{"gene":"KCNE5","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2002,"finding":"KCNE5 physically interacts with KCNQ1 and shifts the voltage activation curve of the KCNQ1 channel by more than 140 mV in the positive direction (activation threshold +40 mV, midpoint +116 mV), causing slow activation and rapid deactivation. This modulation is specific to KCNQ1: other KCNQ family members and hERG1 were unaffected. Four residues in the transmembrane domain of KCNE5 were identified as critical for controlling voltage-dependent activation of KCNQ1.","method":"Heterologous co-expression electrophysiology (patch-clamp), transmembrane domain mutagenesis","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro functional reconstitution with mutagenesis identifying specific transmembrane residues, multiple orthogonal measurements (voltage activation curve, kinetics, channel specificity panel)","pmids":["12324418"],"is_preprint":false},{"year":2008,"finding":"Wild-type KCNE5 suppresses IKs (KCNQ1+KCNE1) current in a concentration-dependent manner. The AF-associated missense mutation KCNE5-L65F abolishes this suppression, yielding currents indistinguishable from KCNE5-absent controls and producing a gain-of-function of IKs.","method":"Transient transfection of CHO cells expressing KCNQ1+KCNE1 with wild-type or L65F KCNE5; whole-cell patch-clamp electrophysiology","journal":"Heart rhythm","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct functional reconstitution with disease-linked mutant and concentration-dependent controls in a single focused study","pmids":["18313602"],"is_preprint":false},{"year":2011,"finding":"KCNE5 modulates the transient outward current (Ito) conducted by Kv4.3 (KCND3). Disease-associated variants KCNE5-Y81H and KCNE5-p.[D92E;E93X] significantly increase Ito compared to wild-type KCNE5 when co-expressed with KCND3 (gain-of-function). In contrast, neither variant significantly altered KCNQ1+KCNE5 current properties.","method":"Co-transfection of HEK/heterologous cells with KCND3 or KCNQ1 plus wild-type or mutant KCNE5; whole-cell patch-clamp electrophysiology; action potential simulation model","journal":"Circulation. Arrhythmia and electrophysiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct functional reconstitution with two independent disease mutants, two alpha-subunit partners tested, with simulation validation","pmids":["21493962"],"is_preprint":false},{"year":2018,"finding":"In mouse ventricular myocytes, Kcne5 deletion increased KV current density by augmenting IKslow,1 (KV1.5) and Ito,f (KV4) in the apex and IKslow,2 (KV2.1) in both apex and septum. KCNE5 colocalized with KV2.1 at intercalated discs in ventricular myocytes, and in HL-1 and HEK cells KCNE5 and KV2.1 co-localized predominantly in intracellular vesicles, suggesting KCNE5 reduces KV2.1 surface expression by promoting its intracellular sequestration. The human AF-associated KCNE5-L65F mutation negatively shifted the voltage dependence of KV2.1-KCNE5 channels and increased maximum current density >2-fold.","method":"Kcne5 knockout (Kcne5-/0) mouse model; intracardiac ECG; ventricular myocyte patch-clamp; immunolocalization (co-immunofluorescence of KCNE5 and KV2.1 in native tissue and cell lines); heterologous co-expression of human mutants with KV2.1","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Kcne5 knockout mouse with defined electrophysiological phenotype, subcellular co-localization experiments linking KCNE5 to KV2.1 trafficking, and functional validation with human disease mutants across multiple orthogonal methods","pmids":["30289750"],"is_preprint":false},{"year":2012,"finding":"KCNE5 protein is expressed in first-trimester human placenta and localizes mainly to the syncytiotrophoblast, with additional expression in the mesenchyme, as determined by immunohistochemistry.","method":"Immunohistochemistry and qRT-PCR on first-trimester placental tissue","journal":"Pregnancy hypertension","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization study with no functional consequence established, single lab, no mechanistic follow-up","pmids":["26105295"],"is_preprint":false}],"current_model":"KCNE5 is an ancillary (beta) subunit that modulates multiple voltage-gated potassium channel alpha-subunits: it dramatically right-shifts the voltage activation of KCNQ1 (>140 mV) via specific transmembrane-domain residues, suppresses IKs (KCNQ1/KCNE1) current in a concentration-dependent manner, reduces KV2.1 surface expression by promoting its intracellular sequestration, and modulates Ito through Kv4.3 (KCND3); loss-of-function or gain-of-function mutations in KCNE5 disrupt these regulatory roles and are mechanistically linked to atrial fibrillation and Brugada syndrome through increased ventricular KV currents."