{"gene":"NBEA","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2010,"finding":"NBEA functions as a negative regulator of large dense-core vesicle (LDCV) secretion in mouse beta-TC3 cells: gene silencing of Nbea caused a ~2-fold increase in stimulated LDCV secretion, while overexpression suppressed secretion.","method":"siRNA gene silencing and overexpression in mouse beta-TC3 cells with measurement of stimulated LDCV secretion; ultrastructural analysis of platelet dense-core granules in haploinsufficient patients","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined secretion phenotype, supported by ultrastructural analysis, single lab with two orthogonal methods","pmids":["20071347"],"is_preprint":false},{"year":2021,"finding":"The DUF1088 domain of NBEA is functionally required in vivo: a missense variant (p.Gly1967Arg) in DUF1088, modeled in the C. elegans NBEA ortholog sel-2, caused altered cell fate determination and impaired trafficking of potassium channels in neurons, with effects indistinguishable from the null mutation.","method":"In vivo functional modeling in C. elegans sel-2 (NBEA ortholog): cell fate assays and potassium channel trafficking assays comparing missense variant to null allele","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function in ortholog with two distinct functional readouts (cell fate and channel trafficking), single lab","pmids":["34412939"],"is_preprint":false},{"year":2009,"finding":"NBEA is implicated in membrane trafficking in neurons and protein kinase A (PKA) binding, consistent with its role as a kinase-anchoring protein.","method":"Contextual description within aCGH and expression analysis study; mechanistic role attributed to prior literature cited in the paper","journal":"Experimental hematology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — mechanistic role described from prior literature without direct experimental validation in this paper","pmids":["19135901"],"is_preprint":false},{"year":2009,"finding":"NBEA and LRBA form an evolutionarily conserved nested gene pair with Mab21l1 and Mab21l2 respectively in metazoans; paralogous non-coding elements (enhancers) within LRBA/NBEA introns regulate expression of the nested Mab21 genes in a tissue-specific manner, suggesting that dissociation of the nested pair would disrupt function of at least one gene.","method":"Paralogous genomic sequence comparison, phylogenetic analysis, and enhancer activity assays (reporter assays) in the Mab21l2-Lrba locus","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — enhancer assays performed in the paralogous locus (Lrba), not directly in NBEA; single lab, indirect inference about NBEA","pmids":["19482073"],"is_preprint":false}],"current_model":"NBEA (Neurobeachin) is a brain-enriched kinase-anchoring protein (AKAP) that negatively regulates the secretion of large dense-core vesicles (LDCVs) in neurons and neuroendocrine cells, and its DUF1088 domain is required for in vivo trafficking of potassium channels and cell fate determination in neurons, as established by loss-of-function studies in mouse cells and the C. elegans ortholog sel-2."},"narrative":{"mechanistic_narrative":"NBEA (Neurobeachin) acts as a negative regulator of regulated secretion in neuroendocrine cells, where it restrains the stimulated release of large dense-core vesicles (LDCVs): silencing increases stimulated secretion roughly two-fold while overexpression suppresses it [PMID:20071347]. Its DUF1088 domain is functionally essential in vivo — a DUF1088 missense variant modeled in the C. elegans ortholog sel-2 reproduced the null phenotype, disrupting neuronal cell fate determination and trafficking of potassium channels [PMID:34412939]. Beyond this vesicle-trafficking and channel-trafficking role, no further molecular mechanism of NBEA has been characterized in the available corpus.","teleology":[{"year":2010,"claim":"Established NBEA as a brake on regulated secretion rather than a positive trafficking factor, defining the directionality of its role in dense-core vesicle release.","evidence":"siRNA silencing and overexpression in mouse beta-TC3 cells with stimulated LDCV secretion measurement, plus platelet dense-core granule ultrastructure in haploinsufficient patients","pmids":["20071347"],"confidence":"Medium","gaps":["Molecular partners mediating the secretory brake not identified","Whether the effect is exocytic, biogenesis-related, or both is unresolved","No structural basis for the regulatory activity"]},{"year":2021,"claim":"Identified the DUF1088 domain as functionally indispensable, linking a specific human missense variant to loss-of-function-level defects in neuronal differentiation and channel trafficking.","evidence":"In vivo modeling of the p.Gly1967Arg variant in the C. elegans ortholog sel-2 with cell fate and potassium channel trafficking assays, compared against the null allele","pmids":["34412939"],"confidence":"Medium","gaps":["Direct biochemical activity of DUF1088 not defined","Whether mammalian NBEA traffics the same channel classes is untested","Mechanistic link between DUF1088 function and the secretory phenotype is unestablished"]},{"year":null,"claim":"How NBEA mechanistically couples its proposed kinase-anchoring scaffold function to vesicle secretion and membrane-protein trafficking remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct molecular partners or substrates demonstrated experimentally in the corpus","PKA-anchoring role attributed only from prior literature, not directly validated here","No structural model of the full-length