{"gene":"CHRNB2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2000,"finding":"The CHRNB2 V287M missense mutation within the M2 transmembrane domain causes an approximately 10-fold increase in acetylcholine sensitivity of the nicotinic acetylcholine receptor, as demonstrated by functional expression in Xenopus oocytes.","method":"Xenopus oocyte expression system, electrophysiological functional assay of mutant receptor","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro functional reconstitution in Xenopus oocytes with quantified gain-of-function, replicated in subsequent clinical reports describing the same mutation","pmids":["11104662"],"is_preprint":false},{"year":2005,"finding":"The CHRNB2 I312M mutation in transmembrane region M3 markedly increases receptor sensitivity to acetylcholine, establishing gain-of-function as the mechanism underlying ADNFLE and associated memory deficits.","method":"Functional electrophysiological characterization of mutant receptor (implied from prior Xenopus oocyte framework cited in abstract context); mutation identified in patient/twin cohort","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of mutant receptor with defined gain-of-function phenotype; replicated in independent family (PMID:18534914)","pmids":["15964197","18534914"],"is_preprint":false},{"year":2020,"finding":"The CHRNB2 Thr26Met variant leads to significantly higher whole-cell nicotinic currents when expressed as α4β2 receptors in human cell lines, in both homo- and heterozygous conditions, without major changes in current reversal potential or the shape of the concentration-response relation.","method":"Functional expression of mutant α4β2 receptors in human cell lines; whole-cell current recording","journal":"The Canadian journal of neurological sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro electrophysiological assay in human cell lines, single study, single lab","pmids":["32536355"],"is_preprint":false},{"year":2021,"finding":"CHRNB2 knockdown attenuates gastric cancer cell proliferation, while forced overexpression increases proliferation; CHRNB2 knockout significantly affects cell survival and metastasis-associated functions. Pathway analysis revealed that CHRNB2 interferes with PI3K-AKT and JAK-STAT signaling.","method":"Gene knockout (genome editing), RNA interference knockdown, ectopic overexpression in gastric cancer cell lines; in vitro proliferation assays; mouse xenograft in vivo model; pathway analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal loss- and gain-of-function approaches (KO, KD, OE) with defined cellular phenotypes in vitro and in vivo, single lab","pmids":["34331011"],"is_preprint":false},{"year":2022,"finding":"CHRNB2 inhibits migration and invasion of pancreatic cancer cells via an acetylcholine-independent mechanism by downregulating the β-catenin pathway, with upstream regulators including SOX6, SRY, SOX17, and TCF7L2; CHRNB2 also suppresses EMT.","method":"siRNA knockdown and ectopic overexpression in pancreatic cancer cell lines; Transwell migration/invasion assays; Western blot for β-catenin pathway components and EMT markers","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined molecular pathway readout (Western blot), two orthogonal methods, single lab","pmids":["36344976"],"is_preprint":false},{"year":1998,"finding":"The CHRNB2 gene is localized to chromosome 1 and its genomic structure (intron-exon organization) was determined, providing the framework for mutational analyses of this nicotinic receptor subunit gene.","method":"Genomic sequencing and chromosomal mapping","journal":"Human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — structural genomic characterization without direct functional experiment on the protein","pmids":["9921897"],"is_preprint":false}],"current_model":"CHRNB2 encodes the β2 subunit of the α4β2 neuronal nicotinic acetylcholine receptor (nAChR); gain-of-function mutations in its transmembrane domains (e.g., V287M in M2, I312M in M3, Thr26Met) increase receptor sensitivity to acetylcholine and underlie autosomal dominant nocturnal frontal lobe epilepsy, while in cancer contexts CHRNB2 suppresses cell proliferation, migration, and invasion through PI3K-AKT/JAK-STAT (gastric cancer) and β-catenin/EMT (pancreatic cancer) pathways via acetylcholine-independent mechanisms."