},"narrative":{"mechanistic_narrative":"KCNE5 is an ancillary (beta) subunit that modulates the gating, current amplitude, and trafficking of multiple voltage-gated potassium channel alpha-subunits in cardiac tissue [PMID:12324418, PMID:30289750]. Through specific transmembrane-domain residues, KCNE5 physically associates with KCNQ1 and dramatically right-shifts its voltage-dependent activation by more than 140 mV, slowing activation and accelerating deactivation in a manner specific to KCNQ1 among the channels tested [PMID:12324418]; it also suppresses the KCNQ1/KCNE1 (IKs) current in a concentration-dependent manner [PMID:18313602]. Beyond KCNQ1, KCNE5 modulates the transient outward current carried by Kv4.3 (KCND3) [PMID:21493962] and reduces KV2.1 surface expression, co-localizing with KV2.1 at intercalated discs in native myocytes and in intracellular vesicles in cell lines, consistent with promotion of intracellular sequestration; Kcne5 deletion in mouse ventricle increases KV1.5, KV4, and KV2.1 current densities [PMID:30289750]. Disease-associated variants disrupt these regulatory roles: the atrial-fibrillation-linked KCNE5-L65F abolishes IKs suppression to produce a gain of function [PMID:18313602] and negatively shifts and amplifies KV2.1 current [PMID:30289750], while the variants Y81H and p.[D92E;E93X] increase Kv4.3-mediated Ito as a gain of function [PMID:21493962], mechanistically linking KCNE5 dysfunction to atrial fibrillation and Brugada syndrome.","teleology":[{"year":2002,"claim":"Established that KCNE5 is a channel-modulating subunit by showing it binds KCNQ1 and imposes an extreme positive shift in voltage-dependent activation through defined transmembrane residues, defining its core biophysical mechanism and channel selectivity.","evidence":"Heterologous co-expression patch-clamp with transmembrane-domain mutagenesis and a channel specificity panel","pmids":["12324418"],"confidence":"High","gaps":["No structural model of the KCNE5-KCNQ1 interface","Physiological significance of a >140 mV shift in native tissue not addressed","Whether KCNE5 modulates channels beyond the KCNQ/hERG panel not tested here"]},{"year":2008,"claim":"Connected KCNE5 function to arrhythmia by demonstrating it suppresses IKs and that the AF-associated L65F mutation abolishes this suppression, providing a gain-of-function mechanism for disease.","evidence":"Transient transfection of CHO cells with KCNQ1+KCNE1 plus wild-type or L65F KCNE5; whole-cell patch-clamp","pmids":["18313602"],"confidence":"High","gaps":["Single focused study without native-tissue confirmation","Mechanism by which L65F loses suppression not resolved at the residue level"]},{"year":2011,"claim":"Broadened KCNE5's alpha-subunit repertoire by showing it modulates Kv4.3-mediated Ito and that distinct disease variants (Y81H, D92E;E93X) cause gain-of-function selectively through Kv4.3 rather than KCNQ1.","evidence":"Co-transfection of heterologous cells with KCND3 or KCNQ1 plus mutant KCNE5; patch-clamp with action potential simulation","pmids":["21493962"],"confidence":"High","gaps":["No direct biochemical demonstration of KCNE5-Kv4.3 physical interaction","Native myocyte validation of variant effects on Ito not performed"]},{"year":2018,"claim":"Provided in vivo and trafficking-level mechanism by showing Kcne5 deletion augments multiple ventricular KV currents and that KCNE5 controls KV2.1 surface expression via intracellular sequestration, with the L65F mutant altering KV2.1 gating and amplitude.","evidence":"Kcne5 knockout mouse with intracardiac ECG and myocyte patch-clamp; co-immunofluorescence of KCNE5 and KV2.1; heterologous expression of human mutants","pmids":["30289750"],"confidence":"High","gaps":["Molecular machinery of KCNE5-mediated KV2.1 retention not defined","Mouse-to-human extrapolation of KV current repertoire uncertain","Whether intracellular co-localization reflects direct binding versus shared trafficking unresolved"]},{"year":2012,"claim":"Reported KCNE5 protein expression outside the heart, localizing it to first-trimester placental syncytiotrophoblast, raising the possibility of a non-cardiac role.","evidence":"Immunohistochemistry and qRT-PCR on first-trimester human placental tissue","pmids":["26105295"],"confidence":"Low","gaps":["Single localization study with no functional consequence established","No mechanistic follow-up or channel partner identified in placenta"]},{"year":null,"claim":"The structural basis of KCNE5 selectivity across its alpha-subunit partners and the trafficking machinery it engages to sequester KV2.1 remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of KCNE5 bound to any alpha-subunit","Mechanism of KV2.1 intracellular retention unknown","Non-cardiac (e.g. placental) function uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["KCNQ1","KCNE1","KCND3","KCNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UJ90","full_name":"Potassium voltage-gated channel subfamily E regulatory beta subunit 5","aliases":["AMME syndrome candidate gene 2 protein","Potassium channel subunit beta MiRP4","Potassium voltage-gated channel subfamily E member 