{"gene":"NPTN","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1997,"finding":"Synaptic membrane glycoproteins gp65 and gp55 (rat Neuroplastin isoforms) were identified as members of the immunoglobulin superfamily, produced by alternative splicing of a single gene transcript. cDNA cloning revealed open reading frames of 397 and 281 amino acids containing three and two Ig domains respectively, with ~40% sequence identity to neurothelin/basigin. Expression in HEK293 cells with tunicamycin confirmed the core protein sizes match deglycosylated gp65 and gp55. Northern analysis showed gp65 is brain-specific while gp55 is ubiquitously expressed.","method":"cDNA library screening, heterologous expression in HEK293 cells, tunicamycin deglycosylation, Northern blot, in situ hybridization, immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — cDNA cloning with functional confirmation in heterologous cells, immunoprecipitation, multiple orthogonal methods in one study","pmids":["8995369"],"is_preprint":false},{"year":1998,"finding":"Gp65 and gp55 are produced by alternative splicing of the same gene and exhibit tissue-specific glycoforms. Deglycosylation studies demonstrated that outside the brain, all immunoreactive species derive from the gp55 isoform. Transfection of HEK cells with gp65 or gp55 cDNAs showed that glycosylation patterns depend on the cell type expressing these molecules, not solely on the isoform.","method":"Monoclonal antibody detection, concanavalin A binding, deglycosylation assays, HEK cell transfection","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods, single lab","pmids":["9662433"],"is_preprint":false},{"year":2014,"finding":"Neuroplastin Np65 and Np55 play roles in neurite outgrowth, regulation of inhibitory and excitatory synapses, and synaptic plasticity. Mechanistically, Np65 undergoes trans-homophilic binding leading to activation of p38 MAPK and internalization of GluR1 glutamate receptor subunits; both isoforms act as accessory proteins for monocarboxylate transporters affecting neuronal energy supply; and both bind GABA-A receptor α1, 2, and 5 subunits, regulating GABA-A receptor composition and localization. Neuroplastins also bind to and activate the fibroblast growth factor receptor (FGFR).","method":"Co-immunoprecipitation, cell adhesion assays, electrophysiology, receptor internalization assays, binding studies (review summarizing experimental findings from multiple primary studies)","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple labs, multiple orthogonal methods across primary studies summarized; review compilation","pmids":["25040546"],"is_preprint":false},{"year":2016,"finding":"Neuroplastin (NPTN) and basigin (BSG) were identified as obligatory subunits of the Xkr8 phospholipid scramblase complex. In BSG−/−NPTN−/− double-knockout cells, Xkr8 was retained intracellularly and failed to execute phosphatidylserine exposure upon apoptotic stimulation, demonstrating that BSG and NPTN chaperone Xkr8 to the plasma membrane. Upon apoptotic signaling, Xkr8 is cleaved at its C-terminus and the Xkr8/BSG or Xkr8/NPTN complex assembles into a higher-order complex (likely a heterotetramer of two Xkr8 and two BSG/NPTN molecules) required for scrambling activity. Mutational analysis of BSG showed that an atypical glutamic acid in its transmembrane region is required for association with Xkr8.","method":"Double-knockout cell lines (BSG−/−NPTN−/−), subcellular localization assays, phosphatidylserine exposure assay, co-immunoprecipitation, transmembrane domain mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — genetic knockout with defined molecular phenotype, mutagenesis, complex formation assay, multiple orthogonal methods","pmids":["27503893"],"is_preprint":false},{"year":2016,"finding":"Neuroplastin isoform Np55 is specifically expressed in stereocilia of outer hair cells (OHCs) but not inner hair cells. A point mutation in Nptn identified by ENU mutagenesis causes deafness in mice. Np55 is required for stable mechanical coupling of OHC stereocilia with the tectorial membrane; mutant mice lack cochlear amplification as shown by in vivo vibrometry. Hair bundles develop morphological defects with age and mechanotransduction is impaired. This reveals functional diversification between Np55 (OHC stereocilia function) and Np65 (synaptic regulation).","method":"ENU mutagenesis screen, in vivo vibrometry, immunofluorescence localization, cochlear microphonics recording, morphological analysis of hair bundles","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with multiple functional readouts (vibrometry, electrophysiology, morphology) across multiple methods","pmids":["27581460"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of human PMCA1 (hPMCA1) in complex with NPTN was solved at 4.1 Å overall (3.9 Å for the transmembrane domain). The single transmembrane helix of NPTN interacts with the TM8-9 linker and TM10 of hPMCA1. NPTN is required for hPMCA1 functional activity (Ca2+-ATPase function), and the