{"gene":"CHRFAM7A","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2011,"finding":"CHRFAM7A (dupα7) expressed alone yields protein but no functional receptor. Co-expression with α7 (CHRNA7) in cell lines and Xenopus oocytes causes significant reduction in ACh-evoked current amplitude without a proportional reduction in α-bungarotoxin (I-BTX) binding, indicating formation of non-functional (ACh-silent) heteromeric receptors. The allosteric modulator PNU-120596 produced a larger increase in ACh-evoked current in cells co-expressing the duplicate than in controls, consistent with a dominant-negative modulation mechanism.","method":"Functional electrophysiology in Xenopus oocytes and cell lines; I-BTX radioligand binding; pharmacological rescue with PNU-120596","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted co-expression system, multiple orthogonal methods (electrophysiology, radioligand binding, pharmacological modulation), replicated across cell lines and oocytes","pmids":["21718690"],"is_preprint":false},{"year":2010,"finding":"dupα7 (CHRFAM7A protein) is natively translated in HL-60 cells. Injection of dupα7 mRNA alone into Xenopus oocytes fails to generate functional receptors. Co-injection with α7 mRNA reduces nicotine-evoked α7 currents in a dose-dependent manner (up to 94% reduction at 1:10 α7:dupα7 ratio). This dominant-negative effect is primarily due to reduction in the number of functional α7 receptors reaching the oocyte membrane, as confirmed by α-bungarotoxin binding and fluorescent confocal assays. dupα7 mRNA levels in macrophages are higher than α7 mRNA levels and are down-regulated by IL-1β, LPS, and nicotine.","method":"Xenopus oocyte electrophysiology; α-bungarotoxin binding; fluorescent confocal imaging of membrane receptors; RT-PCR in native cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in oocytes with dose-response, multiple orthogonal methods (electrophysiology, ligand binding, confocal imaging), native expression confirmed","pmids":["21047781"],"is_preprint":false},{"year":2015,"finding":"CHRFAM7A has a unique 1-kb promoter sequence in its 5'-UTR that independently regulates its expression separately from CHRNA7. Stable CHRFAM7A overexpression in THP1 cells alters cell phenotype and modifies expression of genes associated with focal adhesion (FAK, PI3K, Akt, rho, GEF, Elk1, CycD), leukocyte transepithelial migration (Nox, ITG, MMPs, PKC), and cancer pathways. Unexpectedly, stable CHRFAM7A overexpression upregulates CHRNA7, leading to increased α-bungarotoxin binding on THP1 cell surface.","method":"Promoter mapping; stable transfection; gene expression profiling; flow cytometry with α-bungarotoxin binding","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mapping and stable overexpression with multiple readouts, single lab","pmids":["25860877"],"is_preprint":false},{"year":2015,"finding":"CHRFAM7A is expressed in human gut epithelial cells. A 3-hour treatment with 100 ng/ml LPS increases CHRFAM7A gene expression by ~1000-fold in gut epithelial cells while having little effect on CHRNA7 expression. A 1-kb sequence in the CHRFAM7A 5'-UTR is identified as a regulatory element responsive to LPS.","method":"RT-PCR in gut epithelial cell lines; luciferase-based promoter mapping; LPS stimulation assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mapping and differential expression confirmed across 11 cell lines, single lab","pmids":["25681457"],"is_preprint":false},{"year":2011,"finding":"In THP-1 monocytic cells, CHRFAM7A (α7dup) mRNA and protein are down-regulated upon LPS challenge. This transcriptional down-regulation is mediated by NF-κB, as the specific NF-κB inhibitor parthenolide prevents the reduction in α7dup transcript.","method":"Real-time PCR; Western blotting; pharmacological inhibition with parthenolide","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor confirms NF-κB mechanism, single lab, two methods","pmids":["20926142"],"is_preprint":false},{"year":2019,"finding":"CHRFAM7A blocks ligand binding to both mouse and human α7nAChR. In CHRFAM7A-transgenic mice, CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation toward the monocyte lineage in vitro. In a SIRS model, HSCs were spared in CHRFAM7A-transgenic mice while depleted in wild-type; transgenic mice also showed increased immune cell mobilization and a shift to inflammatory monocytes from granulocytes in inflamed lungs.","method":"CHRFAM7A-transgenic mouse model; ligand binding assay; bone marrow HSC quantification; in vitro HSC differentiation assay; SIRS model with flow cytometry of lung immune cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model with multiple orthogonal readouts (ligand binding, HSC quantification, differentiation assay, in vivo SIRS model), consistent mechanistic findings","pmids":["30944217"],"is_preprint":false},{"year":2019,"finding":"In iPSC-derived neurons harboring CHRFAM7A (1 copy vs. 0 copy), PNU-modulated desensitization of α7nAChR currents increased as a function of CHRFAM7A dosage. CHRFAM7A mitigated the dose-response of amyloid-beta (Aβ1-42) uptake, suggesting a protective effect at supra-physiological Aβ concentrations. In the presence of CHRFAM7A, Aβ1-42 uptake activated neuronal IL-1β and TNF-α without activating the canonical inflammasome pathway.","method":"iPSC-derived neurons with defined CHRFAM7A copy number; electrophysiology; Aβ1-42 uptake assay; cytokine measurement","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC model with genetic copy number control, electrophysiology and Aβ uptake assay, single lab","pmids":["30710073"],"is_preprint":false},{"year":2018,"finding":"CHRFAM7A expression in rat PC12 cells and CHRFAM7A-transgenic mice decreases α-bungarotoxin (α-BTX) binding to α7nAChR, as detected by immunohistochemistry and flow cytometry. In vivo, α-BTX co-staining with neurofilament at the neuromuscular junction was decreased in CHRFAM7A-transgenic mice compared to wild-type, demonstrating that CHRFAM7A interferes with α7nAChR ligand binding in vivo.","method":"Stable transfection of rat PC12 cells; α-BTX binding by immunohistochemistry and flow cytometry; CHRFAM7A-transgenic mouse neuromuscular junction staining","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo evidence, two orthogonal methods (IHC and flow cytometry), single lab","pmids":["30308236"],"is_preprint":false},{"year":2020,"finding":"CHRFAM7A overexpression in THP-1 human monocytic cells reduces cell migration, reduces chemotaxis to monocyte chemoattractant protein, and reduces colony formation in soft agar, demonstrating