},"narrative":{"mechanistic_narrative":"CHRNB2 encodes the β2 subunit of the neuronal nicotinic acetylcholine receptor, where it assembles into α4β2 receptors that conduct acetylcholine-gated whole-cell currents [PMID:32536355]. Multiple missense mutations clustered in the transmembrane domains act through a common gain-of-function mechanism: V287M in M2 and I312M in M3 each markedly increase receptor sensitivity to acetylcholine, and the Thr26Met variant elevates whole-cell α4β2 currents without altering reversal potential or the concentration–response relationship [PMID:11104662, PMID:15964197, PMID:18534914, PMID:32536355]. These gain-of-function changes underlie autosomal dominant nocturnal frontal lobe epilepsy and associated memory deficits [PMID:11104662, PMID:15964197, PMID:18534914]. Independently of its receptor role in neurons, CHRNB2 functions in cancer cells through acetylcholine-independent mechanisms: in gastric cancer it promotes proliferation, survival, and metastasis-associated functions and interfaces with PI3K-AKT and JAK-STAT signaling [PMID:34331011], while in pancreatic cancer it suppresses migration, invasion, and EMT by downregulating the β-catenin pathway, with upstream regulators including SOX6, SRY, SOX17, and TCF7L2 [PMID:36344976].","teleology":[{"year":1998,"claim":"Establishing the genomic organization and chromosomal location of CHRNB2 was the prerequisite for systematic mutational analysis of this receptor subunit gene.","evidence":"Genomic sequencing and chromosomal mapping to chromosome 1","pmids":["9921897"],"confidence":"Low","gaps":["No functional experiment on the protein","Does not address subunit assembly or physiology"]},{"year":2000,"claim":"It was unknown how a CHRNB2 mutation could cause epilepsy; functional expression showed the M2 V287M mutation increases acetylcholine sensitivity ~10-fold, establishing a gain-of-function mechanism.","evidence":"Xenopus oocyte expression with electrophysiological recording of mutant receptor","pmids":["11104662"],"confidence":"High","gaps":["Single mutation tested in a heterologous system","Does not establish in vivo circuit consequences"]},{"year":2005,"claim":"Whether gain-of-function generalized beyond one residue was open; the M3 I312M mutation also markedly increased acetylcholine sensitivity and linked the receptor change to ADNFLE with memory deficits.","evidence":"Functional characterization of mutant receptor; mutation identified in patient/twin cohort, replicated in an independent family","pmids":["15964197","18534914"],"confidence":"Medium","gaps":["Functional assay details inferred from prior framework","Mechanism linking receptor hyperactivity to memory phenotype not defined"]},{"year":2020,"claim":"It was unclear whether an N-terminal variant outside the channel-lining helices alters function; Thr26Met raised whole-cell α4β2 currents without changing reversal potential or response shape, extending gain-of-function to a non-transmembrane variant.","evidence":"Functional expression of mutant α4β2 receptors in human cell lines with whole-cell current recording","pmids":["32536355"],"confidence":"Medium","gaps":["Single study, single lab","Biophysical basis of increased current not resolved"]},{"year":2021,"claim":"Beyond neuronal signaling, a role in cancer was untested; loss- and gain-of-function in gastric cancer showed CHRNB2 modulates proliferation, survival, and metastasis-associated functions and interfaces with PI3K-AKT and JAK-STAT signaling.","evidence":"CRISPR knockout, RNAi knockdown, overexpression in gastric cancer lines; in vitro assays; mouse xenograft; pathway analysis","pmids":["34331011"],"confidence":"Medium","gaps":["Single lab","Direct molecular link between CHRNB2 and PI3K-AKT/JAK-STAT not mechanistically defined"]},{"year":2022,"claim":"Whether CHRNB2's cancer role depends on its ligand-gated channel activity was open; in pancreatic cancer it suppressed migration, invasion, and EMT via acetylcholine-independent β-catenin downregulation with defined upstream regulators.","evidence":"siRNA knockdown and overexpression in pancreatic cancer lines; Transwell assays; Western blot for β-catenin and EMT markers","pmids":["36344976"],"confidence":"Medium","gaps":["Acetylcholine-independent mechanism not structurally explained","Apparently opposite directionality versus gastric cancer not reconciled"]},{"year":null,"claim":"How a neuronal acetylcholine receptor subunit exerts ligand-independent, tissue-specific effects on cancer signaling pathways remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or biochemical basis for acetylcholine-independent activity","Opposite proliferative effects across cancer types not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]}],"complexes":["α4β2 nicotinic acetylcholine receptor"],"partners":["CHRNA4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17787","full_name":"Neuronal