NPTN-bound hPMCA1 resembles the E1-Mg2+ state of SERCA with an open cytoplasmic Ca2+ entry pathway. This established NPTN as an obligatory subunit of plasma membrane Ca2+-ATPases that dramatically increases efficiency of PMCA-mediated Ca2+ clearance.","method":"Cryo-EM structure determination, functional Ca2+-ATPase activity assay, transmembrane domain interaction analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure at near-atomic resolution with functional validation, strong mechanistic evidence","pmids":["30190470"],"is_preprint":false},{"year":2022,"finding":"Np55 is the functionally sufficient isoform for cochlear hair cell function and hearing. Np65-specific knockout mice have normal hearing thresholds, demonstrating Np65 is functionally redundant for hearing. Nptn-knockout OHCs have significantly reduced maximal MET currents and MET channel open probabilities, and both OHCs and IHCs fail to develop mature basolateral currents. Continued Neuroplastin expression in adult OHCs is required for membrane localization of PMCA2 (encoded by Atp2b2), which is essential for hearing. Nptn haploinsufficiency phenocopies Atp2b2 mutations and shows genetic interaction with the Cdh23ahl allele.","method":"Isoform-specific knockout mice, auditory brainstem response (ABR) threshold measurement, whole-cell patch-clamp electrophysiology (MET currents), immunofluorescence for PMCA2 localization, genetic interaction analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple distinct mouse genetic models, electrophysiology, protein localization, genetic epistasis; multiple orthogonal methods","pmids":["35100259"],"is_preprint":false},{"year":2022,"finding":"Neuroplastin Np55 and Np65 isoforms are present in cochlear cells, and the role of Neuroplastin in macrophages during bacterial infection was attributed to one of the two isoforms. Critical re-analysis indicates that assignment of macrophage roles requires distinguishing between Np55 and Np65 splice variants, as the two isoforms have distinct expression patterns and likely distinct functions in innate immune cells.","method":"Isoform-specific expression analysis, critical review of experimental evidence","journal":"Molecular immunology","confidence":"Low","confidence_rationale":"Tier 3–4 — commentary/critical discussion without new primary experimental data","pmids":["38615628"],"is_preprint":false},{"year":2015,"finding":"NPTN was identified as a component of the human interactome via high-throughput affinity-purification mass spectrometry (AP-MS) in HEK293T cells (BioPlex network), revealing protein-protein interaction partners for NPTN within the cellular proteome.","method":"Affinity-purification mass spectrometry (AP-MS), high-throughput interactome mapping","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 3 — single large-scale AP-MS dataset, no functional follow-up for NPTN specifically","pmids":["26186194"],"is_preprint":false},{"year":2021,"finding":"Proteome-scale BioPlex 3.0 interaction network confirmed NPTN interaction partners in both HEK293T and HCT116 cell lines via AP-MS, providing cell-line-specific interaction data for NPTN.","method":"Affinity-purification mass spectrometry (AP-MS) in two cell lines","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 3 — large-scale dataset, no NPTN-specific functional validation","pmids":["33961781"],"is_preprint":false}],"current_model":"NPTN encodes the Neuroplastin isoforms Np55 and Np65, members of the immunoglobulin superfamily produced by alternative splicing, which function as: (1) obligatory subunits of plasma membrane Ca2+-ATPases (PMCAs), with the NPTN transmembrane helix directly contacting PMCA1 TM8-9-linker and TM10 to enable Ca2+ clearance (cryo-EM validated); (2) chaperones that traffic the Xkr8 phospholipid scramblase to the plasma membrane for apoptotic phosphatidylserine exposure; (3) synaptic regulators mediating FGFR activation, p38 MAPK signaling via Np65 trans-homophilic binding, GluR1 internalization, GABA-A receptor localization, and monocarboxylate transporter function; and (4) essential factors for outer hair cell mechanotransduction and cochlear amplification, with Np55 specifically required in OHC stereocilia for PMCA2 membrane localization and tectorial membrane coupling."},"narrative":{"teleology":[{"year":1997,"claim":"Molecular cloning established that the synaptic glycoproteins gp65 and gp55 are immunoglobulin superfamily members produced by alternative splicing from a single gene, resolving the identity and domain architecture of Neuroplastin isoforms.","evidence":"cDNA library screening, heterologous expression in HEK293 cells with tunicamycin deglycosylation, Northern blot, and immunoprecipitation","pmids":["8995369"],"confidence":"High","gaps":["No binding partners or functional roles identified beyond structural characterization","Mechanism of tissue-specific splicing regulation unknown"]},{"year":1998,"claim":"Tissue-specific glycosylation was shown to depend on the expressing cell type rather than the