{"gene":"KCNG1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1996,"finding":"Kv6.1 (KCNG1) cannot form functional homomeric channels but assembles into heteromultimeric channels with Kv2.1 via protein-protein interactions at the amino-terminal portions. Coexpression with Kv2.1 produces a novel current with decreased rates of deactivation, decreased sensitivity to TEA block, and a hyperpolarizing shift of the half-maximal activation potential compared to Kv2.1 alone.","method":"Two-electrode voltage clamp in Xenopus oocytes, yeast two-hybrid protein-protein interaction assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein-protein interaction (yeast two-hybrid) plus functional electrophysiology in Xenopus oocytes; independently confirmed in subsequent studies","pmids":["8980147"],"is_preprint":false},{"year":1998,"finding":"Kv6.1 coassembled with Kv2.1 modulates gating by producing a negative shift in the steady-state activation curve and markedly slowing deactivation tail currents. Unlike Kv5.1, Kv6.1 has a slowing effect on inactivation at strong depolarizations and no effect on cumulative inactivation. Biochemical evidence of Kv5.1/Kv2.1 protein-protein interaction and single-channel measurements of heterogeneity in unitary conductance supported heteromeric assembly.","method":"Two-electrode voltage clamp in Xenopus oocytes, biochemical co-assembly assay, single-channel recordings","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, biochemistry, single-channel), replicated the heteromeric assembly finding from the 1996 paper","pmids":["9696692"],"is_preprint":false},{"year":2021,"finding":"A heterozygous missense variant in KCNG1 (p.Trp416Cys) affecting a conserved residue predicted to alter the pore helix of the ion transport domain was identified in a calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, implicating KCNG1 in neurodegeneration and neuromuscular disease.","method":"Whole-genome sequencing, variant prediction analysis, histopathology","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single genetic variant in a single animal; no functional reconstitution performed to confirm mechanism","pmids":["34828398"],"is_preprint":false},{"year":2025,"finding":"Disease-linked Kv6.1 variants (L284P from a pediatric patient; W416C from a calf) reduce Kv2.1 current when coexpressed, with W416C causing nearly complete suppression. Both variants attenuate Kv6.1-mediated effects on Kv2.1 inactivation. Coexpression with Kv2.1 decreases protein expression levels of both Kv2.1 and Kv6.1, particularly for W416C. Kv2.1 promotes phosphorylation of Kv6.1, but this post-translational modification is largely absent in the W416C mutant.","method":"Electrophysiology (voltage clamp), Western blot protein expression analysis, phosphorylation assay in HEK293 or Xenopus expression system","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, protein expression, phosphorylation assay) in a single study; novel finding of Kv2.1-dependent phosphorylation of Kv6.1","pmids":["41241096"],"is_preprint":false}],"current_model":"KCNG1 (Kv6.1) is an electrically silent voltage-gated potassium channel α-subunit that cannot form functional homomeric channels but co-assembles with Kv2.1 via N-terminal protein-protein interactions to form heteromeric channels with distinct gating properties, including a hyperpolarizing shift in activation, slowed deactivation, and altered inactivation kinetics; additionally, coassembly with Kv2.1 promotes phosphorylation of Kv6.1, and disease-associated variants in the pore helix (W416C) nearly abolish Kv2.1 current and abrogate this phosphorylation."},"narrative":{"mechanistic_narrative":"KCNG1 encodes Kv6.1, an electrically silent voltage-gated potassium channel α-subunit that does not form functional homomeric channels but instead co-assembles with Kv2.1 through protein-protein interactions at the amino-terminal portions of the subunits [PMID:8980147]. Incorporation of Kv6.1 into Kv2.1-containing heteromers confers distinct gating: a hyperpolarizing shift in steady-state activation, markedly slowed deactivation, reduced TEA sensitivity, and altered (slowed) inactivation at strong depolarizations [PMID:8980147, PMID:9696692]. Co-assembly with Kv2.1 also drives phosphorylation of Kv6.1, indicating that the heteromeric partnership controls both gating and post-translational modification of the silent subunit [PMID:41241096]. Disease-associated Kv6.1 variants in the ion transport domain disrupt this regulatory partnership: the