{"gene":"NPTN","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"Neuroplastin glycoproteins gp65 and gp55 are members of the immunoglobulin superfamily, containing three and two Ig domains respectively, produced by alternative splicing of the same gene transcript. The identity was confirmed by immunoprecipitation with antisera against a recombinant fragment and by expression in HEK293 cells treated with tunicamycin, yielding unglycosylated core proteins of identical size to deglycosylated native gp65/gp55. gp65 transcripts are brain-specific while gp55 is expressed in most tissues.","method":"cDNA library screening, recombinant protein expression, immunoprecipitation, Northern blot, in situ hybridization, tunicamycin deglycosylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (cloning, expression, immunoprecipitation, deglycosylation) in a single rigorous study establishing identity and IgSF membership","pmids":["8995369"],"is_preprint":false},{"year":1998,"finding":"Gp65 and gp55 are produced by alternative splicing of the same NPTN gene transcript. In all tissues tested other than brain, immunoreactive species are derived from gp55. The pattern of glycosylation of gp65 and gp55 is dependent upon the cell type in which they are expressed, as shown by transfection of HEK cells with gp65 or gp55 constructs yielding different glycoforms from those in brain.","method":"Monoclonal antibody tissue profiling, concanavalin A binding, deglycosylation studies, transfection of HEK cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — single lab, multiple methods (lectin binding, deglycosylation, transfection) confirming alternative splicing and cell-type-dependent glycosylation","pmids":["9662433"],"is_preprint":false},{"year":2016,"finding":"Neuroplastin isoform Np55 is expressed in stereocilia of outer hair cells (OHCs) but not inner hair cells, and is required for normal OHC function. In Nptn mutant mice generated by ENU mutagenesis, OHC stereocilia fail to maintain stable interactions with the tectorial membrane, cochlear amplification is absent as measured by in vivo vibrometry, and mechanotransduction is progressively impaired. Np65 is implicated in synaptic function while Np55 is essential for OHC function, demonstrating functional diversification through differential splicing.","method":"ENU mutagenesis screen, immunolocalization, in vivo vibrometry, cochlear microphonics recordings, mechanotransduction current measurements","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with multiple orthogonal functional readouts (vibrometry, electrophysiology, mechanotransduction) establishing isoform-specific role","pmids":["27581460"],"is_preprint":false},{"year":2022,"finding":"Np65-specific knockout mice have normal hearing thresholds, indicating Np65 is functionally redundant for hearing. In contrast, Nptn-knockout mice show significantly reduced maximal mechanotransduction (MET) currents and MET channel open probabilities in mature OHCs, and both OHCs and IHCs fail to develop fully mature basolateral currents. Continued expression of Neuroplastin in OHCs of adult mice is required for membrane localization of Plasma Membrane Ca2+ ATPase 2 (PMCA2). Nptn haploinsufficiency phenocopies Atp2b2 mutations, and heterozygous Nptn-knockout mice exhibit hearing loss through genetic interaction with the Cdh23ahl allele.","method":"Conditional and global knockout mouse models, auditory brainstem response, patch-clamp electrophysiology in hair cells, immunolocalization of PMCA2, genetic epistasis with Cdh23ahl and Atp2b2","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple mouse models, electrophysiology, protein localization, and genetic epistasis establishing Np55 as required for PMCA2 membrane targeting and MET channel function","pmids":["35100259"],"is_preprint":false},{"year":2024,"finding":"Neuroplastin functions as an auxiliary subunit of plasma membrane calcium ATPases (PMCAs) in both neurons and adaptive immune cells. The paper critically discusses isoform-specific assignment of this role between Np55 and Np65 in macrophages.","method":"Literature analysis and critical discussion of published experimental data on splice variants in macrophages","journal":"Molecular immunology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — commentary/critical discussion without new primary experimental data; PMCA auxiliary subunit role referenced from prior work not directly assayed in this paper","pmids":["38615628"],"is_preprint":false}],"current_model":"Neuroplastin (NPTN) is an immunoglobulin superfamily cell adhesion molecule expressed as two alternatively spliced isoforms, Np65 (brain-specific, three Ig domains) and Np55 (ubiquitous, two Ig domains); Np55 localizes to outer hair cell stereocilia and is required for mechanotransduction current amplitude, PMCA2 membrane localization, and stable coupling of OHC stereocilia to the tectorial membrane, while Np65 is dispensable for hearing but implicated in synaptic regulation, and both isoforms can serve as auxiliary subunits of plasma membrane calcium ATPases."