isoform, establishing that post-translational modification diversity of Neuroplastin is host-cell-determined.","evidence":"Deglycosylation assays and HEK cell transfection with isoform-specific constructs","pmids":["9662433"],"confidence":"Medium","gaps":["Functional consequences of differential glycosylation remain unresolved","Single-lab observation without independent replication"]},{"year":2014,"claim":"A body of work revealed that Neuroplastin participates in synaptic regulation through multiple mechanisms: Np65 trans-homophilic binding activates p38 MAPK and drives GluR1 internalization, both isoforms act as monocarboxylate transporter accessories, and both bind GABA-A receptor subunits, placing NPTN at the intersection of excitatory/inhibitory synapse regulation and neuronal metabolism.","evidence":"Co-immunoprecipitation, cell adhesion assays, electrophysiology, receptor internalization assays across multiple primary studies (compiled in review)","pmids":["25040546"],"confidence":"Medium","gaps":["Structural basis of Np65 trans-homophilic interaction unknown","Relative contributions of FGFR vs. p38 MAPK arms to synaptic plasticity not dissected","Evidence compiled from review; individual findings vary in rigor"]},{"year":2016,"claim":"Two parallel discoveries revealed unexpected non-synaptic roles: NPTN was shown to be an obligatory subunit of the Xkr8 phospholipid scramblase complex required for apoptotic PS exposure, and Np55 was found to be essential for outer hair cell stereocilia function and cochlear amplification, broadening the gene's functional scope beyond the nervous system.","evidence":"BSG⁻/⁻NPTN⁻/⁻ double-knockout cells with scramblase assays and mutagenesis (Xkr8); ENU mutagenesis screen with in vivo vibrometry and cochlear microphonics (hearing)","pmids":["27503893","27581460"],"confidence":"High","gaps":["Stoichiometry and assembly pathway of the Xkr8–NPTN complex not fully resolved","Whether NPTN versus BSG preferentially partners with Xkr8 in specific tissues is unknown","Molecular basis of tectorial membrane coupling via Np55 not identified"]},{"year":2018,"claim":"Cryo-EM structure of the hPMCA1–NPTN complex at near-atomic resolution revealed the direct transmembrane interface and established NPTN as an obligatory PMCA subunit that opens the cytoplasmic Ca²⁺ entry pathway, providing the first structural explanation for NPTN-dependent Ca²⁺ clearance.","evidence":"Cryo-EM at 4.1 Å resolution with functional Ca²⁺-ATPase activity assays","pmids":["30190470"],"confidence":"High","gaps":["Structures of NPTN with PMCA2, PMCA3, or PMCA4 not determined","How NPTN binding shifts the conformational cycle of PMCAs beyond the E1-Mg²⁺ state is unresolved","Role of NPTN Ig ectodomains in PMCA regulation not addressed structurally"]},{"year":2022,"claim":"Isoform-specific knockout mice demonstrated that Np55, not Np65, is the functionally essential isoform for hearing; continued adult expression is required for PMCA2 membrane localization in OHCs, and NPTN haploinsufficiency genetically interacts with the Cdh23ahl deafness allele, directly linking NPTN dosage to hearing loss.","evidence":"Isoform-specific knockout mice, ABR thresholds, whole-cell patch-clamp for MET currents, PMCA2 immunofluorescence, genetic interaction with Cdh23ahl","pmids":["35100259"],"confidence":"High","gaps":["Mechanism by which NPTN maintains PMCA2 at the stereocilia membrane is unknown","Whether NPTN haploinsufficiency contributes to age-related hearing loss in humans is untested","How loss of NPTN impairs MET channel open probability independently of PMCA2 is unexplained"]},{"year":null,"claim":"The structural basis of Np65 trans-homophilic adhesion, the mechanism by which NPTN maintains PMCA2 at stereocilia membranes in adulthood, and the tissue-specific logic determining whether NPTN or BSG partners with Xkr8 and PMCAs remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of Np65 Ig1 domain in trans-homophilic configuration","No reconstitution of NPTN–PMCA2 complex for structural or functional analysis","Functional role of NPTN in immune cells beyond cochlea and brain lacks rigorous primary data"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5,6]}],"pathway":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5,6]}],"complexes":["PMCA1–NPTN complex","PMCA2–NPTN complex","Xkr8–NPTN scramblase complex"],"partners":["ATP2B1","ATP2B2","XKR8","BSG","FGFR1","GABRA1"],"other_free_text":[]},"mechanistic_narrative":"Neuroplastin (NPTN) encodes two immunoglobulin superfamily glycoproteins, Np65 (three Ig domains, brain-specific) and Np55 (two Ig domains, ubiquitous), generated by alternative splicing [PMID:8995369]. NPTN functions as an obligatory subunit of plasma membrane Ca²⁺-ATPases (PMCAs), with its single transmembrane helix contacting PMCA1 TM8–9 linker and TM10 to enable Ca²⁺ clearance, as demonstrated by cryo-EM at 4.1 Å resolution [PMID:30190470]; in cochlear outer hair cells, Np55 is specifically required for PMCA2 membrane localization, mechanotransduction, and tectorial membrane coupling, and its loss causes deafness in mice [PMID:27581460, PMID:35100259]. NPTN also serves as a chaperone that delivers the Xkr8 phospholipid scramblase to the plasma membrane, forming a heterocomplex essential for apoptotic phosphatidylserine exposure [PMID:27503893]. At synapses, Np65 mediates trans-homophilic adhesion activating p38 MAPK signaling and GluR1 internalization, binds GABA-A receptor subunits to regulate inhibitory synapse composition, and activates FGFR signaling [PMID:25040546]."