{"gene":"CHRNB2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2000,"finding":"The CHRNB2 V287M mutation in the M2 (second transmembrane) domain of the β2 nicotinic acetylcholine receptor subunit causes an approximately 10-fold increase in acetylcholine sensitivity when expressed in Xenopus oocytes, establishing gain-of-function of the receptor as the mechanism underlying ADNFLE.","method":"Functional expression in Xenopus oocytes with electrophysiological characterization of mutant vs. wild-type receptor","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro functional assay (Xenopus oocyte expression + electrophysiology) with clear quantitative result","pmids":["11104662"],"is_preprint":false},{"year":2005,"finding":"The CHRNB2 I312M mutation in the third transmembrane domain (M3) markedly increases the receptor's sensitivity to acetylcholine, extending the gain-of-function mechanism to a region outside the M2 ADNFLE mutation cluster and associating with both ADNFLE and verbal memory deficits.","method":"Functional characterization of mutant receptor (implied electrophysiology in heterologous expression system) plus clinical neuropsychological testing","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — functional expression assay demonstrating increased ACh sensitivity, single lab","pmids":["15964197"],"is_preprint":false},{"year":2020,"finding":"The CHRNB2 Thr26Met mutation leads to significantly higher whole-cell nicotinic currents in human cell lines when expressed as α4β2 receptors in both homo- and heterozygous conditions, without major alterations in current reversal potential or concentration-response curve shape.","method":"Functional expression in human cell lines with whole-cell patch-clamp electrophysiology","journal":"The Canadian journal of neurological sciences","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro electrophysiology in human cell lines, single lab","pmids":["32536355"],"is_preprint":false},{"year":2021,"finding":"CHRNB2 knockdown attenuates gastric cancer cell proliferation, and its knockout significantly impairs cell survival and functions associated with metastasis; pathway analysis revealed CHRNB2 signals through the PI3K-AKT and JAK-STAT pathways in cancer cells.","method":"CRISPR knockout, RNAi knockdown, ectopic overexpression, in vitro proliferation/invasion assays, mouse xenograft models, pathway analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal loss/gain-of-function approaches with defined cellular phenotypes and in vivo validation, single lab","pmids":["34331011"],"is_preprint":false},{"year":2022,"finding":"CHRNB2 inhibits migration and invasion of pancreatic cancer cells through an acetylcholine-independent mechanism involving downregulation of the β-catenin pathway and its upstream regulators SOX6, SRY, SOX17, and TCF7L2, and suppresses epithelial-mesenchymal transition (EMT).","method":"Transwell migration/invasion assays with CHRNB2 knockdown and overexpression, Western blot for β-catenin pathway components and EMT markers","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation (KD and OE) with defined pathway readouts, single lab","pmids":["36344976"],"is_preprint":false},{"year":1998,"finding":"The genomic structure of CHRNB2 was determined and the gene was mapped to chromosome 1, providing the structural framework for mutational analyses of the β2 nicotinic acetylcholine receptor subunit gene.","method":"Genomic sequencing and chromosomal mapping","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic characterization establishing gene structure and chromosomal location","pmids":["9921897"],"is_preprint":false}],"current_model":"CHRNB2 encodes the β2 subunit of the neuronal α4β2 nicotinic acetylcholine receptor; disease-associated mutations in the M2 and M3 transmembrane domains (e.g., V287M, I312M, Thr26Met) produce gain-of-function receptors with markedly increased acetylcholine sensitivity, causing ADNFLE, while in cancer contexts CHRNB2 acts as a suppressor of cell proliferation, migration, and invasion via PI3K-AKT/JAK-STAT and β-catenin pathway regulation in an acetylcholine-independent manner."