},"narrative":{"mechanistic_narrative":"Neuroplastin (NPTN) is an immunoglobulin superfamily glycoprotein produced as two alternatively spliced isoforms from a single transcript: Np65, which contains three Ig domains and is brain-specific, and Np55, which contains two Ig domains and is broadly expressed across tissues [PMID:8995369, PMID:9662433]. These isoforms are functionally diversified: Np55 localizes to the stereocilia of outer hair cells (OHCs) and is required for normal cochlear function, where its loss abolishes stable coupling of OHC stereocilia to the tectorial membrane, eliminates cochlear amplification, and progressively impairs mechanotransduction, whereas Np65 is dispensable for hearing [PMID:27581460, PMID:35100259]. Mechanistically, continued Neuroplastin expression in adult OHCs is required for membrane localization of the plasma membrane Ca2+ ATPase PMCA2, and Nptn loss reduces maximal mechanotransduction current and channel open probability while preventing maturation of basolateral currents in both OHCs and inner hair cells; Nptn haploinsufficiency phenocopies Atp2b2 mutations and interacts genetically with the Cdh23ahl allele to produce hearing loss [PMID:35100259]. Across neurons and adaptive immune cells, Neuroplastin serves as an auxiliary subunit of plasma membrane calcium ATPases [PMID:38615628].","teleology":[{"year":1997,"claim":"Establishing that the two neuroplastin glycoproteins are not distinct gene products but splice isoforms of one gene defined the molecular identity of NPTN and placed it in the immunoglobulin superfamily.","evidence":"cDNA cloning, recombinant expression, immunoprecipitation, and tunicamycin deglycosylation showing gp65 (three Ig domains, brain-specific) and gp55 (two Ig domains, broad) share a common core","pmids":["8995369"],"confidence":"High","gaps":["No ligand or binding partner identified","No functional role assigned to either isoform","Subcellular localization not resolved beyond tissue expression"]},{"year":1998,"claim":"Confirming alternative splicing as the origin of the isoforms and demonstrating cell-type-dependent glycosylation showed that NPTN protein diversity arises at both the transcript and post-translational levels.","evidence":"monoclonal antibody tissue profiling, concanavalin A lectin binding, deglycosylation, and HEK cell transfection","pmids":["9662433"],"confidence":"Medium","gaps":["Functional consequence of differential glycosylation not tested","No mechanism linking splicing to any cellular process"]},{"year":2016,"claim":"Identifying Np55 in OHC stereocilia and showing that Nptn mutation abolishes cochlear amplification and tectorial-membrane coupling assigned the first concrete physiological function and demonstrated isoform-specific diversification.","evidence":"ENU mutagenesis mouse model, immunolocalization, in vivo vibrometry, cochlear microphonics, and mechanotransduction current measurements","pmids":["27581460"],"confidence":"High","gaps":["Molecular partner mediating stereocilia–tectorial membrane coupling not identified","Mechanism by which Np55 supports mechanotransduction not resolved","Np65 synaptic role not directly tested here"]},{"year":2022,"claim":"Defining the requirement of Neuroplastin for PMCA2 membrane localization and demonstrating genetic interaction with Atp2b2 and Cdh23ahl established a molecular mechanism: NPTN supports hair cell calcium handling and current maturation, with Np65 redundant for hearing.","evidence":"conditional and global knockout mice, ABR, hair cell patch-clamp, PMCA2 immunolocalization, and genetic epistasis","pmids":["35100259"],"confidence":"High","gaps":["Structural basis of NPTN–PMCA2 association not defined","How NPTN loss reduces MET channel open probability mechanistically unclear","Relationship between basolateral current maturation defect and PMCA2 not fully separated"]},{"year":2024,"claim":"Generalizing the PMCA auxiliary-subunit role to neurons and adaptive immune cells extended NPTN beyond the cochlea, but the isoform-specific assignment in macrophages remains contested.","evidence":"critical literature discussion of splice-variant data in macrophages (no new primary data)","pmids":["38615628"],"confidence":"Low","gaps":["Commentary without new primary experimental data","Np55 vs Np65 assignment in macrophages unresolved","Direct PMCA interaction not assayed in this work"]},{"year":null,"claim":"The structural basis of the NPTN–PMCA interaction and the molecular function of brain-specific