pore-helix variant W416C nearly abolishes Kv2.1 current, reduces protein levels of both subunits, and abrogates Kv6.1 phosphorylation, while L284P attenuates Kv6.1-mediated modulation of Kv2.1 inactivation [PMID:41241096]. The W416C variant was identified in a calf with paradoxical myotonia congenita and associated neuromuscular and craniofacial pathology, linking KCNG1 to neuromuscular disease [PMID:34828398].","teleology":[{"year":1996,"claim":"Established that Kv6.1 is not an independent channel but a modulatory subunit, answering whether KCNG1 produces current on its own and how it acts.","evidence":"Two-electrode voltage clamp in Xenopus oocytes plus yeast two-hybrid showing N-terminal interaction with Kv2.1","pmids":["8980147"],"confidence":"High","gaps":["Stoichiometry of Kv6.1:Kv2.1 in native heteromers not defined","Structural basis of the N-terminal interaction not resolved","Physiological tissue context of the heteromer not addressed"]},{"year":1998,"claim":"Resolved how Kv6.1 reshapes Kv2.1 gating, distinguishing its inactivation effects from those of the related Kv5.1 subunit and confirming true heteromeric assembly.","evidence":"Two-electrode voltage clamp, biochemical co-assembly assay, and single-channel recordings in Xenopus oocytes","pmids":["9696692"],"confidence":"High","gaps":["Mechanism by which Kv6.1 slows deactivation/inactivation not defined at the structural level","Native conductance heterogeneity not linked to defined subunit ratios"]},{"year":2021,"claim":"Implicated KCNG1 in neuromuscular disease by associating a pore-helix variant with a myotonia/neurodegeneration phenotype, raising the question of functional consequence.","evidence":"Whole-genome sequencing, variant prediction, and histopathology in a single calf","pmids":["34828398"],"confidence":"Low","gaps":["Single genetic case with no functional reconstitution to confirm causality","Whether the phenotype reflects a Kv2.1/Kv6.1 channel defect untested at this stage"]},{"year":2025,"claim":"Connected disease variants to mechanism by showing they impair Kv2.1 current, subunit expression, and a newly identified Kv2.1-dependent phosphorylation of Kv6.1.","evidence":"Voltage clamp, Western blot expression analysis, and phosphorylation assays in HEK293/Xenopus expression systems","pmids":["41241096"],"confidence":"Medium","gaps":["Phosphorylation site(s) and responsible kinase not identified","Single study; functional consequences in native tissue not established","Mechanism linking reduced phosphorylation to loss of current unresolved"]},{"year":null,"claim":"How Kv6.1 phosphorylation regulates heteromeric channel trafficking, stability, and gating in native neuromuscular tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Kinase and phosphosite controlling Kv6.1 modification unknown","Endogenous Kv2.1/Kv6.1 channel function in affected tissues uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3]}],"localization":[],"pathway":[],"complexes":["Kv2.1/Kv6.1 heteromeric voltage-gated potassium channel"],"partners":["KCNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIX4","full_name":"Voltage-gated potassium channel regulatory subunit KCNG1","aliases":["Potassium voltage-gated channel subfamily G member 1","Voltage-gated potassium channel subunit Kv6.1","kH2"],"length_aa":513,"mass_kda":57.9,"function":"Regulatory alpha-subunit of the voltage-gated potassium (Kv) channel which, when coassembled with KCNB1 or KCNB2, can modulate their expression and their gating kinetics by acting on deactivation upon repolarization and inactivation during maintained depolarization (PubMed:19074135). Potassium channel subunit that does not form functional channels by itself (PubMed:19074135)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UIX4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNG1","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNG1","total_profiled":1310},"omim":[{"mim_id":"607603","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY G, MEMBER 4; KCNG4","url":"https://www.omim.org/entry/607603"},{"mim_id":"605696","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY G, MEMBER 2; KCNG2","url":"https://www.omim.org/entry/605696"},{"mim_id":"603788","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY G, MEMBER 1; KCNG1","url":"https://www.omim.org/entry/603788"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":49.5},{"tissue":"endometrium 