},"narrative":{"teleology":[{"year":1998,"claim":"Determining the genomic structure and chromosomal location of CHRNB2 provided the essential framework for subsequent mutational analyses linking this gene to disease.","evidence":"Genomic sequencing and chromosomal mapping to chromosome 1","pmids":["9921897"],"confidence":"Medium","gaps":["No functional characterization of the encoded protein was performed","Regulatory elements controlling CHRNB2 expression were not mapped"]},{"year":2000,"claim":"Electrophysiological characterization of the V287M mutation in the M2 transmembrane domain revealed a ~10-fold increase in acetylcholine sensitivity, establishing gain-of-function as the pathogenic mechanism underlying ADNFLE.","evidence":"Functional expression of mutant and wild-type α4β2 receptors in Xenopus oocytes with electrophysiological recording","pmids":["11104662"],"confidence":"High","gaps":["Mechanism by which increased ACh sensitivity leads to seizure generation in neural circuits was not addressed","Single mutation studied; generalizability to other CHRNB2 ADNFLE mutations was unknown"]},{"year":2005,"claim":"Discovery that the I312M mutation in the M3 domain also increases ACh sensitivity extended the gain-of-function mechanism beyond the M2 domain and linked CHRNB2 mutations to cognitive phenotypes (verbal memory deficits) in addition to epilepsy.","evidence":"Functional expression assay of mutant receptor combined with clinical neuropsychological testing in mutation carriers","pmids":["15964197"],"confidence":"Medium","gaps":["Single-lab study; independent replication of the cognitive phenotype not reported","Structural basis for how an M3 mutation increases ACh sensitivity was not resolved"]},{"year":2020,"claim":"Characterization of the Thr26Met mutation demonstrated increased whole-cell nicotinic currents in human cell lines, confirming the gain-of-function paradigm in a mammalian expression system and showing it applies to mutations at yet another position.","evidence":"Whole-cell patch-clamp electrophysiology of α4β2 receptors reconstituted in human cell lines","pmids":["32536355"],"confidence":"Medium","gaps":["Single-lab study with one mutation","No analysis of receptor trafficking or surface expression changes that might contribute to increased currents"]},{"year":2021,"claim":"Loss-of-function studies revealed an unexpected role for CHRNB2 in promoting gastric cancer cell survival through PI3K–AKT and JAK–STAT signaling, broadening the gene's functional relevance beyond neuronal ion channel activity.","evidence":"CRISPR knockout, RNAi knockdown, ectopic overexpression, in vitro proliferation/invasion assays, and mouse xenograft models with pathway analysis","pmids":["34331011"],"confidence":"Medium","gaps":["Whether CHRNB2's cancer role depends on ion channel function or a non-canonical mechanism was not resolved","Single cancer type studied in one lab"]},{"year":2022,"claim":"Bidirectional manipulation of CHRNB2 in pancreatic cancer cells established an acetylcholine-independent suppression of migration and invasion via β-catenin pathway downregulation and EMT inhibition, defining a non-canonical signaling function.","evidence":"Transwell migration/invasion assays with CHRNB2 knockdown and overexpression; Western blot for β-catenin pathway components and EMT markers","pmids":["36344976"],"confidence":"Medium","gaps":["Direct binding partners mediating the acetylcholine-independent mechanism are unidentified","Apparent oncogenic role in gastric cancer versus tumor-suppressive role in pancreatic cancer is unreconciled"]},{"year":null,"claim":"The structural basis for how distinct transmembrane domain mutations converge on gain-of-function, the neural circuit mechanisms linking receptor hypersensitivity to seizures, and the molecular basis of CHRNB2's acetylcholine-independent signaling in cancer remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of disease-mutant α4β2 receptors","No in vivo neural circuit-level explanation for ADNFLE pathogenesis","Direct molecular partners mediating non-canonical cancer signaling are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]}],"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]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2]}],"complexes":["α4β2 neuronal nicotinic acetylcholine receptor"],"partners":["CHRNA4"],"other_free_text":[]},"mechanistic_narrative":"CHRNB2 encodes the β2 subunit of neuronal nicotinic acetylcholine receptors (nAChRs), primarily forming α4β2 heteropentameric ligand-gated cation channels that mediate fast cholinergic neurotransmission. Disease-causing missense mutations in the second (V287M) and third (I312M, Thr26Met) transmembrane domains produce gain-of-function receptors with markedly increased acetylcholine sensitivity, establishing this mechanism as the basis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [PMID:11104662, PMID:15964197, PMID:32536355]. In cancer contexts, CHRNB2 suppresses cell proliferation, migration, invasion, and epithelial–mesenchymal transition through PI3K–AKT/JAK–STAT and β-catenin pathway regulation, operating via an acetylcholine-independent mechanism [PMID:34331011, PMID:36344976]."