Np65 at synapses remain to be defined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of NPTN–PMCA complex","Np65 synaptic mechanism uncharacterized in the available corpus","Extracellular Ig-domain ligands unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[3]}],"complexes":[],"partners":["ATP2B2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y639","full_name":"Neuroplastin","aliases":["Stromal cell-derived receptor 1","SDR-1"],"length_aa":398,"mass_kda":44.4,"function":"Probable homophilic and heterophilic cell adhesion molecule involved in long term potentiation at hippocampal excitatory synapses through activation of p38MAPK. May also regulate neurite outgrowth by activating the FGFR1 signaling pathway. May play a role in synaptic plasticity (By similarity). Also acts as a chaperone for ATP2B1; stabilizes ATP2B1 and increases its ATPase activity (PubMed:30190470). Promotes localization of XKR8 at the cell membrane (PubMed:27503893)","subcellular_location":"Postsynaptic density","url":"https://www.uniprot.org/uniprotkb/Q9Y639/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPTN","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/NPTN","total_profiled":1310},"omim":[{"mim_id":"619940","title":"X KELL BLOOD GROUP PRECURSOR-RELATED FAMILY, MEMBER 8; XKR8","url":"https://www.omim.org/entry/619940"},{"mim_id":"615176","title":"NPTN INTRONIC TRANSCRIPT 1, NONCODING; NPTNIT1","url":"https://www.omim.org/entry/615176"},{"mim_id":"612820","title":"NEUROPLASTIN; NPTN","url":"https://www.omim.org/entry/612820"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NPTN"},"hgnc":{"alias_symbol":["SDR1","GP55","GP65","np65","np55"],"prev_symbol":["SDFR1"]},"alphafold":{"accession":"Q9Y639","domains":[{"cath_id":"2.60.40.10","chopping":"29-121_135-144","consensus_level":"high","plddt":94.7479,"start":29,"end":144},{"cath_id":"2.60.40.10","chopping":"148-236","consensus_level":"high","plddt":93.1244,"start":148,"end":236},{"cath_id":"2.60.40.10","chopping":"244-333","consensus_level":"high","plddt":96.2817,"start":244,"end":333}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y639","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y639-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y639-F1-predicted_aligned_error_v6.png","plddt_mean":86.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPTN","jax_strain_url":"https://www.jax.org/strain/search?query=NPTN"},"sequence":{"accession":"Q9Y639","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y639.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y639/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y639"}},"corpus_meta":[{"pmid":"2154701","id":"PMC_2154701","title":"Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor.","date":"1990","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2154701","citation_count":448,"is_preprint":false},{"pmid":"2154594","id":"PMC_2154594","title":"Cell surface expression of human cytomegalovirus (HCMV) gp55-116 (gB): use of HCMV-recombinant vaccinia virus-infected cells in analysis of the human neutralizing antibody response.","date":"1990","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/2154594","citation_count":278,"is_preprint":false},{"pmid":"2161534","id":"PMC_2161534","title":"Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of 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endogenous mink cell focus-forming virus env gene.","date":"1984","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/6464355","citation_count":17,"is_preprint":false},{"pmid":"2495728","id":"PMC_2495728","title":"Aldosterone-induced proteins: purification and localization of GP65,70.","date":"1989","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2495728","citation_count":17,"is_preprint":false},{"pmid":"9058053","id":"PMC_9058053","title":"GP55 inhibits both cell adhesion and growth of neurons, but not non-neuronal cells, via a G-protein-coupled receptor.","date":"1997","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9058053","citation_count":16,"is_preprint":false},{"pmid":"12496274","id":"PMC_12496274","title":"Mutational and functional analysis of a segment of the sigma family bacteriophage T4 late promoter recognition protein gp55.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12496274","citation_count":16,"is_preprint":false},{"pmid":"1451111","id":"PMC_1451111","title":"The interaction of the erythropoietin receptor and gp55.","date":"1992","source":"Cancer surveys","url":"https://pubmed.ncbi.nlm.nih.gov/1451111","citation_count":15,"is_preprint":false},{"pmid":"27217918","id":"PMC_27217918","title":"Single Chain Antibodies Against gp55 of Human Cytomegalovirus (HCMV) for Prophylaxis and Treatment of HCMV Infections.","date":"2016","source":"Jundishapur journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27217918","citation_count":12,"is_preprint":false},{"pmid":"35100259","id":"PMC_35100259","title":"Neuroplastin genetically interacts with Cadherin 23 and the encoded isoform Np55 is sufficient for cochlear hair cell function and hearing.