1-like protein"],"length_aa":142,"mass_kda":15.0,"function":"Potassium channel ancillary subunit that is essential for generation of some native K(+) currents by virtue of formation of heteromeric ion channel complex with voltage-gated potassium (Kv) channel pore-forming alpha subunits. Functions as an inhibitory beta-subunit of the repolarizing cardiac potassium ion channel KCNQ1","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UJ90/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNE5","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/KCNE5","total_profiled":1310},"omim":[{"mim_id":"607554","title":"ATRIAL FIBRILLATION, FAMILIAL, 3; ATFB3","url":"https://www.omim.org/entry/607554"},{"mim_id":"607542","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1","url":"https://www.omim.org/entry/607542"},{"mim_id":"604433","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 3; KCNE3","url":"https://www.omim.org/entry/604433"},{"mim_id":"300328","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED FAMILY, MEMBER 1-LIKE; KCNE1L","url":"https://www.omim.org/entry/300328"},{"mim_id":"300194","title":"AMME COMPLEX","url":"https://www.omim.org/entry/300194"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":16.6},{"tissue":"tongue","ntpm":4.5}],"url":"https://www.proteinatlas.org/search/KCNE5"},"hgnc":{"alias_symbol":[],"prev_symbol":["KCNE1L"]},"alphafold":{"accession":"Q9UJ90","domains":[{"cath_id":"1.20.5","chopping":"54-91","consensus_level":"medium","plddt":81.9232,"start":54,"end":91}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJ90","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJ90-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJ90-F1-predicted_aligned_error_v6.png","plddt_mean":62.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNE5","jax_strain_url":"https://www.jax.org/strain/search?query=KCNE5"},"sequence":{"accession":"Q9UJ90","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJ90.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJ90/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJ90"}},"corpus_meta":[{"pmid":"18313602","id":"PMC_18313602","title":"Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.","date":"2008","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/18313602","citation_count":100,"is_preprint":false},{"pmid":"12324418","id":"PMC_12324418","title":"KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current.","date":"2002","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12324418","citation_count":94,"is_preprint":false},{"pmid":"21493962","id":"PMC_21493962","title":"KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation.","date":"2011","source":"Circulation. Arrhythmia and electrophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/21493962","citation_count":94,"is_preprint":false},{"pmid":"16054468","id":"PMC_16054468","title":"Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation.","date":"2005","source":"The American journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/16054468","citation_count":53,"is_preprint":false},{"pmid":"27484720","id":"PMC_27484720","title":"KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27484720","citation_count":39,"is_preprint":false},{"pmid":"30289750","id":"PMC_30289750","title":"Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30289750","citation_count":25,"is_preprint":false},{"pmid":"21985337","id":"PMC_21985337","title":"KCNE5 polymorphism rs697829 is associated with QT interval and survival in acute coronary syndromes patients.","date":"2011","source":"Journal of cardiovascular electrophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/21985337","citation_count":13,"is_preprint":false},{"pmid":"15193977","id":"PMC_15193977","title":"Does KCNE5 play a role in long QT syndrome?","date":"2004","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15193977","citation_count":10,"is_preprint":false},{"pmid":"30129429","id":"PMC_30129429","title":"Case report of familial sudden cardiac death caused by a DSG2 p.F531C mutation as genetic background when carrying with heterozygous KCNE5 p.D92E/E93X mutation.","date":"2018","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30129429","citation_count":9,"is_preprint":false},{"pmid":"26105295","id":"PMC_26105295","title":"OS081. Novel KCNQ3/KCNE5 isoform protein and mRNA expression in first trimester human placentae.","date":"2012","source":"Pregnancy hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/26105295","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7969,"output_tokens":1661,"usd":0.024411,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8295,"output_tokens":2342,"usd":0.050013,"stage2_stop_reason":"end_turn"},"total_usd":0.074424,"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\": 2002,\n      \"finding\": \"KCNE5 physically interacts with KCNQ1 and shifts the voltage activation curve of the KCNQ1 channel by more than 140 mV in the positive direction (activation threshold +40 mV, midpoint +116 mV), causing slow activation and rapid deactivation. This modulation is specific to KCNQ1: other KCNQ family members and hERG1 were unaffected. Four residues in the transmembrane domain of KCNE5 were identified as critical for controlling voltage-dependent activation of KCNQ1.