},"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":75,"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 dependence.","date":"2008","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/18534558","citation_count":52,"is_preprint":false},{"pmid":"11906688","id":"PMC_11906688","title":"Genetic and functional analysis of single nucleotide polymorphisms in the beta2-neuronal nicotinic acetylcholine receptor gene (CHRNB2).","date":"2002","source":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","url":"https://pubmed.ncbi.nlm.nih.gov/11906688","citation_count":45,"is_preprint":false},{"pmid":"15026168","id":"PMC_15026168","title":"Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease.","date":"2004","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/15026168","citation_count":38,"is_preprint":false},{"pmid":"19755656","id":"PMC_19755656","title":"Nicotinic acetylcholine receptor beta2 subunit (CHRNB2) 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 with basal ganglia calcifications and mutations in SLC20A2 and CHRNB2.","date":"2015","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26475232","citation_count":25,"is_preprint":false},{"pmid":"34331011","id":"PMC_34331011","title":"Blockade of CHRNB2 signaling with a therapeutic monoclonal antibody attenuates the aggressiveness of gastric cancer cells.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34331011","citation_count":20,"is_preprint":false},{"pmid":"18534914","id":"PMC_18534914","title":"Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor.","date":"2008","source":"Epilepsy & behavior : E&B","url":"https://pubmed.ncbi.nlm.nih.gov/18534914","citation_count":20,"is_preprint":false},{"pmid":"29666375","id":"PMC_29666375","title":"Association and cis-mQTL analysis of variants in CHRNA3-A5, CHRNA7, CHRNB2, and CHRNB4 in relation to nicotine dependence in a Chinese Han population.","date":"2018","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/29666375","citation_count":18,"is_preprint":false},{"pmid":"21497487","id":"PMC_21497487","title":"The identification of a novel mutation of nicotinic acetylcholine receptor gene CHRNB2 in a Chinese patient: Its possible implication in non-familial nocturnal frontal lobe epilepsy.","date":"2011","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/21497487","citation_count":18,"is_preprint":false},{"pmid":"34957168","id":"PMC_34957168","title":"Long Non-coding RNAs Gabarapl2 and Chrnb2 Positively Regulate Inflammatory Signaling in a Mouse Model of Dry Eye.","date":"2021","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34957168","citation_count":15,"is_preprint":false},{"pmid":"36344976","id":"PMC_36344976","title":"CHRNB2 represses pancreatic cancer migration and invasion via inhibiting β-catenin pathway.","date":"2022","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/36344976","citation_count":13,"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":"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":"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":"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":"22897520","id":"PMC_22897520","title":"Hippocampal sclerosis worsens autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) phenotype related to CHRNB2 mutation.","date":"2012","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22897520","citation_count":8,"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":"35163155","id":"PMC_35163155","title":"Increased Risky Choice and Reduced CHRNB2 Expression in Adult Male Rats Exposed to Nicotine Vapor.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163155","citation_count":5,"is_preprint":false},{"pmid":"23032131","id":"PMC_23032131","title":"A case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) coexisting with pervasive developmental disorder harboring SCN1A mutation in addition to CHRNB2 mutation.","date":"2012","source":"Epilepsy & behavior : E&B","url":"https://pubmed.ncbi.nlm.nih.gov/23032131","citation_count":5,"is_preprint":false},{"pmid":"25640319","id":"PMC_25640319","title":"The possible role of maternal bonding style and 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 targets","date":"2025-02-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.19.25322532","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17010,"output_tokens":1364,"usd":0.035745},"stage2":{"model":"claude-opus-4-6","input_tokens":4633,"output_tokens":1762,"usd":0.100822},"total_usd":0.136567,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"The CHRNB2 V287M mutation in the M2 (second transmembrane) domain of the β2 nicotinic acetylcholine receptor subunit causes an approximately 10-fold increase in acetylcholine sensitivity when expressed in Xenopus oocytes, establishing gain-of-function of the receptor as the mechanism underlying ADNFLE.