acetylcholine receptor subunit beta-2","aliases":[],"length_aa":502,"mass_kda":57.0,"function":"Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection of nAChR subunits known to mediate synaptic transmission in the nervous system and the neuromuscular junction. Each nAchR subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, cation permeability, and binding to allosteric modulators (PubMed:22361591, PubMed:27698419, PubMed:29720657, PubMed:38454578). CHRNB2 forms heteropentameric neuronal acetylcholine receptors with CHRNA2, CHRNA3, CHRNA4 and CHRNA6, as well as CHRNA5 and CHRNB3 as accesory subunits (PubMed:16835356, PubMed:20881005, PubMed:22361591, PubMed:27698419, PubMed:29720657, PubMed:38454578, PubMed:8663494). Found in two major stoichiometric forms,(CHRNA4)3:(CHRNB2)2 and (CHRNA4)2:(CHRNB2)3, the two stoichiometric forms differ in their unitary conductance, calcium permeability, ACh sensitivity and potentiation by divalent cation (PubMed:27698419, PubMed:29720657, PubMed:38454578). Heteropentameric channels with CHRNA6 and CHRNA4 exhibit high sensitivity to ACh and nicotine and are predominantly expressed in only a few brain areas, including dopaminergic neurons, norepirephrine neurons and cells of the visual system. nAChrs containing CHRNA6 subunits mediate endogenous cholinergic modulation of dopamine and gamma-aminobutyric acid (GABA) release in response to nicotine at nerve terminals (By similarity). Also forms functional nAChRs with other subunits such as CHRNA7:CHRNB2, mainly expressed in basal forebrain cholinergic neurons (PubMed:33239400, PubMed:38161283)","subcellular_location":"Synaptic cell membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P17787/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHRNB2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHRNB2","total_profiled":1310},"omim":[{"mim_id":"615005","title":"EPILEPSY, NOCTURNAL FRONTAL LOBE, 5; ENFL5","url":"https://www.omim.org/entry/615005"},{"mim_id":"606888","title":"CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 6; CHRNA6","url":"https://www.omim.org/entry/606888"},{"mim_id":"605375","title":"EPILEPSY, NOCTURNAL FRONTAL LOBE, 3; ENFL3","url":"https://www.omim.org/entry/605375"},{"mim_id":"603204","title":"EPILEPSY, NOCTURNAL FRONTAL LOBE, 2; ENFL2","url":"https://www.omim.org/entry/603204"},{"mim_id":"600513","title":"EPILEPSY, NOCTURNAL FRONTAL LOBE, 1; ENFL1","url":"https://www.omim.org/entry/600513"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":13.7},{"tissue":"pituitary gland","ntpm":3.4},{"tissue":"retina","ntpm":7.7}],"url":"https://www.proteinatlas.org/search/CHRNB2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P17787","domains":[{"cath_id":"2.70.170.10","chopping":"28-232","consensus_level":"high","plddt":91.7989,"start":28,"end":232},{"cath_id":"1.20.58.390","chopping":"234-350_431-482","consensus_level":"medium","plddt":88.0901,"start":234,"end":482}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17787","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17787-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17787-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHRNB2","jax_strain_url":"https://www.jax.org/strain/search?query=CHRNB2"},"sequence":{"accession":"P17787","fasta_url":"https://rest.uniprot.org/uniprotkb/P17787.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17787/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17787"}},"corpus_meta":[{"pmid":"11104662","id":"PMC_11104662","title":"CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy.","date":"2000","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11104662","citation_count":233,"is_preprint":false},{"pmid":"17226798","id":"PMC_17226798","title":"Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine.","date":"2007","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17226798","citation_count":96,"is_preprint":false},{"pmid":"15964197","id":"PMC_15964197","title":"The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits.","date":"2005","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/15964197","citation_count":76,"is_preprint":false},{"pmid":"11054772","id":"PMC_11054772","title":"Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor beta2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence.","date":"2000","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11054772","citation_count":65,"is_preprint":false},{"pmid":"18534558","id":"PMC_18534558","title":"Gene-gene interactions among CHRNA4, CHRNB2, BDNF, and NTRK2 in nicotine 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gene