},"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 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B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28298427","id":"PMC_28298427","title":"Systematic protein-protein interaction mapping for clinically relevant human GPCRs.","date":"2017","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/28298427","citation_count":58,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8619474","id":"PMC_8619474","title":"A \"double adaptor\" method for improved shotgun library construction.","date":"1996","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8619474","citation_count":53,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24514566","id":"PMC_24514566","title":"Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents.","date":"2014","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24514566","citation_count":48,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35170,"output_tokens":1549,"usd":0.064372},"stage2":{"model":"claude-opus-4-6","input_tokens":4783,"output_tokens":1449,"usd":0.09021},"total_usd":0.399702,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":47949,"output_tokens":4242,"usd":0.103738},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6631,"output_tokens":2444,"usd":0.141382}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Neuroplastin (NPTN) isoforms gp65 and gp55 are members of the immunoglobulin superfamily, produced by alternative splicing of the same gene, containing three and two Ig domains respectively, with ~40% sequence identity to neurothelin/basigin. Their identity was confirmed by recombinant expression in HEK293 cells and deglycosylation producing core proteins matching deglycosylated native gp65/gp55.\",\n      \"method\": \"cDNA library screening, recombinant expression in HEK293 cells with tunicamycin deglycosylation, immunoprecipitation with new antisera, Northern blot, in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in single study confirming 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 gene transcript; their pattern of glycosylation is cell-type dependent, as demonstrated by different glycoforms when expressed in HEK cells versus brain tissue, and all immunoreactive species outside brain are derived from gp55.\",\n      \"method\": \"Monoclonal antibody detection, concanavalin A binding, deglycosylation studies, transfection of HEK cells with gp65 or gp55 constructs\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct transfection experiments with deglycosylation confirming cell-type-dependent glycoforms\",\n      \"pmids\": [\"9662433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuroplastin isoform Np55 (NPTN) is expressed in stereocilia of outer hair cells (OHCs) but not inner hair cells, and is required for stable mechanical coupling of OHC stereocilia to the tectorial membrane and cochlear amplification; loss-of-function mutation causes absence of cochlear amplification in vivo.\",\n      \"method\": \"N-ethyl-N-nitrosourea mutagenesis screen, mouse genetics (Nptn mutant line), in vivo vibrometry, cochlear microphonics recordings, mechanotransduction current measurements, immunolocalization\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts (vibrometry, electrophysiology, morphology) in Nptn mutant mice\",\n      \"pmids\": [\"27581460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Np55 isoform of NPTN is sufficient for cochlear hair cell function; Np65-specific knockout mice have normal hearing thresholds. Nptn knockout reduces maximal MET currents and MET channel open probabilities in mature OHCs, impairs basolateral current development in both OHCs and IHCs, and is required for membrane localisation of PMCA2 (plasma membrane Ca2+ ATPase 2) in OHCs. Nptn haploinsufficiency genetically interacts with Cdh23ahl, causing hearing loss.\",\n      \"method\": \"Multiple mouse knockout models (Np65-specific KO, full Nptn-KO, hair-cell-specific KO), electrophysiology (MET currents, basolateral currents), auditory brainstem responses, immunolocalization of PMCA2, genetic epistasis with Cdh23ahl\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple distinct mouse models with orthogonal electrophysiological and molecular readouts\",\n      \"pmids\": [\"35100259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Neuroplastin (NPTN) is required for membrane localisation of PMCA2 in outer hair cells, establishing NPTN as an auxiliary subunit/regulator of plasma membrane calcium ATPase function in cochlear hair cells.