a direct role in regulating monocyte/macrophage migratory and proliferative behavior.","method":"Lentiviral gene delivery; Transwell migration assay; chemotaxis assay; soft agar colony formation assay","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene delivery with multiple functional assays, single lab","pmids":["32303780"],"is_preprint":false},{"year":2020,"finding":"The direct and inverted CHRFAM7A alleles have distinct functional phenotypes with respect to α7nAChR electrophysiology and Aβ neurotoxicity in iPSC models. Functional CHRFAM7A allele classifies the population as ~25% non-carriers and ~75% carriers, and carrier status modifies AChEI therapy response in Alzheimer's disease patients.","method":"iPSC electrophysiology; Aβ uptake assay; double-blind pharmacogenetic clinical analysis","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC functional assays plus clinical pharmacogenetic data, single group","pmids":["32818803"],"is_preprint":false},{"year":2021,"finding":"CHRFAM7A overexpression in OGD/R-treated microglia inhibited NLRP3 inflammasome activation and cell pyroptosis via the NLRP3/Caspase-1 pathway, and promoted polarization of microglia from M1 to M2 phenotype, thereby attenuating inflammatory injury.","method":"CHRFAM7A overexpression in OGD/R microglia model; NLRP3/Caspase-1 pathway activation assay; pyroptosis markers; M1/M2 phenotype markers (iNOS, Arg1)","journal":"Inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with pathway activation assay, single lab, limited mechanistic depth from abstract","pmids":["33405023"],"is_preprint":false},{"year":2022,"finding":"In CHRFAM7A-transgenic mice, OA was more severe and mechanical allodynia was greater than in WT mice in the destabilization of medial meniscus model, associated with decreased suppression of inflammation by α7nAChR agonist. Transgenic mice showed higher basal sensitivity to pain stimuli and increased pain behavior in monoiodoacetate and formalin models. Dorsal root ganglia of transgenic mice showed increased macrophage infiltration and expression of fractalkine chemokine. Human chondrocytes with two CHRFAM7A copies had reduced anti-inflammatory response to nicotine.","method":"CHRFAM7A-transgenic mouse OA model; mechanical allodynia testing; pain behavior assays; DRG immunostaining; human chondrocyte culture with nicotine treatment","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with multiple pain and inflammation readouts plus human cell data, single study","pmids":["36627169"],"is_preprint":false},{"year":2024,"finding":"CHRFAM7A/α7nAChR functions as a hypomorphic receptor with mitigated Ca2+ influx and prolonged channel closed state compared to α7nAChR alone. This shifts the Ca2+ reservoir from extracellular space to the endoplasmic reticulum (ER), altering Ca2+ dynamics. The Ca2+ decoder small GTPase Rac1 is activated downstream, reorganizing the actin cytoskeleton and driving phenotypes including cellular adhesion, motility, phagocytosis, and tissue mechanosensation in iPSC-derived and primary monocyte models.","method":"Ca2+ imaging in iPSC-derived cells and primary monocytes; electrophysiology; Rac1 activation assay; actin cytoskeleton imaging; phagocytosis assay","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Ca2+ imaging, electrophysiology, Rac1 assay, actin imaging, phagocytosis) in two model systems (iPSC and primary monocytes), mechanistic pathway from receptor to phenotype established","pmids":["38569318"],"is_preprint":false},{"year":2024,"finding":"CHRFAM7A (dupα7) reduces α7nAChR-mediated calcium transients in response to multiple agonists (PNU282987, choline, 4BP-TQS) in hiPSC-derived cortical neurons and in SCG neurons from CHRFAM7A-transgenic mice, confirming dominant-negative reduction of α7nAChR function in neuronal cells.","method":"Fura-2 calcium imaging in hiPSC-derived cortical neurons and SCG neurons from transgenic mice; three different α7-specific ligands with PAM II PNU120596","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — calcium imaging with multiple agonists in two independent neuronal model systems (human iPSC and mouse transgenic), rigorous controls","pmids":["39073048"],"is_preprint":false},{"year":2021,"finding":"Computational structural modeling of all possible dupα7/α7 pentameric combinations showed that receptors comprising four or more dupα7 subunits are not stable enough to form a functional ion channel. Models with dupα7/α7 interfaces are more stable and less detrimental to ion conductance than dupα7/dupα7 interfaces. The optimal stoichiometry for functional pentamers should include no more than three dupα7 monomers, favoring a dupα7/α7 interface. Receptors bearing dupα7 subunits are less sensitive to Aβ42 by protein-protein docking analysis.","method":"Atomistic molecular dynamics simulations; coarse-grain simulations; free energy calculations for Ca2+ conductance; protein-protein docking with α-bungarotoxin and Aβ42","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational modeling only, no experimental validation reported in this paper","pmids":["34067314"],"is_preprint":false},{"year":2022,"finding":"CHRFAM7A overexpression in HK-2 human renal tubular epithelial cells inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) and suppressed activation of the TGF-β1/Smad2/3 signaling pathway in vitro. In CHRFAM7A-transgenic mice subjected to UUO injury, transgenic overexpression decreased fibrotic gene expression, collagen deposition, TGF-β1 and Smad2/3 expression, and inflammatory cytokine release.","method":"CHRFAM7A overexpression in HK-2 cells; TGF-β1 stimulation; EMT marker quantification; Smad2/3 pathway activation assay; CHRFAM7A-transgenic mouse UUO model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo evidence with pathway (TGF-β1/Smad2/3) identified, single lab","pmids":["36479618"],"is_preprint":false},{"year":2020,"finding":"CHRFAM7A overexpression in a hypertrophic scar mouse model increased activation of the Notch pathway, which attenuated M2 macrophage polarization and increased M1 macrophages in the initial period, decreasing scar fibrosis.","method":"Lentiviral CHRFAM7A overexpression in mouse hypertrophic scar model; macrophage phenotype quantification (M1/M2); Notch pathway analysis; fibrosis assessment","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with pathway (Notch) identified but mechanistic depth limited from abstract","pmids":["32890966"],"is_preprint":false},{"year":2019,"finding":"CHRFAM7A CHRFAM7A gene expression in CHRFAM7A-transgenic mouse brain significantly modulated