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35100259","citation_count":11,"is_preprint":false},{"pmid":"20016000","id":"PMC_20016000","title":"Activation of the N-terminally truncated form of the Stk receptor tyrosine kinase Sf-Stk by Friend virus-encoded gp55 is mediated by cysteine residues in the ecotropic domain of gp55 and the extracellular domain of Sf-Stk.","date":"2009","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/20016000","citation_count":11,"is_preprint":false},{"pmid":"9875316","id":"PMC_9875316","title":"Role of the transmembrane sequence of spleen focus-forming virus gp55 in erythroleukemogenesis.","date":"1998","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/9875316","citation_count":10,"is_preprint":false},{"pmid":"37466368","id":"PMC_37466368","title":"Trypanosoma brucei Invariant Surface gp65 Inhibits the Alternative Pathway of Complement by Accelerating C3b Degradation.","date":"2023","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/37466368","citation_count":9,"is_preprint":false},{"pmid":"8507186","id":"PMC_8507186","title":"Erythropoietin receptor binds to Friend virus gp55 through other membrane components.","date":"1993","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8507186","citation_count":9,"is_preprint":false},{"pmid":"7494268","id":"PMC_7494268","title":"Both the changes of six amino acids and the C-terminal truncation caused by a one-base insertion in the defective env gene of Friend spleen focus-forming virus significantly affect the pathogenic activity of the encoded leukemogenic membrane glycoprotein (gp55).","date":"1995","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/7494268","citation_count":9,"is_preprint":false},{"pmid":"8468555","id":"PMC_8468555","title":"The role of gp55 N-glycosylation in pathogenesis of Friend spleen focus-forming virus.","date":"1993","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/8468555","citation_count":8,"is_preprint":false},{"pmid":"35703693","id":"PMC_35703693","title":"LncRNA KCNQ1OT1 promotes the apoptosis and inflammatory response of microglia by regulating the miR-589-5p/NPTN axis after spinal cord injury.","date":"2022","source":"Anais da Academia Brasileira de Ciencias","url":"https://pubmed.ncbi.nlm.nih.gov/35703693","citation_count":7,"is_preprint":false},{"pmid":"8779689","id":"PMC_8779689","title":"Tumor necrosis factor-induced expression of porcine glycoproteins gp65 and gp100 recognized by human xenoreactive natural antibodies.","date":"1996","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/8779689","citation_count":6,"is_preprint":false},{"pmid":"37587479","id":"PMC_37587479","title":"Durable response to afatinib in advanced lung adenocarcinoma harboring a novel NPTN-NRG1 fusion: a case report.","date":"2023","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37587479","citation_count":6,"is_preprint":false},{"pmid":"7744699","id":"PMC_7744699","title":"A mouse erythroleukemia cell line possessing friend spleen focus-forming virus gp55 transgene and temperature-sensitive mutant p53 gene.","date":"1995","source":"Japanese journal of cancer research : Gann","url":"https://pubmed.ncbi.nlm.nih.gov/7744699","citation_count":6,"is_preprint":false},{"pmid":"9209415","id":"PMC_9209415","title":"Activation of the JAK1-STAT5 pathway by binding of the Friend virus gp55 glycoprotein to the erythropoietin receptor.","date":"1997","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9209415","citation_count":6,"is_preprint":false},{"pmid":"9852060","id":"PMC_9852060","title":"Abortive initiation of transcription at a hybrid promoter. An analysis of the sliding clamp activator of bacteriophage T4 late transcription, and a comparison of the sigma70 and T4 gp55 promoter recognition proteins.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9852060","citation_count":6,"is_preprint":false},{"pmid":"3891758","id":"PMC_3891758","title":"Purification and characterization of GP-55, a protein associated with actin-based cytoplasmic gels derived from brain tissue.