\",\n      \"method\": \"Heterologous co-expression electrophysiology (patch-clamp), transmembrane domain mutagenesis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro functional reconstitution with mutagenesis identifying specific transmembrane residues, multiple orthogonal measurements (voltage activation curve, kinetics, channel specificity panel)\",\n      \"pmids\": [\"12324418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wild-type KCNE5 suppresses IKs (KCNQ1+KCNE1) current in a concentration-dependent manner. The AF-associated missense mutation KCNE5-L65F abolishes this suppression, yielding currents indistinguishable from KCNE5-absent controls and producing a gain-of-function of IKs.\",\n      \"method\": \"Transient transfection of CHO cells expressing KCNQ1+KCNE1 with wild-type or L65F KCNE5; whole-cell patch-clamp electrophysiology\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional reconstitution with disease-linked mutant and concentration-dependent controls in a single focused study\",\n      \"pmids\": [\"18313602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KCNE5 modulates the transient outward current (Ito) conducted by Kv4.3 (KCND3). Disease-associated variants KCNE5-Y81H and KCNE5-p.[D92E;E93X] significantly increase Ito compared to wild-type KCNE5 when co-expressed with KCND3 (gain-of-function). In contrast, neither variant significantly altered KCNQ1+KCNE5 current properties.\",\n      \"method\": \"Co-transfection of HEK/heterologous cells with KCND3 or KCNQ1 plus wild-type or mutant KCNE5; whole-cell patch-clamp electrophysiology; action potential simulation model\",\n      \"journal\": \"Circulation. Arrhythmia and electrophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional reconstitution with two independent disease mutants, two alpha-subunit partners tested, with simulation validation\",\n      \"pmids\": [\"21493962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mouse ventricular myocytes, Kcne5 deletion increased KV current density by augmenting IKslow,1 (KV1.5) and Ito,f (KV4) in the apex and IKslow,2 (KV2.1) in both apex and septum. KCNE5 colocalized with KV2.1 at intercalated discs in ventricular myocytes, and in HL-1 and HEK cells KCNE5 and KV2.1 co-localized predominantly in intracellular vesicles, suggesting KCNE5 reduces KV2.1 surface expression by promoting its intracellular sequestration. The human AF-associated KCNE5-L65F mutation negatively shifted the voltage dependence of KV2.1-KCNE5 channels and increased maximum current density >2-fold.\",\n      \"method\": \"Kcne5 knockout (Kcne5-/0) mouse model; intracardiac ECG; ventricular myocyte patch-clamp; immunolocalization (co-immunofluorescence of KCNE5 and KV2.1 in native tissue and cell lines); heterologous co-expression of human mutants with KV2.1\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Kcne5 knockout mouse with defined electrophysiological phenotype, subcellular co-localization experiments linking KCNE5 to KV2.1 trafficking, and functional validation with human disease mutants across multiple orthogonal methods\",\n      \"pmids\": [\"30289750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KCNE5 protein is expressed in first-trimester human placenta and localizes mainly to the syncytiotrophoblast, with additional expression in the mesenchyme, as determined by immunohistochemistry.\",\n      \"method\": \"Immunohistochemistry and qRT-PCR on first-trimester placental tissue\",\n      \"journal\": \"Pregnancy hypertension\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization study with no functional consequence established, single lab, no mechanistic follow-up\",\n      \"pmids\": [\"26105295\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNE5 is an ancillary (beta) subunit that modulates multiple voltage-gated potassium channel alpha-subunits: it dramatically right-shifts the voltage activation of KCNQ1 (>140 mV) via specific transmembrane-domain residues, suppresses IKs (KCNQ1/KCNE1) current in a concentration-dependent manner, reduces KV2.1 surface expression by promoting its intracellular sequestration, and modulates Ito through Kv4.3 (KCND3); loss-of-function or gain-of-function mutations in KCNE5 disrupt these regulatory roles and are mechanistically linked to atrial fibrillation and Brugada syndrome through increased ventricular KV currents.