Affinage

NBEA

Neurobeachin · UniProt Q8NFP9

Length
2946 aa
Mass
327.8 kDa
Annotated
2026-06-10
13 papers in source corpus 4 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 2/2 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2010 Medium

    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

    PMID:20071347

    Open questions at the time
    • 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
  2. 2021 Medium

    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

    PMID:34412939

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NBEA mechanistically couples its proposed kinase-anchoring scaffold function to vesicle secretion and membrane-protein trafficking remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
No controlled-vocabulary terms were assigned to this entry.

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. 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 Human molecular genetics Medium 20071347
2021 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. 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 Molecular genetics and metabolism Medium 34412939
2009 NBEA is implicated in membrane trafficking in neurons and protein kinase A (PKA) binding, consistent with its role as a kinase-anchoring protein. Contextual description within aCGH and expression analysis study; mechanistic role attributed to prior literature cited in the paper Experimental hematology Low 19135901
2009 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. Paralogous genomic sequence comparison, phylogenetic analysis, and enhancer activity assays (reporter assays) in the Mab21l2-Lrba locus Genomics Low 19482073

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Frequent PVT1 rearrangement and novel chimeric genes PVT1-NBEA and PVT1-WWOX occur in multiple myeloma with 8q24 abnormality. Cancer research 91 22869583
2010 SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles. Human molecular genetics 81 20071347
2018 NBEA: Developmental disease gene with early generalized epilepsy phenotypes. Annals of neurology 45 30269351
2009 Neurobeachin (NBEA) is a target of recurrent interstitial deletions at 13q13 in patients with MGUS and multiple myeloma. Experimental hematology 26 19135901
2009 An evolutionarily conserved nested gene pair - Mab21 and Lrba/Nbea in metazoan. Genomics 21 19482073
2021 Functional analysis of a de novo variant in the neurodevelopment and generalized epilepsy disease gene NBEA. Molecular genetics and metabolism 13 34412939
2014 Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder. Journal of affective disorders 13 25451450
2021 The circRNA circ-Nbea participates in regulating diabetic encephalopathy. Brain research 12 34695392
2021 Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report. Lung cancer (Amsterdam, Netherlands) 8 34763158
2020 13q13.3 microdeletion associated with apparently balanced translocation of 46,XX,t(7;13) suggests NBEA involvement. Brain & development 6 32507666
2023 Coexistence of a novel STRN-ALK, NBEA-ALK double-fusion in an ovarian malignant mesothelioma patient: a case report and review. Frontiers in oncology 3 37152028
2025 Neurobeachin (NBEA) is a novel gene associated with GLP-1 receptor agonist associated weight loss. Diabetes, obesity & metabolism 2 40677145
2025 NBEA gene variant in a child with developmental disorder and epilepsy: a case report. Frontiers in neuroscience 1 41113443

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