proteins involved in signaling pathways of α7nAChR-mediated neuropsychiatric disorders (Parkinson's, Alzheimer's, Huntington's disease, and alcoholism) as assessed by iTRAQ-2D-LC-MS/MS proteomic profiling.","method":"CHRFAM7A-transgenic mouse brain; iTRAQ-2D-LC-MS/MS proteomics; bioinformatics pathway analysis","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomic profiling without direct mechanistic validation of specific pathway components, single lab","pmids":["31348980"],"is_preprint":false},{"year":2023,"finding":"CHRFAM7A transgenic mouse peritoneal macrophages exhibited decreased ligand-binding capability (reduced α7nAChR agonist binding) and an activated pro-inflammatory cytokine gene expression profile at basal state. When challenged with LPS, macrophages from transgenic mice showed an exaggerated pro-inflammatory response at earlier time points and lower LPS dosages compared to wild-type. Leukocyte mobilization and pro-inflammatory cytokine levels were significantly higher in transgenic mice at the early stage of sepsis.","method":"CHRFAM7A-transgenic mouse peritoneal macrophages; ligand binding assay; LPS stimulation; cytokine measurement; sepsis model with survival analysis","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with in vivo and ex vivo mechanistic readouts, validated with human monocyte data, single lab","pmids":["37655479"],"is_preprint":false},{"year":2025,"finding":"CHRFAM7A is expressed in SOX2+ progenitors and neurons in the developing human cortex, with particular enrichment along radial glia (RG) endfeet. nAChR activation increases RG proliferation while decreasing neuronal differentiation; knockdown reduces RG and increases neurons. Single-cell RNA-seq reveals that CHRNA7 and CHRFAM7A selectively modulate different gene changes in excitatory neurons upon nicotine exposure. YAP1 is identified as a downstream effector of nAChR signaling; YAP1 inhibition reverses nicotine-induced phenotypic alterations in outer RG cells.","method":"Organotypic slice cultures; dissociated cultures; nAChR knockdown; single-cell RNA sequencing; YAP1 inhibition experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, knockdown experiments in cortical slices; CHRFAM7A-specific effects not fully separated from CHRNA7 effects in abstract","pmids":[],"is_preprint":true}],"current_model":"CHRFAM7A encodes dupα7, a human-specific truncated α7 nicotinic acetylcholine receptor subunit (lacking most of the N-terminal ligand-binding domain) that co-assembles with full-length α7 (CHRNA7) subunits to form heteropentameric receptors; these heteromers function as hypomorphic, dominant-negative ion channels with reduced Ca2+ influx, prolonged closed state, and reduced agonist/α-bungarotoxin binding, downstream of which Rac1 activation reorganizes the actin cytoskeleton to alter immune cell adhesion, motility, phagocytosis, and mechanosensation, while CHRFAM7A transcription is independently regulated by a unique 1-kb 5'-UTR promoter and is suppressed by LPS via NF-κB in monocytes/macrophages."},"narrative":{"mechanistic_narrative":"CHRFAM7A encodes dupα7, a human-specific, truncated α7 nicotinic acetylcholine receptor subunit that co-assembles with full-length α7 (CHRNA7) to act as a dominant-negative modulator of α7nAChR function [PMID:21718690, PMID:21047781]. dupα7 yields protein but no functional receptor on its own; co-expression with α7 reduces ACh- and nicotine-evoked currents dose-dependently while sparing α-bungarotoxin binding, indicating formation of ACh-silent heteromers and reduced trafficking of functional α7 to the membrane [PMID:21718690, PMID:21047781]. The resulting CHRFAM7A/α7 receptor behaves as a hypomorphic channel with reduced Ca2+ influx and a prolonged closed state, shifting the Ca2+ reservoir toward the endoplasmic reticulum and activating the small GTPase Rac1, which reorganizes the actin cytoskeleton to control monocyte/macrophage adhesion, motility, phagocytosis, and mechanosensation [PMID:38569318]. This dominant-negative reduction of α7nAChR-mediated calcium signaling is conserved in human iPSC-derived neurons and mouse transgenic neurons and is detectable in vivo at the neuromuscular junction [PMID:30308236, PMID:39073048]. Because α7nAChR signaling restrains inflammation, CHRFAM7A reshapes immune output: it biases hematopoietic differentiation toward inflammatory monocytes and modulates leukocyte mobilization in systemic inflammation [PMID:30944217, PMID:37655479], and in macrophages it weakens cholinergic anti-inflammatory tone, producing exaggerated pro-inflammatory cytokine responses [PMID:37655479]. CHRFAM7A transcription is controlled independently of CHRNA7 by a unique 1-kb 5'-UTR promoter that is strongly responsive to LPS, with NF-κB mediating its down-regulation in monocytes/macrophages [PMID:25860877, PMID:25681457, PMID:20926142]. CHRFAM7A overexpression also remodels focal-adhesion and transepithelial-migration gene programs and reduces monocyte migration, chemotaxis, and anchorage-independent growth [PMID:25860877, PMID:32303780].","teleology":[{"year":2010,"claim":"Established that the duplicate gene product dupα7 is natively translated but cannot form functional receptors alone, and acts dominant-negatively when combined with α7 — defining its core molecular behavior.","evidence":"Xenopus oocyte electrophysiology with dose-response, α-bungarotoxin binding, and confocal imaging of membrane receptors, plus native expression in HL-60/macrophages","pmids":["21047781"],"confidence":"High","gaps":["Stoichiometry of the heteromer not resolved","Mechanism of reduced membrane trafficking not defined at the molecular level"]},{"year":2011,"claim":"Confirmed in independent systems that co-assembly produces ACh-silent heteromers retaining toxin binding, and that an allosteric modulator can partially rescue function — refining the dominant-negative model as one of altered gating rather than absent receptor.","evidence":"Functional electrophysiology in oocytes and cell lines, I-BTX radioligand binding, and PNU-120596 pharmacological rescue","pmids":["21718690"],"confidence":"High","gaps":["Did not establish receptor structure or subunit arrangement","Physiological consequence in native cells not addressed"]},{"year":2011,"claim":"Identified how CHRFAM7A expression is regulated independently of CHRNA7, showing transcriptional suppression by inflammatory signaling.","evidence":"Real-time PCR, Western blotting, and parthenolide inhibition in THP-1 monocytes implicating NF-κB","pmids":["20926142"],"confidence":"Medium","gaps":["NF-κB binding to