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3891758","citation_count":6,"is_preprint":false},{"pmid":"39145838","id":"PMC_39145838","title":"LncRNA NPTN-IT1-201 Ameliorates Depressive-like Behavior by Targeting miR-142-5p and Regulating Inflammation and Apoptosis via BDNF.","date":"2024","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/39145838","citation_count":5,"is_preprint":false},{"pmid":"9778688","id":"PMC_9778688","title":"Role of gp55 in restoring the sensitivity of Friend murine erythroleukemia cells to erythropoietin by exposure to dimethyl sulfoxide.","date":"1998","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/9778688","citation_count":3,"is_preprint":false},{"pmid":"9657942","id":"PMC_9657942","title":"Impaired activation and binding of the erythropoietin receptor by a mutant gp55 of Friend spleen focus-forming virus, which has a cytoplasmic domain.","date":"1998","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/9657942","citation_count":2,"is_preprint":false},{"pmid":"9499086","id":"PMC_9499086","title":"Sequence flexibility in the polytropic env gp70-derived region of the membrane glycoprotein (gp55) of Friend spleen focus-forming virus affects its biological activity.","date":"1998","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9499086","citation_count":2,"is_preprint":false},{"pmid":"11699957","id":"PMC_11699957","title":"Epitope mapping of human herpesvirus-7 gp65 using monoclonal antibodies.","date":"2001","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/11699957","citation_count":1,"is_preprint":false},{"pmid":"9623923","id":"PMC_9623923","title":"Pathogenicity of a mutant friend spleen focus-forming virus encoding an Env-like membrane glycoprotein (gp55) with substitution by a xenotropic murine leukemia virus Env gp70 sequence.","date":"1998","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9623923","citation_count":1,"is_preprint":false},{"pmid":"38615628","id":"PMC_38615628","title":"Neuroplastin splice variants Np55 and Np65: Who is doing the job in macrophages?","date":"2024","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38615628","citation_count":0,"is_preprint":false},{"pmid":"41826994","id":"PMC_41826994","title":"Neoadjuvant afatinib in a patient with locally advanced lung adenocarcinoma harboring an NPTN-NRG1 fusion: a case report.","date":"2026","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41826994","citation_count":0,"is_preprint":false},{"pmid":"19069792","id":"PMC_19069792","title":"[Preparation and characteristics of monoclonal antibodies to protein E2 (GP55) of classical hog cholera virus].","date":"2008","source":"Voprosy virusologii","url":"https://pubmed.ncbi.nlm.nih.gov/19069792","citation_count":0,"is_preprint":false},{"pmid":"9209329","id":"PMC_9209329","title":"Mutational analysis of the structure-function relationship of the leukemogenic membrane glycoprotein (GP55) of Friend spleen focus-forming virus (F-SFFV).","date":"1997","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9209329","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35531,"output_tokens":2002,"usd":0.068311,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8350,"output_tokens":2230,"usd":0.04875,"stage2_stop_reason":"end_turn"},"total_usd":0.117061,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the canonical NPTN gene (neuroplastin, GP55/GP65 isoforms, also known as np55/np65/SDFR1).\n\nKey papers about NPTN:\n- Paper 12 (PMID:8995369): Identifies gp65 and gp55 as IgSF members from rat synaptic membranes\n- Paper 26 (PMID:9662433): Tissue distribution of glycoforms, alternative splicing\n- Paper 32 (PMID:27581460): Np55 in stereocilia of OHCs, required for OHC function\n- Paper 51 (PMID:35100259): Np55 sufficient for hair cell function; Nptn required for PMCA2 membrane localization; genetic interaction with Cdh23\n- Paper 71 (PMID:38615628): Role of Np55/Np65 in macrophages, auxiliary subunit of plasma membrane calcium ATPases\n\nMost other papers are about SFFV gp55 (viral), HCMV gp55 (viral), classical swine fever gp55, Leishmania GP65, Aspergillus gp55, Trypanosoma gp65, etc. — these are symbol collisions.\n\nPaper 58 (PMID:35703693) is about lncRNA/miRNA, not the canonical protein.\nPaper 65 (PMID:39145838) is about lncRNA NPTN-IT1-201, not canonical protein.\nPaper 60/72 are about NPTN-NRG1 fusion oncogene in cancer, clinical case reports with no mechanistic experiment on NPTN protein itself.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Neuroplastin glycoproteins gp65 and gp55 are members of the immunoglobulin superfamily, containing three and two Ig domains respectively, produced by alternative splicing of the same gene transcript. The identity was confirmed by immunoprecipitation with antisera against a recombinant fragment and by expression in HEK293 cells treated with tunicamycin, yielding unglycosylated core proteins of identical size to deglycosylated native gp65/gp55. gp65 transcripts are brain-specific while gp55 is expressed in most tissues.