protein"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NFP9","full_name":"Neurobeachin","aliases":["Lysosomal-trafficking regulator 2","Protein BCL8B"],"length_aa":2946,"mass_kda":327.8,"function":"Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the membrane. May anchor the kinase to cytoskeletal and/or organelle-associated proteins (By similarity)","subcellular_location":"Cytoplasm; Membrane","url":"https://www.uniprot.org/uniprotkb/Q8NFP9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NBEA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NBEA","total_profiled":1310},"omim":[{"mim_id":"619157","title":"NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT EARLY-ONSET GENERALIZED EPILEPSY; NEDEGE","url":"https://www.omim.org/entry/619157"},{"mim_id":"614169","title":"NEUROBEACHIN-LIKE 2; NBEAL2","url":"https://www.omim.org/entry/614169"},{"mim_id":"609816","title":"NEUROBEACHIN-LIKE 1; NBEAL1","url":"https://www.omim.org/entry/609816"},{"mim_id":"608049","title":"AUTISM, SUSCEPTIBILITY TO, 3; AUTS3","url":"https://www.omim.org/entry/608049"},{"mim_id":"604889","title":"NEUROBEACHIN; NBEA","url":"https://www.omim.org/entry/604889"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":59.2}],"url":"https://www.proteinatlas.org/search/NBEA"},"hgnc":{"alias_symbol":["KIAA1544","BCL8B","FLJ10197","LYST2"],"prev_symbol":[]},"alphafold":{"accession":"Q8NFP9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFP9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFP9-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFP9-3-F1-predicted_aligned_error_v6.png","plddt_mean":88.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NBEA","jax_strain_url":"https://www.jax.org/strain/search?query=NBEA"},"sequence":{"accession":"Q8NFP9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFP9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFP9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFP9"}},"corpus_meta":[{"pmid":"22869583","id":"PMC_22869583","title":"Frequent PVT1 rearrangement and novel chimeric genes PVT1-NBEA and PVT1-WWOX occur in multiple myeloma with 8q24 abnormality.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22869583","citation_count":91,"is_preprint":false},{"pmid":"20071347","id":"PMC_20071347","title":"SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20071347","citation_count":81,"is_preprint":false},{"pmid":"30269351","id":"PMC_30269351","title":"NBEA: Developmental disease gene with early generalized epilepsy phenotypes.","date":"2018","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30269351","citation_count":45,"is_preprint":false},{"pmid":"19135901","id":"PMC_19135901","title":"Neurobeachin (NBEA) is a target of recurrent interstitial deletions at 13q13 in patients with MGUS and multiple myeloma.","date":"2009","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/19135901","citation_count":26,"is_preprint":false},{"pmid":"19482073","id":"PMC_19482073","title":"An evolutionarily conserved nested gene pair - Mab21 and Lrba/Nbea in metazoan.","date":"2009","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19482073","citation_count":21,"is_preprint":false},{"pmid":"34412939","id":"PMC_34412939","title":"Functional analysis of a de novo variant in the neurodevelopment and generalized epilepsy disease gene NBEA.","date":"2021","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34412939","citation_count":13,"is_preprint":false},{"pmid":"25451450","id":"PMC_25451450","title":"Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder.","date":"2014","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/25451450","citation_count":13,"is_preprint":false},{"pmid":"34695392","id":"PMC_34695392","title":"The circRNA circ-Nbea participates in regulating diabetic encephalopathy.","date":"2021","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/34695392","citation_count":12,"is_preprint":false},{"pmid":"34763158","id":"PMC_34763158","title":"Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report.","date":"2021","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/34763158","citation_count":8,"is_preprint":false},{"pmid":"32507666","id":"PMC_32507666","title":"13q13.3 microdeletion associated with apparently balanced translocation of 46,XX,t(7;13) suggests NBEA involvement.","date":"2020","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/32507666","citation_count":6,"is_preprint":false},{"pmid":"37152028","id":"PMC_37152028","title":"Coexistence of a novel STRN-ALK, NBEA-ALK double-fusion in an ovarian malignant mesothelioma patient: a case report and review.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37152028","citation_count":3,"is_preprint":false},{"pmid":"40677145","id":"PMC_40677145","title":"Neurobeachin (NBEA) is a novel gene associated with GLP-1 receptor agonist associated weight loss.","date":"2025","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40677145","citation_count":2,"is_preprint":false},{"pmid":"41113443","id":"PMC_41113443","title":"NBEA gene variant in a child with developmental disorder and epilepsy: a case report.","date":"2025","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/41113443","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8488,"output_tokens":1037,"usd":0.020509,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7548,"output_tokens":1070,"usd":0.032245,"stage2_stop_reason":"end_turn"},"total_usd":0.052754,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"NBEA functions as a negative regulator of large dense-core vesicle (LDCV) secretion in mouse beta-TC3 cells: gene silencing of Nbea caused a ~2-fold increase in stimulated LDCV secretion, while overexpression suppressed secretion.