and short-term ability to quit smoking in response to nicotine patch.","date":"2009","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19755656","citation_count":34,"is_preprint":false},{"pmid":"17900292","id":"PMC_17900292","title":"Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene.","date":"2007","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/17900292","citation_count":32,"is_preprint":false},{"pmid":"9921897","id":"PMC_9921897","title":"The structures of the human neuronal nicotinic acetylcholine receptor beta2- and alpha3-subunit genes (CHRNB2 and CHRNA3).","date":"1998","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9921897","citation_count":28,"is_preprint":false},{"pmid":"26475232","id":"PMC_26475232","title":"Generalized epilepsy in a family 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inhibiting β-catenin pathway.","date":"2022","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/36344976","citation_count":14,"is_preprint":false},{"pmid":"37308787","id":"PMC_37308787","title":"Rare coding variants in CHRNB2 reduce the likelihood of smoking.","date":"2023","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37308787","citation_count":12,"is_preprint":false},{"pmid":"32536355","id":"PMC_32536355","title":"Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy.","date":"2020","source":"The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques","url":"https://pubmed.ncbi.nlm.nih.gov/32536355","citation_count":11,"is_preprint":false},{"pmid":"11952766","id":"PMC_11952766","title":"Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy.","date":"2002","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/11952766","citation_count":11,"is_preprint":false},{"pmid":"23037950","id":"PMC_23037950","title":"Possible association of nicotinic acetylcholine receptor gene (CHRNA4 and CHRNB2) polymorphisms with nicotine dependence in Japanese males: an exploratory study.","date":"2012","source":"Pharmacopsychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23037950","citation_count":11,"is_preprint":false},{"pmid":"18762859","id":"PMC_18762859","title":"Genetic association analysis of tagging SNPs in alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (CHRNA4 and CHRNB2) with schizophrenia in the Japanese population.","date":"2008","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/18762859","citation_count":10,"is_preprint":false},{"pmid":"26309560","id":"PMC_26309560","title":"Mutational analysis of CHRNB2, CHRNA2 and CHRNA4 genes in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26309560","citation_count":9,"is_preprint":false},{"pmid":"10549797","id":"PMC_10549797","title":"Mutation screening of the CHRNA4 and CHRNB2 nicotinic cholinergic receptor genes in Alzheimer's disease.","date":"1999","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/10549797","citation_count":8,"is_preprint":false},{"pmid":"22897520","id":"PMC_22897520","title":"Hippocampal sclerosis worsens autosomal 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CHRNB2 gene polymorphisms in nicotine dependence and related depressive phenotype.","date":"2015","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25640319","citation_count":4,"is_preprint":false},{"pmid":"39193833","id":"PMC_39193833","title":"Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.","date":"2024","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39193833","citation_count":3,"is_preprint":false},{"pmid":"37706497","id":"PMC_37706497","title":"Two novel variants of the STXBP1 and CHRNB2 genes identified in a Chinese boy with refractory seizures and developmental delay.","date":"2023","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37706497","citation_count":2,"is_preprint":false},{"pmid":"21287502","id":"PMC_21287502","title":"[Mutational analysis of CHRNB2 and CHRNA2 genes in southern Chinese population with autosomal dominant nocturnal frontal lobe epilepsy].","date":"2011","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21287502","citation_count":2,"is_preprint":false},{"pmid":"37033539","id":"PMC_37033539","title":"Familial Epilepsy Associated With Concurrent CHRNB2 Mutation and RBFOX1 Exon Deletion: A Case Report.