\",\n      \"method\": \"Nptn knockout mice, immunolocalization of PMCA2, genetic interaction analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct loss-of-function with protein localisation readout replicated in multiple mouse models\",\n      \"pmids\": [\"35100259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NPTN forms an in-frame fusion with NRG1 (NPTN-NRG1 fusion) in lung adenocarcinoma, functioning as an oncogenic driver detectable by RNA-based NGS; the fusion confers sensitivity to afatinib (EGFR/HER2/HER4 inhibitor), placing NPTN-NRG1 upstream of HER signaling.\",\n      \"method\": \"RNA-based next-generation sequencing, clinical response to afatinib in patient with NPTN-NRG1 fusion\",\n      \"journal\": \"World journal of surgical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single case report, no in vitro mechanistic validation\",\n      \"pmids\": [\"37587479\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPTN encodes two alternatively spliced Ig-superfamily isoforms (Np55 and Np65) with cell-type-dependent glycosylation; Np55 localizes to OHC stereocilia where it maintains mechanical coupling to the tectorial membrane and is required for membrane localization of PMCA2, making it essential for cochlear amplification and hearing, while Np65 is implicated in synaptic plasticity regulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers only.\n\n**Classification:**\n\nPapers 1-11, 14-23, 25, 28-32, 34-36, 38-39, 42-43, 45-46, 49, 52-57, 59, 61-62, 64, 66-68, 71, 73-75: EXCLUDE — these are about gp55 from Friend SFFV, HCMV gB, classical swine fever virus, Leishmania, Aspergillus, zona pellucida, chick brain GP55, bacteriophage T4 gp55, Trypanosoma ISG65, murine mammary tumor virus, or rice SDR1. None are about human NPTN.\n\nPaper 12 (PMID:8995369): KEEP — directly identifies rat brain synaptic membrane glycoproteins gp65 and gp55 as new Ig superfamily members, establishing them as NPTN isoforms.\n\nPaper 13 (PMID:8672430): EXCLUDE — about mouse zona pellucida glycoprotein ZP3-derived gp55.\n\nPaper 24 (PMID:2771426): EXCLUDE — Leishmania GP65.\n\nPaper 26 (PMID:9004047): EXCLUDE — chick brain GP55 family (OBCAM/LAMP family), not NPTN orthologs.\n\nPaper 27 (PMID:9662433): KEEP — directly about Neuroplastin gp65/gp55 tissue distribution of glycoforms.\n\nPaper 31 (PMID:9058053): EXCLUDE — chick brain GP55, different protein family.\n\nPaper 33 (PMID:27581460): KEEP — about Neuroplastin Np55 in outer hair cells.\n\nPaper 37 (PMID:1662693): EXCLUDE — HCMV gp55.\n\nPaper 40 (PMID:2157800): EXCLUDE — HCMV gB.\n\nPaper 41 (PMID:15894629): EXCLUDE — SFFV gp55-P NMR structure.\n\nPaper 44 (PMID:2495728): EXCLUDE — aldosterone-induced GP65/70 in toad bladder.\n\nPaper 47 (PMID:12051907): EXCLUDE — bacteriophage T4 gp55.\n\nPaper 48 (PMID:9058053): EXCLUDE — chick brain GP55.\n\nPaper 50 (PMID:27217918): EXCLUDE — HCMV gp55.\n\nPaper 51 (PMID:35100259): KEEP — about Neuroplastin Np55/Np65 in cochlear hair cells.\n\nPaper 54 (PMID:37466368): EXCLUDE — Trypanosoma ISG65.\n\nPaper 58 (PMID:35703693): EXCLUDE — lncRNA study (alt-locus product, case B).\n\nPaper 60 (PMID:37587479): EXCLUDE — clinical case report about NPTN-NRG1 fusion, no mechanistic finding about NPTN protein.\n\nPaper 63 (PMID:3891758): EXCLUDE — GP-55 Golgi protein (actin-associated), different protein.\n\nPaper 65 (PMID:39145838): EXCLUDE — lncRNA NPTN-IT1-201 (alt-locus product, case B).\n\nPaper 69 (PMID:39105351): EXCLUDE — fission yeast Sdr1 transcription factor, symbol collision.\n\nPaper 70 (PMID:11699957): EXCLUDE — HHV-7 gp65.\n\nPaper 72 (PMID:38615628): KEEP — directly discusses Neuroplastin splice variants Np55/Np65 in macrophages.\n\n**Additional curated papers:**\n- PMID:26186194 (BioPlex): KEEP — identifies NPTN interactions via AP-MS\n- PMID:33961781 (BioPlex 3.0): KEEP — NPTN interactions\n- PMID:30190470 (PMID:30190470): KEEP — cryo-EM structure of PMCA1-NPTN complex\n- PMID:27503893: KEEP — NPTN as obligatory subunit of Xkr8 scramblase complex\n- PMID:25040546: KEEP — review of Neuroplastin mechanisms (cite only if mechanistic findings grounded in experiments described)\n- PMID:24514566: KEEP — SNP in NPTN locus affecting cortical thickness (but this is GWAS/expression, exclude from discoveries)\n- PMID:35271311 (OpenCell): KEEP for localization data\n- PMID:34349018, PMID:32296183, PMID:22939629: KEEP for interaction data\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Synaptic membrane glycoproteins gp65 and gp55 (rat Neuroplastin isoforms) were identified as members of the immunoglobulin superfamily, produced by alternative splicing of a single gene transcript. cDNA cloning revealed open reading frames of 397 and 281 amino acids containing three and two Ig domains respectively, with ~40% sequence identity to neurothelin/basigin. Expression in HEK293 cells with tunicamycin confirmed the core protein sizes match deglycosylated gp65 and gp55. Northern analysis showed gp65 is brain-specific while gp55 is ubiquitously expressed.