybridization, microarray, immunofluorescence double-labeling in mouse cortex","journal":"Frontiers in neuroanatomy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct retrograde tracing combined with ISH for co-localization, single lab with multiple anatomical methods","pmids":["31130851"],"is_preprint":false}],"current_model":"KCNAB1 encodes the auxiliary Kvβ1 subunit of voltage-gated Kv1 potassium channels, which physically associates with Kv1α subunits (e.g., Kv1.5) at the membrane and confers rapid (A-type) inactivation through its N-terminal ball-and-chain domain; this inactivating function is redox-regulated because the AKR/aldo-keto reductase domain of Kvβ1 binds pyridine nucleotides such that NAD⁺ (oxidized state) abolishes inactivation while NADPH (reduced state) permits it, thereby coupling cellular metabolic/redox status to membrane excitability. In the heart, Kvβ1.1 loss in female mice produces cardiac hypertrophy with action-potential prolongation and elevated MHCα expression, partly through a direct Kvβ1–MHCα protein interaction. In the brain, KCNAB1 variant 1.1 marks a subpopulation of unilaterally projecting subplate/layer-6b neurons in the somatosensory cortex."},"narrative":{"mechanistic_narrative":"KCNAB1 encodes the cytoplasmic Kvβ1 auxiliary subunit of voltage-gated Kv1 potassium channels, which associates with pore-forming Kv1α subunits at the membrane and converts otherwise non-inactivating channels into rapidly (A-type) inactivating ones via its N-terminal inactivating domain [PMID:8938711]. Multiple splice variants (Kvβ1.1, Kvβ1.2, Kvβ1.3) arise from alternative 5′ exon use and differ in inactivation potency through differences in their N-terminal domains, which compete with the Kv1.4α inactivating domain for a shared receptor site on Kv1α [PMID:8938711]. High-affinity binding to Kv1.5 drives Kvβ1.3 from a cytoplasmic to a membrane localization and confers pronounced inactivation; this inactivating function is gated by the redox state of bound pyridine nucleotide, as oxidized NAD⁺ abolishes Kvβ1.3-induced inactivation while NADPH permits it, providing a mechanism linking cellular metabolic state to K⁺ channel activity [PMID:12604247]. In coronary arterial myocytes Kvβ1 forms protein–protein complexes with both Kv1.5 and Kvβ2, though Kvβ2 rather than Kvβ1 is the principal chaperone for Kv1.5 sarcolemmal trafficking [PMID:28342889]. Beyond channel modulation, Kvβ1.1 has a sex-specific cardiac role: its loss in female mice produces cardiac hypertrophy, action-potential prolongation, and elevated myosin heavy chain α (MHCα) expression, in part through a direct Kvβ1.1–MHCα interaction, whereas male knockouts show electrical (QTc/APD) prolongation without hypertrophy [PMID:27038296]. In the cerebral cortex, Kcnab1 variant 1.1 marks a molecularly defined subpopulation of subplate/layer-6b neurons in primary somatosensory cortex that project unilaterally to primary motor cortex [PMID:31130851].","teleology":[{"year":1996,"claim":"Established that KCNAB1 is not a channel itself but an auxiliary subunit that imparts rapid A-type inactivation onto non-inactivating Kv1α channels, defining its core molecular function.","evidence":"Heterologous coexpression of hKvβ1.1/1.2 with hKv1.5 in 293 cells, patch-clamp, and inactivating-domain competition assay","pmids":["8938711"],"confidence":"High","gaps":["Inactivation potency differences among splice variants not resolved structurally","Receptor site on Kv1α not mapped at residue level"]},{"year":1996,"claim":"Localized the human Kvβ1 gene to chromosome 3q26.1, providing the genomic anchor for the locus.","evidence":"Somatic cell hybrid mapping, FISH, and YAC library PCR screening","pmids":["8838324"],"confidence":"High","gaps":["Mapping alone gives no functional or regulatory information"]},{"year":1998,"claim":"Characterized KCNAB1 gene architecture (≥350 kb, 14 ORF exons) and showed splice variants arise from alternative 5′ exon use, while related Kvβ3.1 also confers A-type current on