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/37033539","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.19.25322532","title":"Dissecting the genetic etiology of intestinal obstruction: mendelian randomization identifies potential therapeutic 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functional assay of mutant receptor\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro functional reconstitution in Xenopus oocytes with quantified gain-of-function, replicated in subsequent clinical reports describing the same mutation\",\n      \"pmids\": [\"11104662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The CHRNB2 I312M mutation in transmembrane region M3 markedly increases receptor sensitivity to acetylcholine, establishing gain-of-function as the mechanism underlying ADNFLE and associated memory deficits.\",\n      \"method\": \"Functional electrophysiological characterization of mutant receptor (implied from prior Xenopus oocyte framework cited in abstract context); mutation identified in patient/twin cohort\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of mutant receptor with defined gain-of-function phenotype; replicated in independent family (PMID:18534914)\",\n      \"pmids\": [\"15964197\", \"18534914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CHRNB2 Thr26Met variant leads to significantly higher whole-cell nicotinic currents when expressed as α4β2 receptors in human cell lines, in both homo- and heterozygous conditions, without major changes in current reversal potential or the shape of the concentration-response relation.\",\n      \"method\": \"Functional expression of mutant α4β2 receptors in human cell lines; whole-cell current recording\",\n      \"journal\": \"The Canadian journal of neurological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro electrophysiological assay in human cell lines, single study, single lab\",\n      \"pmids\": [\"32536355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHRNB2 knockdown attenuates gastric cancer cell proliferation, while forced overexpression increases proliferation; CHRNB2 knockout significantly affects cell survival and metastasis-associated functions. Pathway analysis revealed that CHRNB2 interferes with PI3K-AKT and JAK-STAT signaling.\",\n      \"method\": \"Gene knockout (genome editing), RNA interference knockdown, ectopic overexpression in gastric cancer cell lines; in vitro proliferation assays; mouse xenograft in vivo model; pathway analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal loss- and gain-of-function approaches (KO, KD, OE) with defined cellular phenotypes in vitro and in vivo, single lab\",\n      \"pmids\": [\"34331011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHRNB2 inhibits migration and invasion of pancreatic cancer cells via an acetylcholine-independent mechanism by downregulating the β-catenin pathway, with upstream regulators including SOX6, SRY, SOX17, and TCF7L2; CHRNB2 also suppresses EMT.\",\n      \"method\": \"siRNA knockdown and ectopic overexpression in pancreatic cancer cell lines; Transwell migration/invasion assays; Western blot for β-catenin pathway components and EMT markers\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined molecular pathway readout (Western blot), two orthogonal methods, single lab\",\n      \"pmids\": [\"36344976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The CHRNB2 gene is localized to chromosome 1 and its genomic structure (intron-exon organization) was determined, providing the framework for mutational analyses of this nicotinic receptor subunit gene.\",\n      \"method\": \"Genomic sequencing and chromosomal mapping\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — structural genomic characterization without direct functional experiment on the protein\",\n      \"pmids\": [\"9921897\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHRNB2 encodes the β2 subunit of the α4β2 neuronal nicotinic acetylcholine receptor (nAChR); gain-of-function mutations in its transmembrane domains (e.g., V287M in M2, I312M in M3, Thr26Met) increase receptor sensitivity to acetylcholine and underlie autosomal dominant nocturnal frontal lobe epilepsy, while in cancer contexts CHRNB2 suppresses cell proliferation, migration, and invasion through PI3K-AKT/JAK-STAT (gastric cancer) and β-catenin/EMT (pancreatic cancer) pathways via acetylcholine-independent mechanisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHRNB2 encodes the β2 subunit of the neuronal nicotinic acetylcholine receptor, where it assembles into α4β2 receptors that conduct acetylcholine-gated whole-cell currents [#2]. Multiple missense mutations clustered in the transmembrane domains act through a common gain-of-function mechanism: V287M in M2 and I312M in M3 each markedly increase receptor sensitivity to acetylcholine, and the Thr26Met variant elevates whole-cell α4β2 currents without altering reversal potential or the concentration–response relationship [#0, #1, #2]. These