\",\n      \"method\": \"cDNA library screening, heterologous expression in HEK293 cells, tunicamycin deglycosylation, Northern blot, in situ hybridization, immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cDNA cloning with functional confirmation in heterologous cells, immunoprecipitation, multiple orthogonal methods in one study\",\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 gene and exhibit tissue-specific glycoforms. Deglycosylation studies demonstrated that outside the brain, all immunoreactive species derive from the gp55 isoform. Transfection of HEK cells with gp65 or gp55 cDNAs showed that glycosylation patterns depend on the cell type expressing these molecules, not solely on the isoform.\",\n      \"method\": \"Monoclonal antibody detection, concanavalin A binding, deglycosylation assays, HEK cell transfection\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods, single lab\",\n      \"pmids\": [\"9662433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Neuroplastin Np65 and Np55 play roles in neurite outgrowth, regulation of inhibitory and excitatory synapses, and synaptic plasticity. Mechanistically, Np65 undergoes trans-homophilic binding leading to activation of p38 MAPK and internalization of GluR1 glutamate receptor subunits; both isoforms act as accessory proteins for monocarboxylate transporters affecting neuronal energy supply; and both bind GABA-A receptor α1, 2, and 5 subunits, regulating GABA-A receptor composition and localization. Neuroplastins also bind to and activate the fibroblast growth factor receptor (FGFR).\",\n      \"method\": \"Co-immunoprecipitation, cell adhesion assays, electrophysiology, receptor internalization assays, binding studies (review summarizing experimental findings from multiple primary studies)\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple labs, multiple orthogonal methods across primary studies summarized; review compilation\",\n      \"pmids\": [\"25040546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuroplastin (NPTN) and basigin (BSG) were identified as obligatory subunits of the Xkr8 phospholipid scramblase complex. In BSG−/−NPTN−/− double-knockout cells, Xkr8 was retained intracellularly and failed to execute phosphatidylserine exposure upon apoptotic stimulation, demonstrating that BSG and NPTN chaperone Xkr8 to the plasma membrane. Upon apoptotic signaling, Xkr8 is cleaved at its C-terminus and the Xkr8/BSG or Xkr8/NPTN complex assembles into a higher-order complex (likely a heterotetramer of two Xkr8 and two BSG/NPTN molecules) required for scrambling activity. Mutational analysis of BSG showed that an atypical glutamic acid in its transmembrane region is required for association with Xkr8.\",\n      \"method\": \"Double-knockout cell lines (BSG−/−NPTN−/−), subcellular localization assays, phosphatidylserine exposure assay, co-immunoprecipitation, transmembrane domain mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic knockout with defined molecular phenotype, mutagenesis, complex formation assay, multiple orthogonal methods\",\n      \"pmids\": [\"27503893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuroplastin isoform Np55 is specifically expressed in stereocilia of outer hair cells (OHCs) but not inner hair cells. A point mutation in Nptn identified by ENU mutagenesis causes deafness in mice. Np55 is required for stable mechanical coupling of OHC stereocilia with the tectorial membrane; mutant mice lack cochlear amplification as shown by in vivo vibrometry. Hair bundles develop morphological defects with age and mechanotransduction is impaired. This reveals functional diversification between Np55 (OHC stereocilia function) and Np65 (synaptic regulation).\",\n      \"method\": \"ENU mutagenesis screen, in vivo vibrometry, immunofluorescence localization, cochlear microphonics recording, morphological analysis of hair bundles\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with multiple functional readouts (vibrometry, electrophysiology, morphology) across multiple methods\",\n      \"pmids\": [\"27581460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of human PMCA1 (hPMCA1) in complex with NPTN was solved at 4.1 Å overall (3.9 Å for the transmembrane domain). The single transmembrane helix of NPTN interacts with the TM8-9 linker and TM10 of hPMCA1. NPTN is required for hPMCA1 functional activity (Ca2+-ATPase function), and the NPTN-bound hPMCA1 resembles the E1-Mg2+ state of SERCA with an open cytoplasmic Ca2+ entry pathway. This established NPTN as an obligatory subunit of plasma membrane Ca2+-ATPases that dramatically increases efficiency of PMCA-mediated Ca2+ clearance.