1","ntpm":80.2}],"url":"https://www.proteinatlas.org/search/KCNG1"},"hgnc":{"alias_symbol":["Kv6.1","kH2","K13"],"prev_symbol":["KCNG"]},"alphafold":{"accession":"Q9UIX4","domains":[{"cath_id":"3.30.710.10","chopping":"39-179","consensus_level":"high","plddt":84.3762,"start":39,"end":179},{"cath_id":"1.20.120.350","chopping":"219-324_333-359","consensus_level":"medium","plddt":83.7716,"start":219,"end":359},{"cath_id":"1.10.287.70","chopping":"363-489","consensus_level":"high","plddt":89.9793,"start":363,"end":489}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIX4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIX4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIX4-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNG1","jax_strain_url":"https://www.jax.org/strain/search?query=KCNG1"},"sequence":{"accession":"Q9UIX4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIX4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIX4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIX4"}},"corpus_meta":[{"pmid":"15805463","id":"PMC_15805463","title":"Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes.","date":"2005","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15805463","citation_count":212,"is_preprint":false},{"pmid":"9696692","id":"PMC_9696692","title":"Modulation of potassium channel gating by coexpression of Kv2.1 with regulatory Kv5.1 or Kv6.1 alpha-subunits.","date":"1998","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9696692","citation_count":94,"is_preprint":false},{"pmid":"8980147","id":"PMC_8980147","title":"Kv2.1 and electrically silent Kv6.1 potassium channel subunits combine and express a novel current.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8980147","citation_count":90,"is_preprint":false},{"pmid":"17164330","id":"PMC_17164330","title":"Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17164330","citation_count":80,"is_preprint":false},{"pmid":"17850748","id":"PMC_17850748","title":"Fragile X mental retardation syndrome: structure of the KH1-KH2 domains of fragile X mental retardation protein.","date":"2007","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/17850748","citation_count":57,"is_preprint":false},{"pmid":"20417602","id":"PMC_20417602","title":"A functional requirement for PAK1 binding to the KH(2) domain of the fragile X protein-related FXR1.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20417602","citation_count":46,"is_preprint":false},{"pmid":"35181083","id":"PMC_35181083","title":"Immune-enhancing effects of postbiotic produced by Bacillus velezensis Kh2-2 isolated from Korea Foods.","date":"2021","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/35181083","citation_count":30,"is_preprint":false},{"pmid":"30864660","id":"PMC_30864660","title":"IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30864660","citation_count":23,"is_preprint":false},{"pmid":"23527791","id":"PMC_23527791","title":"Molecular dynamics simulations show how the FMRP Ile304Asn mutation destabilizes the KH2 domain structure and affects its function.","date":"2013","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/23527791","citation_count":21,"is_preprint":false},{"pmid":"34828398","id":"PMC_34828398","title":"KCNG1-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34828398","citation_count":16,"is_preprint":false},{"pmid":"12469313","id":"PMC_12469313","title":"Purification and characterization of a novel chitinase from Burkholderia cepacia strain KH2 isolated from the bed log of Lentinus edodes, Shiitake mushroom.","date":"2002","source":"The Journal of general and applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12469313","citation_count":15,"is_preprint":false},{"pmid":"33520568","id":"PMC_33520568","title":"Anti-Influenza virus effects of Enterococcus faecalis KH2 and Lactobacillus plantarum SNK12 RNA.","date":"2020","source":"Bioscience of microbiota, food and health","url":"https://pubmed.ncbi.nlm.nih.gov/33520568","citation_count":14,"is_preprint":false},{"pmid":"2793241","id":"PMC_2793241","title":"Suppression of c-myc mRNA expression by steroid hormones in HTLV-I-infected T-cell line, KH-2.","date":"1989","source":"International journal of 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KH2 and the involvement of Dectin-2.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40574842","citation_count":4,"is_preprint":false},{"pmid":"41241096","id":"PMC_41241096","title":"Regulation of Kv2.1 biogenesis and gating by candidate disease-linked Kv6.1 variants.