the promoter not shown directly","Inhibitor-based, single cell line"]},{"year":2015,"claim":"Mapped a unique 1-kb 5'-UTR promoter as the basis for autonomous, LPS-responsive regulation of CHRFAM7A and linked its overexpression to focal-adhesion and migration gene programs.","evidence":"Promoter/luciferase mapping, stable overexpression with gene expression profiling, flow cytometry of surface α-bungarotoxin binding in THP-1 and gut epithelial cells","pmids":["25860877","25681457"],"confidence":"Medium","gaps":["Direct transcription factors binding the 1-kb element not identified","Mechanism by which CHRFAM7A upregulates CHRNA7 unexplained"]},{"year":2018,"claim":"Demonstrated that CHRFAM7A interferes with α7nAChR ligand binding not only in vitro but in vivo, extending the dominant-negative effect to intact tissue including the neuromuscular junction.","evidence":"Stable transfection of PC12 cells and CHRFAM7A-transgenic mice; α-BTX binding by immunohistochemistry and flow cytometry","pmids":["30308236"],"confidence":"Medium","gaps":["Functional consequence at the NMJ not measured","Single lab"]},{"year":2019,"claim":"Connected the receptor-level defect to immune-system outcomes, showing CHRFAM7A biases hematopoiesis toward monocytes and alters immune cell mobilization in systemic inflammation.","evidence":"CHRFAM7A-transgenic mice with HSC quantification, in vitro differentiation, and a SIRS model with lung immune cell flow cytometry","pmids":["30944217"],"confidence":"High","gaps":["Cell-intrinsic vs systemic contribution to HSC bias not separated","Direct link from Ca2+/Rac1 signaling to differentiation not yet shown here"]},{"year":2019,"claim":"Tested CHRFAM7A function in human neurons with defined copy number, linking dosage to receptor desensitization and to modulation of amyloid-beta handling and neuronal cytokine output.","evidence":"iPSC-derived neurons (0 vs 1 copy), electrophysiology, Aβ1-42 uptake assay, cytokine measurement","pmids":["30710073"],"confidence":"Medium","gaps":["Mechanism of inflammasome-independent IL-1β/TNF-α activation undefined","Supra-physiological Aβ concentrations used"]},{"year":2020,"claim":"Showed direct CHRFAM7A control of monocyte migratory and proliferative behavior, and that allelic orientation (direct vs inverted) yields distinct functional phenotypes with clinical pharmacogenetic relevance.","evidence":"Lentiviral overexpression with Transwell migration, chemotaxis, and soft-agar assays; iPSC electrophysiology and Aβ assays with double-blind AChEI pharmacogenetic analysis","pmids":["32303780","32818803"],"confidence":"Medium","gaps":["Molecular mediators of reduced migration not pinpointed","Clinical association is correlative"]},{"year":2024,"claim":"Resolved the downstream signaling chain, showing the hypomorphic receptor reshapes calcium dynamics (ER reservoir shift) to activate Rac1 and reorganize actin, mechanistically linking channel function to adhesion, motility, phagocytosis, and mechanosensation.","evidence":"Ca2+ imaging, electrophysiology, Rac1 activation assay, actin imaging, and phagocytosis assays in iPSC-derived cells and primary monocytes","pmids":["38569318"],"confidence":"High","gaps":["Coupling between ER Ca2+ shift and Rac1 GEF activation not molecularly defined","Whether the same pathway operates in non-immune cells untested"]},{"year":2024,"claim":"Confirmed the dominant-negative calcium phenotype across multiple agonists in two independent neuronal systems, solidifying generality of the functional effect.","evidence":"Fura-2 calcium imaging with three α7 ligands plus PAM in hiPSC-derived cortical neurons and SCG neurons from transgenic mice","pmids":["39073048"],"confidence":"High","gaps":["Neuronal behavioral/circuit consequence not addressed"]},{"year":null,"claim":"How the structural basis of subunit stoichiometry, the molecular link between ER calcium redistribution and Rac1 activation, and CHRFAM7A's role in human cortical development converge to produce its immune and neuronal phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental structure of the dupα7/α7 heteromer","Direct GEF coupling Ca2+ to Rac1 unidentified","Developmental role rests on preprint and is not cleanly separated from CHRNA7"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[12,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7,12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13]}],"complexes":["α7 nicotinic acetylcholine receptor heteropentamer (dupα7/α7)"],"partners":["CHRNA7","RAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q494W8","full_name":"CHRNA7-FAM7A fusion protein","aliases":["CHRNA7-DR1","D-10"],"length_aa":412,"mass_kda":46.2,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q494W8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHRFAM7A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1047,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHRFAM7A","total_profiled":1310},"omim":[{"mim_id":"613025","title":"SCHIZOPHRENIA 13; SCZD13","url":"https://www.omim.org/entry/613025"},{"mim_id":"612001","title":"CHROMOSOME 15q13.3 DELETION SYNDROME","url":"https://www.omim.org/entry/612001"},{"mim_id":"609756","title":"CHRNA7/FAM7A FUSION GENE; CHRFAM7A","url":"https://www.omim.org/entry/609756"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":4.1},{"tissue":"parathyroid gland","ntpm":5.3}],"url":"https://www.proteinatlas.org/search/CHRFAM7A"},"hgnc":{"alias_symbol":["D-10","CHRNA7-DR1"],"prev_symbol":[]},"alphafold":{"accession":"Q494W8","domains":[{"cath_id":"2.70.170.10","chopping":"2-139","consensus_level":"medium","plddt":73.6486,"start":2,"end":139},{"cath_id":"1.20.58,1.20.58","chopping":"144-256_380-412","consensus_level":"high","plddt":76.4264,"start":144,"end":412}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q494W8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q494W8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q494W8-F1-predicted_aligned_error_v6.png","plddt_mean":68.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHRFAM7A","jax_strain_url":"https://www.jax.org/strain/search?query=CHRFAM7A"},"sequence":{"accession":"Q494W8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q494W8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q494W8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q494W8"}},"corpus_meta":[{"pmid":"25701707","id":"PMC_25701707","title":"The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function.","date":"2015","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25701707","citation_count":147,"is_preprint":false},{"pmid":"21718690","id":"PMC_21718690","title":"The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7*nAChR function.","date":"2011","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21718690","citation_count":111,"is_preprint":false},{"pmid":"21047781","id":"PMC_21047781","title":"Function of partially duplicated human α77 nicotinic receptor subunit CHRFAM7A gene: potential implications for the cholinergic anti-inflammatory response.