Kv1.5.","evidence":"Gene structure analysis plus heterologous coexpression of Kvβ3.1 with Kv1.5 in CHO cells and patch-clamp","pmids":["9857044"],"confidence":"Medium","gaps":["Functional electrophysiology in this study focused on Kvβ3.1 (KCNA3B), not KCNAB1 product directly","Regulation of alternative 5′ exon usage unknown"]},{"year":2003,"claim":"Demonstrated that Kvβ1–Kv1.5 binding drives membrane localization and that pyridine-nucleotide redox state controls whether Kvβ1 imparts inactivation, linking the AKR-domain cofactor occupancy to channel behavior.","evidence":"COS-7 transient transfection, immunofluorescence localization, and patch-clamp with intracellular NAD⁺ vs NADPH dialysis","pmids":["12604247"],"confidence":"Medium","gaps":["Single lab, single paper","Physiological redox concentrations and in vivo relevance not established","Catalytic mechanism of the AKR domain not directly assayed"]},{"year":2016,"claim":"Revealed a sex-specific cardiac role beyond channel modulation, with Kvβ1.1 loss causing female-specific hypertrophy via MHCα upregulation and a direct Kvβ1.1–MHCα interaction.","evidence":"KCNAB1 knockout mice (both sexes), ECG/monophasic action potential, echocardiography, siRNA knockdown in H9C2, Western blot, and protein binding assay","pmids":["27038296"],"confidence":"High","gaps":["Molecular basis of sex-specificity unknown","How Kvβ1–MHCα binding regulates MHCα expression not defined"]},{"year":2017,"claim":"Placed Kvβ1 within a multi-subunit complex with Kv1.5 and Kvβ2 in arterial myocytes and showed Kvβ2, not Kvβ1, is the dominant trafficking chaperone for Kv1.5.","evidence":"In situ proximity ligation assay, confocal microscopy, membrane fractionation, and Kvβ2-null mouse","pmids":["28342889"],"confidence":"Medium","gaps":["Distinct functional contribution of Kvβ1 vs Kvβ2 to current properties not isolated","Stoichiometry of the Kv1.5/Kvβ1/Kvβ2 assembly unclear"]},{"year":2019,"claim":"Identified Kcnab1 variant 1.1 as a marker of a discrete unilaterally projecting subplate/layer-6b cortical neuron population, extending its biology to neuronal circuit identity.","evidence":"Retrograde tracing, in situ hybridization, microarray, and immunofluorescence co-labeling with L6b/SP markers in mouse cortex","pmids":["31130851"],"confidence":"Medium","gaps":["Functional role of Kvβ1 in these neurons not tested","Whether channel-modulating activity underlies the marker phenotype unknown"]},{"year":null,"claim":"It remains unknown how the redox-sensing AKR domain, the cardiac MHCα interaction, and the cortical neuronal identity functions are mechanistically integrated, and no human disease linkage is established in this corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the Kvβ1–Kv1α complex in the corpus","No human phenotype/disease variant described","Physiological enzymatic substrate of the AKR domain unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[5]}],"complexes":["Kv1.5/Kvβ1/Kvβ2 voltage-gated potassium channel complex"],"partners":["KCNA5","KCNAB2","MYH6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14722","full_name":"Voltage-gated potassium channel subunit beta-1","aliases":["K(+) channel subunit beta-1","Kv-beta-1"],"length_aa":419,"mass_kda":46.6,"function":"Regulatory subunit of the voltage-gated potassium (Kv) Shaker channels composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits (PubMed:17156368, PubMed:17540341, PubMed:19713757, PubMed:7499366, PubMed:7603988). The beta-1/KCNAB1 cytoplasmic subunit mediates closure of delayed rectifier potassium channels by physically obstructing the pore via its N-terminal domain and increases the speed of channel closure for other family members (PubMed:9763623). Promotes the inactivation of Kv1.1/KCNA1, Kv1.2/KCNA2, Kv1.4/KCNA4, Kv1.5/KCNA5 and Kv1.6/KCNA6 alpha subunit-containing channels (PubMed:12077175, PubMed:12130714, PubMed:15361858, PubMed:17156368, PubMed:17540341, PubMed:19713757, PubMed:7499366, PubMed:7603988, PubMed:7649300, PubMed:7890764, PubMed:9763623). Displays