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41241096","citation_count":0,"is_preprint":false},{"pmid":"41391765","id":"PMC_41391765","title":"The RNA-binding protein hnRNP E1 regulates p53 and p21 translation via KH1 and KH2 domain interactions with 3' UTR C-rich motifs.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41391765","citation_count":0,"is_preprint":false},{"pmid":"41407225","id":"PMC_41407225","title":"Engineering of Bacillus subtilis KH2 for effective production of poly-γ-glutamic acid from glutamate waste based on 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channels","date":"2024-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.08.602400","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12703,"output_tokens":1264,"usd":0.028535,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7828,"output_tokens":1886,"usd":0.043145,"stage2_stop_reason":"end_turn"},"total_usd":0.07168,"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\": 1996,\n      \"finding\": \"Kv6.1 (KCNG1) cannot form functional homomeric channels but assembles into heteromultimeric channels with Kv2.1 via protein-protein interactions at the amino-terminal portions. Coexpression with Kv2.1 produces a novel current with decreased rates of deactivation, decreased sensitivity to TEA block, and a hyperpolarizing shift of the half-maximal activation potential compared to Kv2.1 alone.\",\n      \"method\": \"Two-electrode voltage clamp in Xenopus oocytes, yeast two-hybrid protein-protein interaction assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein-protein interaction (yeast two-hybrid) plus functional electrophysiology in Xenopus oocytes; independently confirmed in subsequent studies\",\n      \"pmids\": [\"8980147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Kv6.1 coassembled with Kv2.1 modulates gating by producing a negative shift in the steady-state activation curve and markedly slowing deactivation tail currents. Unlike Kv5.1, Kv6.1 has a slowing effect on inactivation at strong depolarizations and no effect on cumulative inactivation. Biochemical evidence of Kv5.1/Kv2.1 protein-protein interaction and single-channel measurements of heterogeneity in unitary conductance supported heteromeric assembly.\",\n      \"method\": \"Two-electrode voltage clamp in Xenopus oocytes, biochemical co-assembly assay, single-channel recordings\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, biochemistry, single-channel), replicated the heteromeric assembly finding from the 1996 paper\",\n      \"pmids\": [\"9696692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A heterozygous missense variant in KCNG1 (p.Trp416Cys) affecting a conserved residue predicted to alter the pore helix of the ion transport domain was identified in a calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, implicating KCNG1 in neurodegeneration and neuromuscular disease.\",\n      \"method\": \"Whole-genome sequencing, variant prediction analysis, histopathology\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single genetic variant in a single animal; no functional reconstitution performed to confirm mechanism\",\n      \"pmids\": [\"34828398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Disease-linked Kv6.1 variants (L284P from a pediatric patient; W416C from a calf) reduce Kv2.1 current when coexpressed, with W416C causing nearly complete suppression. Both variants attenuate Kv6.1-mediated effects on Kv2.1 inactivation. Coexpression with Kv2.1 decreases protein expression levels of both Kv2.1 and Kv6.1, particularly for W416C. Kv2.1 promotes phosphorylation of Kv6.1, but this post-translational modification is largely absent in the W416C mutant.\",\n      \"method\": \"Electrophysiology (voltage clamp), Western blot protein expression analysis, phosphorylation assay in HEK293 or Xenopus expression system\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, protein expression, phosphorylation assay) in a single study; novel finding of Kv2.1-dependent phosphorylation of Kv6.1\",\n      \"pmids\": [\"41241096\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNG1 (Kv6.1) is an electrically silent voltage-gated potassium channel α-subunit that cannot form functional homomeric channels but co-assembles with Kv2.1 via N-terminal protein-protein interactions to form heteromeric channels with distinct gating properties, including a hyperpolarizing shift in activation, slowed deactivation, and altered inactivation kinetics; additionally, coassembly with Kv2.1 promotes phosphorylation of Kv6.1, and disease-associated variants in the pore helix (W416C) nearly abolish Kv2.1 