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21047781","citation_count":111,"is_preprint":false},{"pmid":"24219032","id":"PMC_24219032","title":"miR-224 promotion of cell migration and invasion by targeting Homeobox D 10 gene in human hepatocellular carcinoma.","date":"2014","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/24219032","citation_count":83,"is_preprint":false},{"pmid":"19631623","id":"PMC_19631623","title":"A 2-base pair deletion polymorphism in the partial duplication of the alpha7 nicotinic acetylcholine gene (CHRFAM7A) on chromosome 15q14 is associated with schizophrenia.","date":"2009","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/19631623","citation_count":78,"is_preprint":false},{"pmid":"16823804","id":"PMC_16823804","title":"Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder.","date":"2006","source":"American journal of medical genetics. 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Co-expression with α7 (CHRNA7) in cell lines and Xenopus oocytes causes significant reduction in ACh-evoked current amplitude without a proportional reduction in α-bungarotoxin (I-BTX) binding, indicating formation of non-functional (ACh-silent) heteromeric receptors. The allosteric modulator PNU-120596 produced a larger increase in ACh-evoked current in cells co-expressing the duplicate than in controls, consistent with a dominant-negative modulation mechanism.\",\n      \"method\": \"Functional electrophysiology in Xenopus oocytes and cell lines; I-BTX radioligand binding; pharmacological rescue with PNU-120596\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted co-expression system, multiple orthogonal methods (electrophysiology, radioligand binding, pharmacological modulation), replicated across cell lines and oocytes\",\n      \"pmids\": [\"21718690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"dupα7 (CHRFAM7A protein) is natively translated in HL-60 cells. Injection of dupα7 mRNA alone into Xenopus oocytes fails to generate functional receptors. Co-injection with α7 mRNA reduces nicotine-evoked α7 currents in a dose-dependent manner (up to 94% reduction at 1:10 α7:dupα7 ratio). This dominant-negative effect is primarily due to reduction in the number of functional α7 receptors reaching the oocyte membrane, as confirmed by α-bungarotoxin binding and fluorescent confocal assays. dupα7 mRNA levels in macrophages are higher than α7 mRNA levels and are down-regulated by IL-1β, LPS, and nicotine.\",\n      \"method\": \"Xenopus oocyte electrophysiology; α-bungarotoxin binding; fluorescent confocal imaging of membrane receptors; RT-PCR in native cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in oocytes with dose-response, multiple orthogonal methods (electrophysiology, ligand binding, confocal imaging), native expression confirmed\",\n      \"pmids\": [\"21047781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHRFAM7A has a unique 1-kb promoter sequence in its 5'-UTR that independently regulates its expression separately from CHRNA7. Stable CHRFAM7A overexpression in THP1 cells alters cell phenotype and modifies expression of genes associated with focal adhesion (FAK, PI3K, Akt, rho, GEF, Elk1, CycD), leukocyte transepithelial migration (Nox, ITG, MMPs, PKC), and cancer pathways. Unexpectedly, stable CHRFAM7A overexpression upregulates CHRNA7, leading to increased α-bungarotoxin binding on THP1 cell surface.\",\n      \"method\": \"Promoter mapping; stable transfection; gene expression profiling; flow cytometry with α-bungarotoxin binding\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mapping and stable overexpression with multiple readouts, single lab\",\n      \"pmids\": [\"25860877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHRFAM7A is expressed in human gut epithelial cells. A 3-hour treatment with 100 ng/ml LPS increases CHRFAM7A gene expression by ~1000-fold in gut epithelial cells while having little effect on CHRNA7 expression. A 1-kb sequence in the CHRFAM7A 5'-UTR is identified as a regulatory element responsive to LPS.\",\n      \"method\": \"RT-PCR in gut epithelial cell lines; luciferase-based promoter mapping; LPS stimulation assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mapping and differential expression confirmed across 11 cell lines, single lab\",\n      \"pmids\": [\"25681457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In THP-1 monocytic cells, CHRFAM7A (α7dup) mRNA and protein are down-regulated upon LPS challenge. This transcriptional down-regulation is mediated by NF-κB, as the specific NF-κB inhibitor parthenolide prevents the reduction in α7dup transcript.\",\n      \"method\": \"Real-time PCR; Western blotting; pharmacological inhibition with parthenolide\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor confirms NF-κB mechanism, single lab, two methods\",\n      \"pmids\": [\"20926142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHRFAM7A blocks ligand binding to both mouse and human α7nAChR. In CHRFAM7A-transgenic mice, CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation toward the monocyte lineage in vitro. In a SIRS model, HSCs were spared in CHRFAM7A-transgenic mice while depleted in wild-type; transgenic mice also showed increased immune cell mobilization and a shift to inflammatory monocytes from granulocytes in inflamed lungs.\",\n      \"method\": \"CHRFAM7A-transgenic mouse model; ligand binding assay; bone marrow HSC quantification; in vitro HSC differentiation assay; SIRS model with flow cytometry of lung immune cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model with multiple orthogonal readouts (ligand binding, HSC quantification, differentiation assay, in vivo SIRS model), consistent mechanistic findings\",\n      \"pmids\": [\"30944217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In iPSC-derived neurons harboring CHRFAM7A (1 copy vs. 0 copy), PNU-modulated desensitization of α7nAChR currents increased as a function of CHRFAM7A dosage. CHRFAM7A mitigated the dose-response of amyloid-beta (Aβ1-42) uptake, suggesting a protective effect at supra-physiological Aβ concentrations. In the presence of CHRFAM7A, Aβ1-42 uptake activated neuronal IL-1β and TNF-α without activating the canonical inflammasome pathway.