\",\n      \"method\": \"Cryo-EM structure determination, functional Ca2+-ATPase activity assay, transmembrane domain interaction analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure at near-atomic resolution with functional validation, strong mechanistic evidence\",\n      \"pmids\": [\"30190470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Np55 is the functionally sufficient isoform for cochlear hair cell function and hearing. Np65-specific knockout mice have normal hearing thresholds, demonstrating Np65 is functionally redundant for hearing. Nptn-knockout OHCs have significantly reduced maximal MET currents and MET channel open probabilities, and both OHCs and IHCs fail to develop mature basolateral currents. Continued Neuroplastin expression in adult OHCs is required for membrane localization of PMCA2 (encoded by Atp2b2), which is essential for hearing. Nptn haploinsufficiency phenocopies Atp2b2 mutations and shows genetic interaction with the Cdh23ahl allele.\",\n      \"method\": \"Isoform-specific knockout mice, auditory brainstem response (ABR) threshold measurement, whole-cell patch-clamp electrophysiology (MET currents), immunofluorescence for PMCA2 localization, genetic interaction analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple distinct mouse genetic models, electrophysiology, protein localization, genetic epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"35100259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Neuroplastin Np55 and Np65 isoforms are present in cochlear cells, and the role of Neuroplastin in macrophages during bacterial infection was attributed to one of the two isoforms. Critical re-analysis indicates that assignment of macrophage roles requires distinguishing between Np55 and Np65 splice variants, as the two isoforms have distinct expression patterns and likely distinct functions in innate immune cells.\",\n      \"method\": \"Isoform-specific expression analysis, critical review of experimental evidence\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 — commentary/critical discussion without new primary experimental data\",\n      \"pmids\": [\"38615628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NPTN was identified as a component of the human interactome via high-throughput affinity-purification mass spectrometry (AP-MS) in HEK293T cells (BioPlex network), revealing protein-protein interaction partners for NPTN within the cellular proteome.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS), high-throughput interactome mapping\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single large-scale AP-MS dataset, no functional follow-up for NPTN specifically\",\n      \"pmids\": [\"26186194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Proteome-scale BioPlex 3.0 interaction network confirmed NPTN interaction partners in both HEK293T and HCT116 cell lines via AP-MS, providing cell-line-specific interaction data for NPTN.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS) in two cell lines\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — large-scale dataset, no NPTN-specific functional validation\",\n      \"pmids\": [\"33961781\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPTN encodes the Neuroplastin isoforms Np55 and Np65, members of the immunoglobulin superfamily produced by alternative splicing, which function as: (1) obligatory subunits of plasma membrane Ca2+-ATPases (PMCAs), with the NPTN transmembrane helix directly contacting PMCA1 TM8-9-linker and TM10 to enable Ca2+ clearance (cryo-EM validated); (2) chaperones that traffic the Xkr8 phospholipid scramblase to the plasma membrane for apoptotic phosphatidylserine exposure; (3) synaptic regulators mediating FGFR activation, p38 MAPK signaling via Np65 trans-homophilic binding, GluR1 internalization, GABA-A receptor localization, and monocarboxylate transporter function; and (4) essential factors for outer hair cell mechanotransduction and cochlear amplification, with Np55 specifically required in OHC stereocilia for PMCA2 membrane localization and tectorial membrane coupling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NPTN encodes neuroplastin, an immunoglobulin superfamily member that produces two alternatively spliced isoforms—Np65 (three Ig domains) and Np55 (two Ig domains)—with cell-type-dependent glycosylation patterns [PMID:8995369, PMID:9662433]. Np55 localizes to outer hair cell (OHC) stereocilia where it is essential for stable mechanical coupling of stereocilia to the tectorial membrane, cochlear amplification, normal mechanotransduction channel function, basolateral current maturation, and membrane localization of the plasma membrane Ca²⁺ ATPase PMCA2 [PMID:27581460, PMID:35100259]. The Np65 isoform is dispensable for hearing, as Np65-specific knockout mice retain normal auditory thresholds, while Nptn haploinsufficiency genetically interacts with the Cdh23ᵃʰˡ deafness allele to cause hearing loss [PMID:35100259].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Molecular cloning established that neuroplastin exists as two Ig-superfamily isoforms (gp65/gp55) generated by alternative splicing, resolving the molecular identity of previously characterized synaptic glycoproteins.