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNE5 is an ancillary (beta) subunit that modulates the gating, current amplitude, and trafficking of multiple voltage-gated potassium channel alpha-subunits in cardiac tissue [#0, #3]. Through specific transmembrane-domain residues, KCNE5 physically associates with KCNQ1 and dramatically right-shifts its voltage-dependent activation by more than 140 mV, slowing activation and accelerating deactivation in a manner specific to KCNQ1 among the channels tested [#0]; it also suppresses the KCNQ1/KCNE1 (IKs) current in a concentration-dependent manner [#1]. Beyond KCNQ1, KCNE5 modulates the transient outward current carried by Kv4.3 (KCND3) [#2] and reduces KV2.1 surface expression, co-localizing with KV2.1 at intercalated discs in native myocytes and in intracellular vesicles in cell lines, consistent with promotion of intracellular sequestration; Kcne5 deletion in mouse ventricle increases KV1.5, KV4, and KV2.1 current densities [#3]. Disease-associated variants disrupt these regulatory roles: the atrial-fibrillation-linked KCNE5-L65F abolishes IKs suppression to produce a gain of function [#1] and negatively shifts and amplifies KV2.1 current [#3], while the variants Y81H and p.[D92E;E93X] increase Kv4.3-mediated Ito as a gain of function [#2], mechanistically linking KCNE5 dysfunction to atrial fibrillation and Brugada syndrome.\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that KCNE5 is a channel-modulating subunit by showing it binds KCNQ1 and imposes an extreme positive shift in voltage-dependent activation through defined transmembrane residues, defining its core biophysical mechanism and channel selectivity.\",\n      \"evidence\": \"Heterologous co-expression patch-clamp with transmembrane-domain mutagenesis and a channel specificity panel\",\n      \"pmids\": [\"12324418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the KCNE5-KCNQ1 interface\",\n        \"Physiological significance of a >140 mV shift in native tissue not addressed\",\n        \"Whether KCNE5 modulates channels beyond the KCNQ/hERG panel not tested here\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected KCNE5 function to arrhythmia by demonstrating it suppresses IKs and that the AF-associated L65F mutation abolishes this suppression, providing a gain-of-function mechanism for disease.\",\n      \"evidence\": \"Transient transfection of CHO cells with KCNQ1+KCNE1 plus wild-type or L65F KCNE5; whole-cell patch-clamp\",\n      \"pmids\": [\"18313602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Single focused study without native-tissue confirmation\",\n        \"Mechanism by which L65F loses suppression not resolved at the residue level\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Broadened KCNE5's alpha-subunit repertoire by showing it modulates Kv4.3-mediated Ito and that distinct disease variants (Y81H, D92E;E93X) cause gain-of-function selectively through Kv4.3 rather than KCNQ1.\",\n      \"evidence\": \"Co-transfection of heterologous cells with KCND3 or KCNQ1 plus mutant KCNE5; patch-clamp with action potential simulation\",\n      \"pmids\": [\"21493962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct biochemical demonstration of KCNE5-Kv4.3 physical interaction\",\n        \"Native myocyte validation of variant effects on Ito not performed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided in vivo and trafficking-level mechanism by showing Kcne5 deletion augments multiple ventricular KV currents and that KCNE5 controls KV2.1 surface expression via intracellular sequestration, with the L65F mutant altering KV2.1 gating and amplitude.\",\n      \"evidence\": \"Kcne5 knockout mouse with intracardiac ECG and myocyte patch-clamp; co-immunofluorescence of KCNE5 and KV2.1; heterologous expression of human mutants\",\n      \"pmids\": [\"30289750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular machinery of KCNE5-mediated KV2.1 retention not defined\",\n        \"Mouse-to-human extrapolation of KV current repertoire uncertain\",\n        \"Whether intracellular co-localization reflects direct binding versus shared trafficking unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reported KCNE5 protein expression outside the heart, localizing it to first-trimester placental syncytiotrophoblast, raising the possibility of a non-cardiac role.\",\n      \"evidence\": \"Immunohistochemistry and qRT-PCR on first-trimester human placental tissue\",\n      \"pmids\": [\"26105295\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single localization study with no functional consequence established\",\n        \"No mechanistic follow-up or channel partner identified in placenta\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of KCNE5 selectivity across its alpha-subunit partners and the trafficking machinery it engages to sequester KV2.1 remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of KCNE5 bound to any alpha-subunit\",\n        \"Mechanism of KV2.1 intracellular retention unknown\",\n        \"Non-cardiac (e.g. placental) function uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KCNQ1\", \"KCNE1\", \"KCND3\", \"KCNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}