\",\n      \"method\": \"cDNA library screening, recombinant protein expression, immunoprecipitation, Northern blot, in situ hybridization, tunicamycin deglycosylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cloning, expression, immunoprecipitation, deglycosylation) in a single rigorous study establishing identity and IgSF membership\",\n      \"pmids\": [\"8995369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Gp65 and gp55 are produced by alternative splicing of the same NPTN gene transcript. In all tissues tested other than brain, immunoreactive species are derived from gp55. The pattern of glycosylation of gp65 and gp55 is dependent upon the cell type in which they are expressed, as shown by transfection of HEK cells with gp65 or gp55 constructs yielding different glycoforms from those in brain.\",\n      \"method\": \"Monoclonal antibody tissue profiling, concanavalin A binding, deglycosylation studies, transfection of HEK cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — single lab, multiple methods (lectin binding, deglycosylation, transfection) confirming alternative splicing and cell-type-dependent glycosylation\",\n      \"pmids\": [\"9662433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuroplastin isoform Np55 is expressed in stereocilia of outer hair cells (OHCs) but not inner hair cells, and is required for normal OHC function. In Nptn mutant mice generated by ENU mutagenesis, OHC stereocilia fail to maintain stable interactions with the tectorial membrane, cochlear amplification is absent as measured by in vivo vibrometry, and mechanotransduction is progressively impaired. Np65 is implicated in synaptic function while Np55 is essential for OHC function, demonstrating functional diversification through differential splicing.\",\n      \"method\": \"ENU mutagenesis screen, immunolocalization, in vivo vibrometry, cochlear microphonics recordings, mechanotransduction current measurements\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with multiple orthogonal functional readouts (vibrometry, electrophysiology, mechanotransduction) establishing isoform-specific role\",\n      \"pmids\": [\"27581460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Np65-specific knockout mice have normal hearing thresholds, indicating Np65 is functionally redundant for hearing. In contrast, Nptn-knockout mice show significantly reduced maximal mechanotransduction (MET) currents and MET channel open probabilities in mature OHCs, and both OHCs and IHCs fail to develop fully mature basolateral currents. Continued expression of Neuroplastin in OHCs of adult mice is required for membrane localization of Plasma Membrane Ca2+ ATPase 2 (PMCA2). Nptn haploinsufficiency phenocopies Atp2b2 mutations, and heterozygous Nptn-knockout mice exhibit hearing loss through genetic interaction with the Cdh23ahl allele.\",\n      \"method\": \"Conditional and global knockout mouse models, auditory brainstem response, patch-clamp electrophysiology in hair cells, immunolocalization of PMCA2, genetic epistasis with Cdh23ahl and Atp2b2\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple mouse models, electrophysiology, protein localization, and genetic epistasis establishing Np55 as required for PMCA2 membrane targeting and MET channel function\",\n      \"pmids\": [\"35100259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neuroplastin functions as an auxiliary subunit of plasma membrane calcium ATPases (PMCAs) in both neurons and adaptive immune cells. The paper critically discusses isoform-specific assignment of this role between Np55 and Np65 in macrophages.\",\n      \"method\": \"Literature analysis and critical discussion of published experimental data on splice variants in macrophages\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — commentary/critical discussion without new primary experimental data; PMCA auxiliary subunit role referenced from prior work not directly assayed in this paper\",\n      \"pmids\": [\"38615628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Neuroplastin (NPTN) is an immunoglobulin superfamily cell adhesion molecule expressed as two alternatively spliced isoforms, Np65 (brain-specific, three Ig domains) and Np55 (ubiquitous, two Ig domains); Np55 localizes to outer hair cell stereocilia and is required for mechanotransduction current amplitude, PMCA2 membrane localization, and stable coupling of OHC stereocilia to the tectorial membrane, while Np65 is dispensable for hearing but implicated in synaptic regulation, and both isoforms can serve as auxiliary subunits of plasma membrane calcium ATPases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Neuroplastin (NPTN) is an immunoglobulin superfamily glycoprotein produced as two alternatively spliced isoforms from a single transcript: Np65, which contains three Ig domains and is brain-specific, and Np55, which contains two Ig domains and is broadly expressed across tissues [#0, #1]. These isoforms are functionally diversified: Np55 localizes to the stereocilia of