nicotinamide adenine dinucleotide phosphate (NADPH)-dependent aldoketoreductase activity by catalyzing the NADPH-dependent reduction of a variety of endogenous aldehydes and ketones (By similarity). The binding of NADPH is required for efficient down-regulation of potassium channel activity (PubMed:17540341). Oxidation of the bound NADPH restrains N-terminal domain from blocking the channel, thereby decreasing N-type inactivation of potassium channel activity (By similarity) Isoform KvB1.2 shows no effect on KCNA1, KCNA2 or KCNB1","subcellular_location":"Cytoplasm; Membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14722/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNAB1","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/KCNAB1","total_profiled":1310},"omim":[{"mim_id":"615697","title":"EPILEPSY, FAMILIAL TEMPORAL LOBE, 6; ETL6","url":"https://www.omim.org/entry/615697"},{"mim_id":"604619","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 1; LGI1","url":"https://www.omim.org/entry/604619"},{"mim_id":"601141","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, BETA MEMBER 1; KCNAB1","url":"https://www.omim.org/entry/601141"},{"mim_id":"601014","title":"DISCS LARGE MAGUK SCAFFOLD PROTEIN 1; DLG1","url":"https://www.omim.org/entry/601014"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":91.5},{"tissue":"brain","ntpm":61.2}],"url":"https://www.proteinatlas.org/search/KCNAB1"},"hgnc":{"alias_symbol":["AKR6A3","KCNA1B","hKvBeta3","Kvb1.3","hKvb3"],"prev_symbol":[]},"alphafold":{"accession":"Q14722","domains":[{"cath_id":"3.20.20.100","chopping":"80-305_368-380","consensus_level":"high","plddt":97.1729,"start":80,"end":380}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14722","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14722-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14722-F1-predicted_aligned_error_v6.png","plddt_mean":86.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNAB1","jax_strain_url":"https://www.jax.org/strain/search?query=KCNAB1"},"sequence":{"accession":"Q14722","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14722.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14722/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14722"}},"corpus_meta":[{"pmid":"26544041","id":"PMC_26544041","title":"Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26544041","citation_count":75,"is_preprint":false},{"pmid":"28431800","id":"PMC_28431800","title":"Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes.","date":"2017","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/28431800","citation_count":65,"is_preprint":false},{"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":"16815889","id":"PMC_16815889","title":"Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells.","date":"2006","source":"American journal of physiology. 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The N-terminal inactivating domain of Kvβ1.1 and that of Kv1.4α compete for the same receptor site(s) on Kv1α subunits.\",\n      \"method\": \"Heterologous coexpression in 293 cells, patch-clamp electrophysiology, competition assay between inactivating domains\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological reconstitution with coexpression and domain competition assay, single lab but multiple orthogonal functional tests\",\n      \"pmids\": [\"8938711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Coexpression of human Kvβ3.1 (encoded by KCNA3B, a distinct Kvβ gene) with Kv1.5 in CHO cells yields a novel A-type (fast-inactivating) outward K+ current upon depolarization. Additionally, KCNA1B (Kvβ1) gene structure was comparatively analyzed, revealing it spans ≥350 kb with 14 exons encoding the open reading frame, and Kvβ1/Kvβ2 splice variants arise from alternative use of 5′ exons.