current and abrogate this phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNG1 encodes Kv6.1, an electrically silent voltage-gated potassium channel \\u03b1-subunit that does not form functional homomeric channels but instead co-assembles with Kv2.1 through protein-protein interactions at the amino-terminal portions of the subunits [#0]. Incorporation of Kv6.1 into Kv2.1-containing heteromers confers distinct gating: a hyperpolarizing shift in steady-state activation, markedly slowed deactivation, reduced TEA sensitivity, and altered (slowed) inactivation at strong depolarizations [#0, #1]. Co-assembly with Kv2.1 also drives phosphorylation of Kv6.1, indicating that the heteromeric partnership controls both gating and post-translational modification of the silent subunit [#3]. Disease-associated Kv6.1 variants in the ion transport domain disrupt this regulatory partnership: the pore-helix variant W416C nearly abolishes Kv2.1 current, reduces protein levels of both subunits, and abrogates Kv6.1 phosphorylation, while L284P attenuates Kv6.1-mediated modulation of Kv2.1 inactivation [#3]. The W416C variant was identified in a calf with paradoxical myotonia congenita and associated neuromuscular and craniofacial pathology, linking KCNG1 to neuromuscular disease [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that Kv6.1 is not an independent channel but a modulatory subunit, answering whether KCNG1 produces current on its own and how it acts.\",\n      \"evidence\": \"Two-electrode voltage clamp in Xenopus oocytes plus yeast two-hybrid showing N-terminal interaction with Kv2.1\",\n      \"pmids\": [\n        \"8980147\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry of Kv6.1:Kv2.1 in native heteromers not defined\",\n        \"Structural basis of the N-terminal interaction not resolved\",\n        \"Physiological tissue context of the heteromer not addressed\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved how Kv6.1 reshapes Kv2.1 gating, distinguishing its inactivation effects from those of the related Kv5.1 subunit and confirming true heteromeric assembly.\",\n      \"evidence\": \"Two-electrode voltage clamp, biochemical co-assembly assay, and single-channel recordings in Xenopus oocytes\",\n      \"pmids\": [\n        \"9696692\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which Kv6.1 slows deactivation/inactivation not defined at the structural level\",\n        \"Native conductance heterogeneity not linked to defined subunit ratios\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated KCNG1 in neuromuscular disease by associating a pore-helix variant with a myotonia/neurodegeneration phenotype, raising the question of functional consequence.\",\n      \"evidence\": \"Whole-genome sequencing, variant prediction, and histopathology in a single calf\",\n      \"pmids\": [\n        \"34828398\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single genetic case with no functional reconstitution to confirm causality\",\n        \"Whether the phenotype reflects a Kv2.1/Kv6.1 channel defect untested at this stage\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected disease variants to mechanism by showing they impair Kv2.1 current, subunit expression, and a newly identified Kv2.1-dependent phosphorylation of Kv6.1.\",\n      \"evidence\": \"Voltage clamp, Western blot expression analysis, and phosphorylation assays in HEK293/Xenopus expression systems\",\n      \"pmids\": [\n        \"41241096\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phosphorylation site(s) and responsible kinase not identified\",\n        \"Single study; functional consequences in native tissue not established\",\n        \"Mechanism linking reduced phosphorylation to loss of current unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Kv6.1 phosphorylation regulates heteromeric channel trafficking, stability, and gating in native neuromuscular tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Kinase and phosphosite controlling Kv6.1 modification unknown\",\n        \"Endogenous Kv2.1/Kv6.1 channel function in affected tissues uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005215\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      },\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          3\n        ]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [\n      \"Kv2.1/Kv6.1 heteromeric voltage-gated potassium channel\"\n    ],\n    \"partners\": [\n      \"KCNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}