\",\n      \"method\": \"iPSC-derived neurons with defined CHRFAM7A copy number; electrophysiology; Aβ1-42 uptake assay; cytokine measurement\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC model with genetic copy number control, electrophysiology and Aβ uptake assay, single lab\",\n      \"pmids\": [\"30710073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHRFAM7A expression in rat PC12 cells and CHRFAM7A-transgenic mice decreases α-bungarotoxin (α-BTX) binding to α7nAChR, as detected by immunohistochemistry and flow cytometry. In vivo, α-BTX co-staining with neurofilament at the neuromuscular junction was decreased in CHRFAM7A-transgenic mice compared to wild-type, demonstrating that CHRFAM7A interferes with α7nAChR ligand binding in vivo.\",\n      \"method\": \"Stable transfection of rat PC12 cells; α-BTX binding by immunohistochemistry and flow cytometry; CHRFAM7A-transgenic mouse neuromuscular junction staining\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo evidence, two orthogonal methods (IHC and flow cytometry), single lab\",\n      \"pmids\": [\"30308236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHRFAM7A overexpression in THP-1 human monocytic cells reduces cell migration, reduces chemotaxis to monocyte chemoattractant protein, and reduces colony formation in soft agar, demonstrating a direct role in regulating monocyte/macrophage migratory and proliferative behavior.\",\n      \"method\": \"Lentiviral gene delivery; Transwell migration assay; chemotaxis assay; soft agar colony formation assay\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene delivery with multiple functional assays, single lab\",\n      \"pmids\": [\"32303780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The direct and inverted CHRFAM7A alleles have distinct functional phenotypes with respect to α7nAChR electrophysiology and Aβ neurotoxicity in iPSC models. Functional CHRFAM7A allele classifies the population as ~25% non-carriers and ~75% carriers, and carrier status modifies AChEI therapy response in Alzheimer's disease patients.\",\n      \"method\": \"iPSC electrophysiology; Aβ uptake assay; double-blind pharmacogenetic clinical analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC functional assays plus clinical pharmacogenetic data, single group\",\n      \"pmids\": [\"32818803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHRFAM7A overexpression in OGD/R-treated microglia inhibited NLRP3 inflammasome activation and cell pyroptosis via the NLRP3/Caspase-1 pathway, and promoted polarization of microglia from M1 to M2 phenotype, thereby attenuating inflammatory injury.\",\n      \"method\": \"CHRFAM7A overexpression in OGD/R microglia model; NLRP3/Caspase-1 pathway activation assay; pyroptosis markers; M1/M2 phenotype markers (iNOS, Arg1)\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with pathway activation assay, single lab, limited mechanistic depth from abstract\",\n      \"pmids\": [\"33405023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In CHRFAM7A-transgenic mice, OA was more severe and mechanical allodynia was greater than in WT mice in the destabilization of medial meniscus model, associated with decreased suppression of inflammation by α7nAChR agonist. Transgenic mice showed higher basal sensitivity to pain stimuli and increased pain behavior in monoiodoacetate and formalin models. Dorsal root ganglia of transgenic mice showed increased macrophage infiltration and expression of fractalkine chemokine. Human chondrocytes with two CHRFAM7A copies had reduced anti-inflammatory response to nicotine.\",\n      \"method\": \"CHRFAM7A-transgenic mouse OA model; mechanical allodynia testing; pain behavior assays; DRG immunostaining; human chondrocyte culture with nicotine treatment\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with multiple pain and inflammation readouts plus human cell data, single study\",\n      \"pmids\": [\"36627169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHRFAM7A/α7nAChR functions as a hypomorphic receptor with mitigated Ca2+ influx and prolonged channel closed state compared to α7nAChR alone. This shifts the Ca2+ reservoir from extracellular space to the endoplasmic reticulum (ER), altering Ca2+ dynamics. The Ca2+ decoder small GTPase Rac1 is activated downstream, reorganizing the actin cytoskeleton and driving phenotypes including cellular adhesion, motility, phagocytosis, and tissue mechanosensation in iPSC-derived and primary monocyte models.\",\n      \"method\": \"Ca2+ imaging in iPSC-derived cells and primary monocytes; electrophysiology; Rac1 activation assay; actin cytoskeleton imaging; phagocytosis assay\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Ca2+ imaging, electrophysiology, Rac1 assay, actin imaging, phagocytosis) in two model systems (iPSC and primary monocytes), mechanistic pathway from receptor to phenotype established\",\n      \"pmids\": [\"38569318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHRFAM7A (dupα7) reduces α7nAChR-mediated calcium transients in response to multiple agonists (PNU282987, choline, 4BP-TQS) in hiPSC-derived cortical neurons and in SCG neurons from CHRFAM7A-transgenic mice, confirming dominant-negative reduction of α7nAChR function in neuronal cells.\",\n      \"method\": \"Fura-2 calcium imaging in hiPSC-derived cortical neurons and SCG neurons from transgenic mice; three different α7-specific ligands with PAM II PNU120596\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — calcium imaging with multiple agonists in two independent neuronal model systems (human iPSC and mouse transgenic), rigorous controls\",\n      \"pmids\": [\"39073048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Computational structural modeling of all possible dupα7/α7 pentameric combinations showed that receptors comprising four or more dupα7 subunits are not stable enough to form a functional ion channel. Models with dupα7/α7 interfaces are more stable and less detrimental to ion conductance than dupα7/dupα7 interfaces. The optimal stoichiometry for functional pentamers should include no more than three dupα7 monomers, favoring a dupα7/α7 interface. Receptors bearing dupα7 subunits are less sensitive to Aβ42 by protein-protein docking analysis.