\",\n      \"method\": \"Heterologous coexpression in CHO cells, patch-clamp electrophysiology, gene structure analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct electrophysiological reconstitution in CHO cells, single lab; structural characterization of KCNA1B gene noted but functional work focuses on Kvβ3.1\",\n      \"pmids\": [\"9857044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human KCNA1B (Kvβ1) gene was mapped to chromosome 3q26.1 by somatic cell hybrid mapping and fluorescence in situ hybridization (FISH), corroborated by PCR screening of the CEPH YAC library.\",\n      \"method\": \"Somatic cell hybrid mapping, FISH, YAC library PCR screening\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal cytogenetic methods (somatic hybrid, FISH, YAC PCR) all confirming the same chromosomal location\",\n      \"pmids\": [\"8838324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kvβ1.3 (AKR6A3/KCNAB1 product) co-transfected with Kv1.5 in COS-7 cells localizes to the membrane (whereas Kvβ1.3 alone is cytoplasmic), indicating high-affinity binding between the two proteins. Kvβ1.3 confers pronounced inactivation on Kv1.5 currents. NAD⁺ (1 mM, intracellular) abolishes Kvβ1.3-induced inactivation of Kv1.5 currents, while NADPH (0.1 mM) does not, demonstrating that the pyridine nucleotide redox state (NAD⁺ vs. NADPH) bound to the Kvβ subunit controls whether it imparts inactivation, providing a potential redox-sensing mechanism linking cellular metabolic state to K+ channel activity.\",\n      \"method\": \"Transient transfection of COS-7 cells, patch-clamp electrophysiology with intracellular nucleotide dialysis, subcellular localization by immunofluorescence\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct electrophysiological reconstitution with pharmacological manipulation of cofactor, single lab, single paper\",\n      \"pmids\": [\"12604247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In murine coronary arterial myocytes, KVβ1 (AKR6A3, product of KCNAB1) protein is detected and forms protein–protein interactions with KV1.5 channels (demonstrated by in situ proximity ligation assay). KVβ1 also interacts with KVβ2 in the same cells. KVβ2-null mice show reduced sarcolemmal KV1.5 abundance (assessed by confocal microscopy and membrane fractionation), suggesting KVβ2 is the principal chaperone for KV1.5 membrane trafficking; KVβ1 is present but does not appear to be the primary chaperone.\",\n      \"method\": \"In situ proximity ligation assay, confocal microscopy, membrane fractionation, real-time qPCR, Western blot, KVβ2 knockout mouse model\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal proximity ligation + membrane fractionation + KO mouse, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28342889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic ablation of Kvβ1.1 (KCNAB1 isoform 1) in female mice causes cardiac hypertrophy (increased heart size and area), prolonged monophasic action potentials, elevated blood pressure, and increased myosin heavy chain α (MHCα) expression. siRNA-mediated knockdown of Kvβ1 in H9C2 cells upregulates MHCα expression. Kvβ1.1 protein was shown to bind MHCα directly. Male Kvβ1.1 KO mice show prolonged QTc and APD but do not develop cardiac hypertrophy, revealing a sex-specific role.\",\n      \"method\": \"KCNAB1 knockout mouse model (female and male), ECG, monophasic action potential recordings, echocardiography, siRNA knockdown in H9C2 cells, Western blot, co-immunoprecipitation/protein binding assay for Kvβ1–MHCα interaction\",\n      \"journal\": \"Experimental physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cardiac phenotype + siRNA functional validation + protein binding assay, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"27038296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In the mouse cerebral cortex, Kcnab1 mRNA (variant 1.1) is specifically expressed in subplate (SP)/layer 6b neurons. Retrograde tracing combined with in situ hybridization demonstrated that Kcnab1-expressing neurons in L6b/SP of primary somatosensory cortex project unilaterally to primary motor cortex and do not exhibit callosal projections. Kvβ1 protein co-localizes with L6b/SP markers Ctgf (88%), Cplx3 (79%), and Nurr1 (58%), indicating molecular subdivision of these projection neurons.