gain-of-function changes underlie autosomal dominant nocturnal frontal lobe epilepsy and associated memory deficits [#0, #1]. Independently of its receptor role in neurons, CHRNB2 functions in cancer cells through acetylcholine-independent mechanisms: in gastric cancer it promotes proliferation, survival, and metastasis-associated functions and interfaces with PI3K-AKT and JAK-STAT signaling [#3], while in pancreatic cancer it suppresses migration, invasion, and EMT by downregulating the β-catenin pathway, with upstream regulators including SOX6, SRY, SOX17, and TCF7L2 [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the genomic organization and chromosomal location of CHRNB2 was the prerequisite for systematic mutational analysis of this receptor subunit gene.\",\n      \"evidence\": \"Genomic sequencing and chromosomal mapping to chromosome 1\",\n      \"pmids\": [\"9921897\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional experiment on the protein\", \"Does not address subunit assembly or physiology\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"It was unknown how a CHRNB2 mutation could cause epilepsy; functional expression showed the M2 V287M mutation increases acetylcholine sensitivity ~10-fold, establishing a gain-of-function mechanism.\",\n      \"evidence\": \"Xenopus oocyte expression with electrophysiological recording of mutant receptor\",\n      \"pmids\": [\"11104662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single mutation tested in a heterologous system\", \"Does not establish in vivo circuit consequences\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Whether gain-of-function generalized beyond one residue was open; the M3 I312M mutation also markedly increased acetylcholine sensitivity and linked the receptor change to ADNFLE with memory deficits.\",\n      \"evidence\": \"Functional characterization of mutant receptor; mutation identified in patient/twin cohort, replicated in an independent family\",\n      \"pmids\": [\"15964197\", \"18534914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional assay details inferred from prior framework\", \"Mechanism linking receptor hyperactivity to memory phenotype not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"It was unclear whether an N-terminal variant outside the channel-lining helices alters function; Thr26Met raised whole-cell α4β2 currents without changing reversal potential or response shape, extending gain-of-function to a non-transmembrane variant.\",\n      \"evidence\": \"Functional expression of mutant α4β2 receptors in human cell lines with whole-cell current recording\",\n      \"pmids\": [\"32536355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single lab\", \"Biophysical basis of increased current not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Beyond neuronal signaling, a role in cancer was untested; loss- and gain-of-function in gastric cancer showed CHRNB2 modulates proliferation, survival, and metastasis-associated functions and interfaces with PI3K-AKT and JAK-STAT signaling.\",\n      \"evidence\": \"CRISPR knockout, RNAi knockdown, overexpression in gastric cancer lines; in vitro assays; mouse xenograft; pathway analysis\",\n      \"pmids\": [\"34331011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct molecular link between CHRNB2 and PI3K-AKT/JAK-STAT not mechanistically defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether CHRNB2's cancer role depends on its ligand-gated channel activity was open; in pancreatic cancer it suppressed migration, invasion, and EMT via acetylcholine-independent β-catenin downregulation with defined upstream regulators.\",\n      \"evidence\": \"siRNA knockdown and overexpression in pancreatic cancer lines; Transwell assays; Western blot for β-catenin and EMT markers\",\n      \"pmids\": [\"36344976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylcholine-independent mechanism not structurally explained\", \"Apparently opposite directionality versus gastric cancer not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a neuronal acetylcholine receptor subunit exerts ligand-independent, tissue-specific effects on cancer signaling pathways remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or biochemical basis for acetylcholine-independent activity\", \"Opposite proliferative effects across cancer types not mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0022824\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\"α4β2 nicotinic acetylcholine receptor\"],\n    \"partners\": [\"CHRNA4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}