outer hair cells (OHCs) and is required for normal cochlear function, where its loss abolishes stable coupling of OHC stereocilia to the tectorial membrane, eliminates cochlear amplification, and progressively impairs mechanotransduction, whereas Np65 is dispensable for hearing [#2, #3]. Mechanistically, continued Neuroplastin expression in adult OHCs is required for membrane localization of the plasma membrane Ca2+ ATPase PMCA2, and Nptn loss reduces maximal mechanotransduction current and channel open probability while preventing maturation of basolateral currents in both OHCs and inner hair cells; Nptn haploinsufficiency phenocopies Atp2b2 mutations and interacts genetically with the Cdh23ahl allele to produce hearing loss [#3]. Across neurons and adaptive immune cells, Neuroplastin serves as an auxiliary subunit of plasma membrane calcium ATPases [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that the two neuroplastin glycoproteins are not distinct gene products but splice isoforms of one gene defined the molecular identity of NPTN and placed it in the immunoglobulin superfamily.\",\n      \"evidence\": \"cDNA cloning, recombinant expression, immunoprecipitation, and tunicamycin deglycosylation showing gp65 (three Ig domains, brain-specific) and gp55 (two Ig domains, broad) share a common core\",\n      \"pmids\": [\"8995369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No ligand or binding partner identified\",\n        \"No functional role assigned to either isoform\",\n        \"Subcellular localization not resolved beyond tissue expression\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Confirming alternative splicing as the origin of the isoforms and demonstrating cell-type-dependent glycosylation showed that NPTN protein diversity arises at both the transcript and post-translational levels.\",\n      \"evidence\": \"monoclonal antibody tissue profiling, concanavalin A lectin binding, deglycosylation, and HEK cell transfection\",\n      \"pmids\": [\"9662433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of differential glycosylation not tested\",\n        \"No mechanism linking splicing to any cellular process\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying Np55 in OHC stereocilia and showing that Nptn mutation abolishes cochlear amplification and tectorial-membrane coupling assigned the first concrete physiological function and demonstrated isoform-specific diversification.\",\n      \"evidence\": \"ENU mutagenesis mouse model, immunolocalization, in vivo vibrometry, cochlear microphonics, and mechanotransduction current measurements\",\n      \"pmids\": [\"27581460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular partner mediating stereocilia\\u2013tectorial membrane coupling not identified\",\n        \"Mechanism by which Np55 supports mechanotransduction not resolved\",\n        \"Np65 synaptic role not directly tested here\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining the requirement of Neuroplastin for PMCA2 membrane localization and demonstrating genetic interaction with Atp2b2 and Cdh23ahl established a molecular mechanism: NPTN supports hair cell calcium handling and current maturation, with Np65 redundant for hearing.\",\n      \"evidence\": \"conditional and global knockout mice, ABR, hair cell patch-clamp, PMCA2 immunolocalization, and genetic epistasis\",\n      \"pmids\": [\"35100259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of NPTN\\u2013PMCA2 association not defined\",\n        \"How NPTN loss reduces MET channel open probability mechanistically unclear\",\n        \"Relationship between basolateral current maturation defect and PMCA2 not fully separated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Generalizing the PMCA auxiliary-subunit role to neurons and adaptive immune cells extended NPTN beyond the cochlea, but the isoform-specific assignment in macrophages remains contested.\",\n      \"evidence\": \"critical literature discussion of splice-variant data in macrophages (no new primary data)\",\n      \"pmids\": [\"38615628\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Commentary without new primary experimental data\",\n        \"Np55 vs Np65 assignment in macrophages unresolved\",\n        \"Direct PMCA interaction not assayed in this work\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of the NPTN\\u2013PMCA interaction and the molecular function of brain-specific Np65 at synapses remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of NPTN\\u2013PMCA complex\",\n        \"Np65 synaptic mechanism uncharacterized in the available corpus\",\n        \"Extracellular Ig-domain ligands unidentified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATP2B2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}