\",\n      \"method\": \"Retrograde neuronal tracing, in situ hybridization, microarray, immunofluorescence double-labeling in mouse cortex\",\n      \"journal\": \"Frontiers in neuroanatomy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct retrograde tracing combined with ISH for co-localization, single lab with multiple anatomical methods\",\n      \"pmids\": [\"31130851\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNAB1 encodes the auxiliary Kvβ1 subunit of voltage-gated Kv1 potassium channels, which physically associates with Kv1α subunits (e.g., Kv1.5) at the membrane and confers rapid (A-type) inactivation through its N-terminal ball-and-chain domain; this inactivating function is redox-regulated because the AKR/aldo-keto reductase domain of Kvβ1 binds pyridine nucleotides such that NAD⁺ (oxidized state) abolishes inactivation while NADPH (reduced state) permits it, thereby coupling cellular metabolic/redox status to membrane excitability. In the heart, Kvβ1.1 loss in female mice produces cardiac hypertrophy with action-potential prolongation and elevated MHCα expression, partly through a direct Kvβ1–MHCα protein interaction. In the brain, KCNAB1 variant 1.1 marks a subpopulation of unilaterally projecting subplate/layer-6b neurons in the somatosensory cortex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNAB1 encodes the cytoplasmic Kv\\u03b21 auxiliary subunit of voltage-gated Kv1 potassium channels, which associates with pore-forming Kv1\\u03b1 subunits at the membrane and converts otherwise non-inactivating channels into rapidly (A-type) inactivating ones via its N-terminal inactivating domain [#0]. Multiple splice variants (Kv\\u03b21.1, Kv\\u03b21.2, Kv\\u03b21.3) arise from alternative 5\\u2032 exon use and differ in inactivation potency through differences in their N-terminal domains, which compete with the Kv1.4\\u03b1 inactivating domain for a shared receptor site on Kv1\\u03b1 [#0]. High-affinity binding to Kv1.5 drives Kv\\u03b21.3 from a cytoplasmic to a membrane localization and confers pronounced inactivation; this inactivating function is gated by the redox state of bound pyridine nucleotide, as oxidized NAD\\u207a abolishes Kv\\u03b21.3-induced inactivation while NADPH permits it, providing a mechanism linking cellular metabolic state to K\\u207a channel activity [#3]. In coronary arterial myocytes Kv\\u03b21 forms protein\\u2013protein complexes with both Kv1.5 and Kv\\u03b22, though Kv\\u03b22 rather than Kv\\u03b21 is the principal chaperone for Kv1.5 sarcolemmal trafficking [#4]. Beyond channel modulation, Kv\\u03b21.1 has a sex-specific cardiac role: its loss in female mice produces cardiac hypertrophy, action-potential prolongation, and elevated myosin heavy chain \\u03b1 (MHC\\u03b1) expression, in part through a direct Kv\\u03b21.1\\u2013MHC\\u03b1 interaction, whereas male knockouts show electrical (QTc/APD) prolongation without hypertrophy [#5]. In the cerebral cortex, Kcnab1 variant 1.1 marks a molecularly defined subpopulation of subplate/layer-6b neurons in primary somatosensory cortex that project unilaterally to primary motor cortex [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that KCNAB1 is not a channel itself but an auxiliary subunit that imparts rapid A-type inactivation onto non-inactivating Kv1\\u03b1 channels, defining its core molecular function.\",\n      \"evidence\": \"Heterologous coexpression of hKv\\u03b21.1/1.2 with hKv1.5 in 293 cells, patch-clamp, and inactivating-domain competition assay\",\n      \"pmids\": [\"8938711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inactivation potency differences among splice variants not resolved structurally\", \"Receptor site on Kv1\\u03b1 not mapped at residue level\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Localized the human Kv\\u03b21 gene to chromosome 3q26.1, providing the genomic anchor for the locus.