\",\n      \"method\": \"siRNA gene silencing and overexpression in mouse beta-TC3 cells with measurement of stimulated LDCV secretion; ultrastructural analysis of platelet dense-core granules in haploinsufficient patients\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined secretion phenotype, supported by ultrastructural analysis, single lab with two orthogonal methods\",\n      \"pmids\": [\"20071347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The DUF1088 domain of NBEA is functionally required in vivo: a missense variant (p.Gly1967Arg) in DUF1088, modeled in the C. elegans NBEA ortholog sel-2, caused altered cell fate determination and impaired trafficking of potassium channels in neurons, with effects indistinguishable from the null mutation.\",\n      \"method\": \"In vivo functional modeling in C. elegans sel-2 (NBEA ortholog): cell fate assays and potassium channel trafficking assays comparing missense variant to null allele\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function in ortholog with two distinct functional readouts (cell fate and channel trafficking), single lab\",\n      \"pmids\": [\"34412939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NBEA is implicated in membrane trafficking in neurons and protein kinase A (PKA) binding, consistent with its role as a kinase-anchoring protein.\",\n      \"method\": \"Contextual description within aCGH and expression analysis study; mechanistic role attributed to prior literature cited in the paper\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — mechanistic role described from prior literature without direct experimental validation in this paper\",\n      \"pmids\": [\"19135901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NBEA and LRBA form an evolutionarily conserved nested gene pair with Mab21l1 and Mab21l2 respectively in metazoans; paralogous non-coding elements (enhancers) within LRBA/NBEA introns regulate expression of the nested Mab21 genes in a tissue-specific manner, suggesting that dissociation of the nested pair would disrupt function of at least one gene.\",\n      \"method\": \"Paralogous genomic sequence comparison, phylogenetic analysis, and enhancer activity assays (reporter assays) in the Mab21l2-Lrba locus\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — enhancer assays performed in the paralogous locus (Lrba), not directly in NBEA; single lab, indirect inference about NBEA\",\n      \"pmids\": [\"19482073\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NBEA (Neurobeachin) is a brain-enriched kinase-anchoring protein (AKAP) that negatively regulates the secretion of large dense-core vesicles (LDCVs) in neurons and neuroendocrine cells, and its DUF1088 domain is required for in vivo trafficking of potassium channels and cell fate determination in neurons, as established by loss-of-function studies in mouse cells and the C. elegans ortholog sel-2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NBEA (Neurobeachin) acts as a negative regulator of regulated secretion in neuroendocrine cells, where it restrains the stimulated release of large dense-core vesicles (LDCVs): silencing increases stimulated secretion roughly two-fold while overexpression suppresses it [#0]. Its DUF1088 domain is functionally essential in vivo — a DUF1088 missense variant modeled in the C. elegans ortholog sel-2 reproduced the null phenotype, disrupting neuronal cell fate determination and trafficking of potassium channels [#1]. Beyond this vesicle-trafficking and channel-trafficking role, no further molecular mechanism of NBEA has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established NBEA as a brake on regulated secretion rather than a positive trafficking factor, defining the directionality of its role in dense-core vesicle release.\",\n      \"evidence\": \"siRNA silencing and overexpression in mouse beta-TC3 cells with stimulated LDCV secretion measurement, plus platelet dense-core granule ultrastructure in haploinsufficient patients\",\n      \"pmids\": [\"20071347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular partners mediating the secretory brake not identified\",\n        \"Whether the effect is exocytic, biogenesis-related, or both is unresolved\",\n        \"No structural basis for the regulatory activity\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the DUF1088 domain as functionally indispensable, linking a specific human missense variant to loss-of-function-level defects in neuronal differentiation and channel trafficking.\",\n      \"evidence\": \"In vivo modeling of the p.Gly1967Arg variant in the C. elegans ortholog sel-2 with cell fate and potassium channel trafficking assays, compared against the null allele\",\n      \"pmids\": [\"34412939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical activity of DUF1088 not defined\",\n        \"Whether mammalian NBEA traffics the same channel classes is untested\",\n        \"Mechanistic link between DUF1088 function and the secretory phenotype is unestablished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NBEA mechanistically couples its proposed kinase-anchoring scaffold function to vesicle secretion and membrane-protein trafficking remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct molecular partners or substrates demonstrated experimentally in the corpus\",\n        \"PKA-anchoring role attributed only from prior literature, not directly validated here\",\n        \"No structural model of the full-length protein\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}