\",\n      \"method\": \"Functional expression in Xenopus oocytes with electrophysiological characterization of mutant vs. wild-type receptor\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro functional assay (Xenopus oocyte expression + electrophysiology) with clear quantitative result\",\n      \"pmids\": [\"11104662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The CHRNB2 I312M mutation in the third transmembrane domain (M3) markedly increases the receptor's sensitivity to acetylcholine, extending the gain-of-function mechanism to a region outside the M2 ADNFLE mutation cluster and associating with both ADNFLE and verbal memory deficits.\",\n      \"method\": \"Functional characterization of mutant receptor (implied electrophysiology in heterologous expression system) plus clinical neuropsychological testing\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional expression assay demonstrating increased ACh sensitivity, single lab\",\n      \"pmids\": [\"15964197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CHRNB2 Thr26Met mutation leads to significantly higher whole-cell nicotinic currents in human cell lines when expressed as α4β2 receptors in both homo- and heterozygous conditions, without major alterations in current reversal potential or concentration-response curve shape.\",\n      \"method\": \"Functional expression in human cell lines with whole-cell patch-clamp electrophysiology\",\n      \"journal\": \"The Canadian journal of neurological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro electrophysiology in human cell lines, single lab\",\n      \"pmids\": [\"32536355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHRNB2 knockdown attenuates gastric cancer cell proliferation, and its knockout significantly impairs cell survival and functions associated with metastasis; pathway analysis revealed CHRNB2 signals through the PI3K-AKT and JAK-STAT pathways in cancer cells.\",\n      \"method\": \"CRISPR knockout, RNAi knockdown, ectopic overexpression, in vitro proliferation/invasion assays, mouse xenograft models, pathway analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal loss/gain-of-function approaches with defined cellular phenotypes and in vivo validation, 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 through an acetylcholine-independent mechanism involving downregulation of the β-catenin pathway and its upstream regulators SOX6, SRY, SOX17, and TCF7L2, and suppresses epithelial-mesenchymal transition (EMT).\",\n      \"method\": \"Transwell migration/invasion assays with CHRNB2 knockdown and overexpression, Western blot for β-catenin pathway components and EMT markers\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (KD and OE) with defined pathway readouts, single lab\",\n      \"pmids\": [\"36344976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The genomic structure of CHRNB2 was determined and the gene was mapped to chromosome 1, providing the structural framework for mutational analyses of the β2 nicotinic acetylcholine receptor subunit gene.\",\n      \"method\": \"Genomic sequencing and chromosomal mapping\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic characterization establishing gene structure and chromosomal location\",\n      \"pmids\": [\"9921897\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHRNB2 encodes the β2 subunit of the neuronal α4β2 nicotinic acetylcholine receptor; disease-associated mutations in the M2 and M3 transmembrane domains (e.g., V287M, I312M, Thr26Met) produce gain-of-function receptors with markedly increased acetylcholine sensitivity, causing ADNFLE, while in cancer contexts CHRNB2 acts as a suppressor of cell proliferation, migration, and invasion via PI3K-AKT/JAK-STAT and β-catenin pathway regulation in an acetylcholine-independent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CHRNB2 encodes the β2 subunit of neuronal nicotinic acetylcholine receptors (nAChRs), primarily forming α4β2 heteropentameric ligand-gated cation channels that mediate fast cholinergic neurotransmission. Disease-causing missense mutations in the second (V287M) and third (I312M, Thr26Met) transmembrane domains produce gain-of-function receptors with markedly increased acetylcholine sensitivity, establishing this mechanism as the basis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [PMID:11104662, PMID:15964197, PMID:32536355]. In cancer contexts, CHRNB2 suppresses cell proliferation, migration, invasion, and epithelial–mesenchymal transition through PI3K–AKT/JAK–STAT and β-catenin pathway regulation, operating via an acetylcholine-independent mechanism [PMID:34331011, PMID:36344976].