\",\n      \"evidence\": \"Somatic cell hybrid mapping, FISH, and YAC library PCR screening\",\n      \"pmids\": [\"8838324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mapping alone gives no functional or regulatory information\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Characterized KCNAB1 gene architecture (\\u2265350 kb, 14 ORF exons) and showed splice variants arise from alternative 5\\u2032 exon use, while related Kv\\u03b23.1 also confers A-type current on Kv1.5.\",\n      \"evidence\": \"Gene structure analysis plus heterologous coexpression of Kv\\u03b23.1 with Kv1.5 in CHO cells and patch-clamp\",\n      \"pmids\": [\"9857044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional electrophysiology in this study focused on Kv\\u03b23.1 (KCNA3B), not KCNAB1 product directly\", \"Regulation of alternative 5\\u2032 exon usage unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that Kv\\u03b21\\u2013Kv1.5 binding drives membrane localization and that pyridine-nucleotide redox state controls whether Kv\\u03b21 imparts inactivation, linking the AKR-domain cofactor occupancy to channel behavior.\",\n      \"evidence\": \"COS-7 transient transfection, immunofluorescence localization, and patch-clamp with intracellular NAD\\u207a vs NADPH dialysis\",\n      \"pmids\": [\"12604247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single paper\", \"Physiological redox concentrations and in vivo relevance not established\", \"Catalytic mechanism of the AKR domain not directly assayed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a sex-specific cardiac role beyond channel modulation, with Kv\\u03b21.1 loss causing female-specific hypertrophy via MHC\\u03b1 upregulation and a direct Kv\\u03b21.1\\u2013MHC\\u03b1 interaction.\",\n      \"evidence\": \"KCNAB1 knockout mice (both sexes), ECG/monophasic action potential, echocardiography, siRNA knockdown in H9C2, Western blot, and protein binding assay\",\n      \"pmids\": [\"27038296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of sex-specificity unknown\", \"How Kv\\u03b21\\u2013MHC\\u03b1 binding regulates MHC\\u03b1 expression not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed Kv\\u03b21 within a multi-subunit complex with Kv1.5 and Kv\\u03b22 in arterial myocytes and showed Kv\\u03b22, not Kv\\u03b21, is the dominant trafficking chaperone for Kv1.5.\",\n      \"evidence\": \"In situ proximity ligation assay, confocal microscopy, membrane fractionation, and Kv\\u03b22-null mouse\",\n      \"pmids\": [\"28342889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinct functional contribution of Kv\\u03b21 vs Kv\\u03b22 to current properties not isolated\", \"Stoichiometry of the Kv1.5/Kv\\u03b21/Kv\\u03b22 assembly unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Kcnab1 variant 1.1 as a marker of a discrete unilaterally projecting subplate/layer-6b cortical neuron population, extending its biology to neuronal circuit identity.\",\n      \"evidence\": \"Retrograde tracing, in situ hybridization, microarray, and immunofluorescence co-labeling with L6b/SP markers in mouse cortex\",\n      \"pmids\": [\"31130851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of Kv\\u03b21 in these neurons not tested\", \"Whether channel-modulating activity underlies the marker phenotype unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the redox-sensing AKR domain, the cardiac MHC\\u03b1 interaction, and the cortical neuronal identity functions are mechanistically integrated, and no human disease linkage is established in this corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the Kv\\u03b21\\u2013Kv1\\u03b1 complex in the corpus\", \"No human phenotype/disease variant described\", \"Physiological enzymatic substrate of the AKR domain unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"Kv1.5/Kv\\u03b21/Kv\\u03b22 voltage-gated potassium channel complex\"],\n    \"partners\": [\"KCNA5\", \"KCNAB2\", \"MYH6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}