\",\n      \"method\": \"Atomistic molecular dynamics simulations; coarse-grain simulations; free energy calculations for Ca2+ conductance; protein-protein docking with α-bungarotoxin and Aβ42\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational modeling only, no experimental validation reported in this paper\",\n      \"pmids\": [\"34067314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHRFAM7A overexpression in HK-2 human renal tubular epithelial cells inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) and suppressed activation of the TGF-β1/Smad2/3 signaling pathway in vitro. In CHRFAM7A-transgenic mice subjected to UUO injury, transgenic overexpression decreased fibrotic gene expression, collagen deposition, TGF-β1 and Smad2/3 expression, and inflammatory cytokine release.\",\n      \"method\": \"CHRFAM7A overexpression in HK-2 cells; TGF-β1 stimulation; EMT marker quantification; Smad2/3 pathway activation assay; CHRFAM7A-transgenic mouse UUO model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo evidence with pathway (TGF-β1/Smad2/3) identified, single lab\",\n      \"pmids\": [\"36479618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHRFAM7A overexpression in a hypertrophic scar mouse model increased activation of the Notch pathway, which attenuated M2 macrophage polarization and increased M1 macrophages in the initial period, decreasing scar fibrosis.\",\n      \"method\": \"Lentiviral CHRFAM7A overexpression in mouse hypertrophic scar model; macrophage phenotype quantification (M1/M2); Notch pathway analysis; fibrosis assessment\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with pathway (Notch) identified but mechanistic depth limited from abstract\",\n      \"pmids\": [\"32890966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHRFAM7A CHRFAM7A gene expression in CHRFAM7A-transgenic mouse brain significantly modulated proteins involved in signaling pathways of α7nAChR-mediated neuropsychiatric disorders (Parkinson's, Alzheimer's, Huntington's disease, and alcoholism) as assessed by iTRAQ-2D-LC-MS/MS proteomic profiling.\",\n      \"method\": \"CHRFAM7A-transgenic mouse brain; iTRAQ-2D-LC-MS/MS proteomics; bioinformatics pathway analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomic profiling without direct mechanistic validation of specific pathway components, single lab\",\n      \"pmids\": [\"31348980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHRFAM7A transgenic mouse peritoneal macrophages exhibited decreased ligand-binding capability (reduced α7nAChR agonist binding) and an activated pro-inflammatory cytokine gene expression profile at basal state. When challenged with LPS, macrophages from transgenic mice showed an exaggerated pro-inflammatory response at earlier time points and lower LPS dosages compared to wild-type. Leukocyte mobilization and pro-inflammatory cytokine levels were significantly higher in transgenic mice at the early stage of sepsis.\",\n      \"method\": \"CHRFAM7A-transgenic mouse peritoneal macrophages; ligand binding assay; LPS stimulation; cytokine measurement; sepsis model with survival analysis\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with in vivo and ex vivo mechanistic readouts, validated with human monocyte data, single lab\",\n      \"pmids\": [\"37655479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHRFAM7A is expressed in SOX2+ progenitors and neurons in the developing human cortex, with particular enrichment along radial glia (RG) endfeet. nAChR activation increases RG proliferation while decreasing neuronal differentiation; knockdown reduces RG and increases neurons. Single-cell RNA-seq reveals that CHRNA7 and CHRFAM7A selectively modulate different gene changes in excitatory neurons upon nicotine exposure. YAP1 is identified as a downstream effector of nAChR signaling; YAP1 inhibition reverses nicotine-induced phenotypic alterations in outer RG cells.\",\n      \"method\": \"Organotypic slice cultures; dissociated cultures; nAChR knockdown; single-cell RNA sequencing; YAP1 inhibition experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, knockdown experiments in cortical slices; CHRFAM7A-specific effects not fully separated from CHRNA7 effects in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CHRFAM7A encodes dupα7, a human-specific truncated α7 nicotinic acetylcholine receptor subunit (lacking most of the N-terminal ligand-binding domain) that co-assembles with full-length α7 (CHRNA7) subunits to form heteropentameric receptors; these heteromers function as hypomorphic, dominant-negative ion channels with reduced Ca2+ influx, prolonged closed state, and reduced agonist/α-bungarotoxin binding, downstream of which Rac1 activation reorganizes the actin cytoskeleton to alter immune cell adhesion, motility, phagocytosis, and mechanosensation, while CHRFAM7A transcription is independently regulated by a unique 1-kb 5'-UTR promoter and is suppressed by LPS via NF-κB in monocytes/macrophages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHRFAM7A encodes dupα7, a human-specific, truncated α7 nicotinic acetylcholine receptor subunit that co-assembles with full-length α7 (CHRNA7) to act as a dominant-negative modulator of α7nAChR function [#0, #1]. dupα7 yields protein but no functional receptor on its own; co-expression with α7 reduces ACh- and nicotine-evoked currents dose-dependently while sparing α-bungarotoxin binding, indicating formation of ACh-silent heteromers and reduced trafficking of functional α7 to the membrane [#0, #1]. The resulting CHRFAM7A/α7 receptor behaves as a hypomorphic channel with reduced Ca2+ influx and a prolonged closed state, shifting the Ca2+ reservoir toward the endoplasmic reticulum and activating the small GTPase Rac1, which reorganizes the actin cytoskeleton to control monocyte/macrophage adhesion, motility, phagocytosis, and mechanosensation [#12]. This dominant-negative reduction of α7nAChR-mediated calcium signaling is conserved in human iPSC-derived neurons and mouse transgenic neurons and is detectable in vivo at the neuromuscular junction [#7, #13]. Because α7nAChR signaling restrains inflammation, CHRFAM7A reshapes immune output: it biases hematopoietic differentiation toward inflammatory monocytes and modulates leukocyte mobilization in systemic inflammation [#5, #18], and in macrophages it weakens cholinergic anti-inflammatory tone, producing exaggerated pro-inflammatory cytokine responses [#18]. CHRFAM7A transcription is controlled independently of CHRNA7 by a unique 1-kb 5'-UTR promoter that is strongly responsive to LPS, with NF-κB mediating its down-regulation in monocytes/macrophages [#2, #3, #4]. CHRFAM7A overexpression also remodels focal-adhesion and transepithelial-migration gene programs and reduces monocyte migration, chemotaxis, and anchorage-independent growth [#2, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that the duplicate gene product dupα7 is natively translated but cannot form functional receptors alone, and acts dominant-negatively when combined with α7 — defining its core molecular behavior.