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Determining the genomic structure and chromosomal location of CHRNB2 provided the essential framework for subsequent mutational analyses linking this gene to disease.\",\n      \"evidence\": \"Genomic sequencing and chromosomal mapping to chromosome 1\",\n      \"pmids\": [\"9921897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional characterization of the encoded protein was performed\",\n        \"Regulatory elements controlling CHRNB2 expression were not mapped\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Electrophysiological characterization of the V287M mutation in the M2 transmembrane domain revealed a ~10-fold increase in acetylcholine sensitivity, establishing gain-of-function as the pathogenic mechanism underlying ADNFLE.\",\n      \"evidence\": \"Functional expression of mutant and wild-type α4β2 receptors in Xenopus oocytes with electrophysiological recording\",\n      \"pmids\": [\"11104662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which increased ACh sensitivity leads to seizure generation in neural circuits was not addressed\",\n        \"Single mutation studied; generalizability to other CHRNB2 ADNFLE mutations was unknown\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that the I312M mutation in the M3 domain also increases ACh sensitivity extended the gain-of-function mechanism beyond the M2 domain and linked CHRNB2 mutations to cognitive phenotypes (verbal memory deficits) in addition to epilepsy.\",\n      \"evidence\": \"Functional expression assay of mutant receptor combined with clinical neuropsychological testing in mutation carriers\",\n      \"pmids\": [\"15964197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication of the cognitive phenotype not reported\",\n        \"Structural basis for how an M3 mutation increases ACh sensitivity was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Characterization of the Thr26Met mutation demonstrated increased whole-cell nicotinic currents in human cell lines, confirming the gain-of-function paradigm in a mammalian expression system and showing it applies to mutations at yet another position.\",\n      \"evidence\": \"Whole-cell patch-clamp electrophysiology of α4β2 receptors reconstituted in human cell lines\",\n      \"pmids\": [\"32536355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study with one mutation\",\n        \"No analysis of receptor trafficking or surface expression changes that might contribute to increased currents\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Loss-of-function studies revealed an unexpected role for CHRNB2 in promoting gastric cancer cell survival through PI3K–AKT and JAK–STAT signaling, broadening the gene's functional relevance beyond neuronal ion channel activity.\",\n      \"evidence\": \"CRISPR knockout, RNAi knockdown, ectopic overexpression, in vitro proliferation/invasion assays, and mouse xenograft models with pathway analysis\",\n      \"pmids\": [\"34331011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CHRNB2's cancer role depends on ion channel function or a non-canonical mechanism was not resolved\",\n        \"Single cancer type studied in one lab\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Bidirectional manipulation of CHRNB2 in pancreatic cancer cells established an acetylcholine-independent suppression of migration and invasion via β-catenin pathway downregulation and EMT inhibition, defining a non-canonical signaling function.\",\n      \"evidence\": \"Transwell migration/invasion assays with CHRNB2 knockdown and overexpression; Western blot for β-catenin pathway components and EMT markers\",\n      \"pmids\": [\"36344976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding partners mediating the acetylcholine-independent mechanism are unidentified\",\n        \"Apparent oncogenic role in gastric cancer versus tumor-suppressive role in pancreatic cancer is unreconciled\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how distinct transmembrane domain mutations converge on gain-of-function, the neural circuit mechanisms linking receptor hypersensitivity to seizures, and the molecular basis of CHRNB2's acetylcholine-independent signaling in cancer remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of disease-mutant α4β2 receptors\",\n        \"No in vivo neural circuit-level explanation for ADNFLE pathogenesis\",\n        \"Direct molecular partners mediating non-canonical cancer signaling are unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 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      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"α4β2 neuronal nicotinic acetylcholine receptor\"\n    ],\n    \"partners\": [\n      \"CHRNA4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}