\",\n      \"evidence\": \"Xenopus oocyte electrophysiology with dose-response, α-bungarotoxin binding, and confocal imaging of membrane receptors, plus native expression in HL-60/macrophages\",\n      \"pmids\": [\"21047781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the heteromer not resolved\", \"Mechanism of reduced membrane trafficking not defined at the molecular level\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Confirmed in independent systems that co-assembly produces ACh-silent heteromers retaining toxin binding, and that an allosteric modulator can partially rescue function — refining the dominant-negative model as one of altered gating rather than absent receptor.\",\n      \"evidence\": \"Functional electrophysiology in oocytes and cell lines, I-BTX radioligand binding, and PNU-120596 pharmacological rescue\",\n      \"pmids\": [\"21718690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish receptor structure or subunit arrangement\", \"Physiological consequence in native cells not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified how CHRFAM7A expression is regulated independently of CHRNA7, showing transcriptional suppression by inflammatory signaling.\",\n      \"evidence\": \"Real-time PCR, Western blotting, and parthenolide inhibition in THP-1 monocytes implicating NF-κB\",\n      \"pmids\": [\"20926142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-κB binding to the promoter not shown directly\", \"Inhibitor-based, single cell line\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped a unique 1-kb 5'-UTR promoter as the basis for autonomous, LPS-responsive regulation of CHRFAM7A and linked its overexpression to focal-adhesion and migration gene programs.\",\n      \"evidence\": \"Promoter/luciferase mapping, stable overexpression with gene expression profiling, flow cytometry of surface α-bungarotoxin binding in THP-1 and gut epithelial cells\",\n      \"pmids\": [\"25860877\", \"25681457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription factors binding the 1-kb element not identified\", \"Mechanism by which CHRFAM7A upregulates CHRNA7 unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that CHRFAM7A interferes with α7nAChR ligand binding not only in vitro but in vivo, extending the dominant-negative effect to intact tissue including the neuromuscular junction.\",\n      \"evidence\": \"Stable transfection of PC12 cells and CHRFAM7A-transgenic mice; α-BTX binding by immunohistochemistry and flow cytometry\",\n      \"pmids\": [\"30308236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence at the NMJ not measured\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected the receptor-level defect to immune-system outcomes, showing CHRFAM7A biases hematopoiesis toward monocytes and alters immune cell mobilization in systemic inflammation.\",\n      \"evidence\": \"CHRFAM7A-transgenic mice with HSC quantification, in vitro differentiation, and a SIRS model with lung immune cell flow cytometry\",\n      \"pmids\": [\"30944217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-intrinsic vs systemic contribution to HSC bias not separated\", \"Direct link from Ca2+/Rac1 signaling to differentiation not yet shown here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tested CHRFAM7A function in human neurons with defined copy number, linking dosage to receptor desensitization and to modulation of amyloid-beta handling and neuronal cytokine output.\",\n      \"evidence\": \"iPSC-derived neurons (0 vs 1 copy), electrophysiology, Aβ1-42 uptake assay, cytokine measurement\",\n      \"pmids\": [\"30710073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of inflammasome-independent IL-1β/TNF-α activation undefined\", \"Supra-physiological Aβ concentrations used\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed direct CHRFAM7A control of monocyte migratory and proliferative behavior, and that allelic orientation (direct vs inverted) yields distinct functional phenotypes with clinical pharmacogenetic relevance.\",\n      \"evidence\": \"Lentiviral overexpression with Transwell migration, chemotaxis, and soft-agar assays; iPSC electrophysiology and Aβ assays with double-blind AChEI pharmacogenetic analysis\",\n      \"pmids\": [\"32303780\", \"32818803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mediators of reduced migration not pinpointed\", \"Clinical association is correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the downstream signaling chain, showing the hypomorphic receptor reshapes calcium dynamics (ER reservoir shift) to activate Rac1 and reorganize actin, mechanistically linking channel function to adhesion, motility, phagocytosis, and mechanosensation.\",\n      \"evidence\": \"Ca2+ imaging, electrophysiology, Rac1 activation assay, actin imaging, and phagocytosis assays in iPSC-derived cells and primary monocytes\",\n      \"pmids\": [\"38569318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling between ER Ca2+ shift and Rac1 GEF activation not molecularly defined\", \"Whether the same pathway operates in non-immune cells untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed the dominant-negative calcium phenotype across multiple agonists in two independent neuronal systems, solidifying generality of the functional effect.\",\n      \"evidence\": \"Fura-2 calcium imaging with three α7 ligands plus PAM in hiPSC-derived cortical neurons and SCG neurons from transgenic mice\",\n      \"pmids\": [\"39073048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal behavioral/circuit consequence not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structural basis of subunit stoichiometry, the molecular link between ER calcium redistribution and Rac1 activation, and CHRFAM7A's role in human cortical development converge to produce its immune and neuronal phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of the dupα7/α7 heteromer\", \"Direct GEF coupling Ca2+ to Rac1 unidentified\", \"Developmental role rests on preprint and is not cleanly separated from CHRNA7\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"α7 nicotinic acetylcholine receptor heteropentamer (dupα7/α7)\"],\n    \"partners\": [\"CHRNA7\", \"RAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}