\",\n      \"evidence\": \"cDNA library screening, recombinant expression in HEK293 cells, deglycosylation, Northern blot, and in situ hybridization\",\n      \"pmids\": [\"8995369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional role of either isoform was unknown\",\n        \"Tissue-specific expression pattern only partially mapped\",\n        \"No binding partners or signaling pathways identified\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cell-type-dependent glycosylation of neuroplastin isoforms was demonstrated, showing that glycoform diversity is not genomically encoded but depends on the expressing cell, and that non-brain tissues exclusively express gp55-derived species.\",\n      \"evidence\": \"Monoclonal antibody detection, concanavalin A binding, deglycosylation studies, and transfection of gp65/gp55 constructs in HEK cells versus brain tissue comparison\",\n      \"pmids\": [\"9662433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of glycoform variation was undetermined\",\n        \"No in vivo loss-of-function data existed\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Forward genetics in mice revealed that NPTN is essential for cochlear amplification: Np55 localizes to OHC stereocilia, mediates their mechanical coupling to the tectorial membrane, and its loss abolishes cochlear amplification without eliminating mechanotransduction per se.\",\n      \"evidence\": \"ENU mutagenesis screen, in vivo vibrometry, cochlear microphonics, mechanotransduction current recordings, and immunolocalization in Nptn mutant mice\",\n      \"pmids\": [\"27581460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Np65 contributes to hearing was not resolved\",\n        \"Molecular partners mediating tectorial membrane attachment were unknown\",\n        \"Mechanism by which NPTN affects transduction channel properties was unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Comprehensive genetic dissection showed that Np55 alone is sufficient for cochlear function while Np65 is dispensable, and identified NPTN as required for PMCA2 membrane localization and normal MET channel open probability in OHCs, establishing it as an auxiliary subunit of the PMCA2 calcium pump.\",\n      \"evidence\": \"Multiple mouse knockout models (Np65-specific KO, full Nptn-KO, hair-cell-specific KO), MET current and basolateral current electrophysiology, ABR, PMCA2 immunolocalization, and genetic epistasis with Cdh23ahl\",\n      \"pmids\": [\"35100259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical interaction interface between NPTN and PMCA2 has not been structurally resolved\",\n        \"How NPTN modulates MET channel open probability remains mechanistically unclear\",\n        \"Role of NPTN in inner hair cell basolateral current maturation is not fully understood\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of the NPTN–PMCA2 interaction, the mechanism by which NPTN influences mechanotransduction channel gating, and the in vivo synaptic plasticity functions attributed to Np65 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of NPTN–PMCA2 complex exists\",\n        \"Mechanism linking NPTN to MET channel gating is unknown\",\n        \"Np65 synaptic function lacks definitive in vivo loss-of-function evidence\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PMCA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Neuroplastin (NPTN) encodes two immunoglobulin superfamily glycoproteins, Np65 (three Ig domains, brain-specific) and Np55 (two Ig domains, ubiquitous), generated by alternative splicing [PMID:8995369]. NPTN functions as an obligatory subunit of plasma membrane Ca²⁺-ATPases (PMCAs), with its single transmembrane helix contacting PMCA1 TM8–9 linker and TM10 to enable Ca²⁺ clearance, as demonstrated by cryo-EM at 4.1 Å resolution [PMID:30190470]; in cochlear outer hair cells, Np55 is specifically required for PMCA2 membrane localization, mechanotransduction, and tectorial membrane coupling, and its loss causes deafness in mice [PMID:27581460, PMID:35100259]. NPTN also serves as a chaperone that delivers the Xkr8 phospholipid scramblase to the plasma membrane, forming a heterocomplex essential for apoptotic phosphatidylserine exposure [PMID:27503893]. At synapses, Np65 mediates trans-homophilic adhesion activating p38 MAPK signaling and GluR1 internalization, binds GABA-A receptor subunits to regulate inhibitory synapse composition, and activates FGFR signaling [PMID:25040546].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Molecular cloning established that the synaptic glycoproteins gp65 and gp55 are immunoglobulin superfamily members produced by alternative splicing from a single gene, resolving the identity and domain architecture of Neuroplastin isoforms.\",\n      \"evidence\": \"cDNA library screening, heterologous expression in HEK293 cells with tunicamycin deglycosylation, Northern blot, and immunoprecipitation\",\n      \"pmids\": [\"8995369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No binding partners or functional roles identified beyond structural characterization\",\n        \"Mechanism of tissue-specific splicing regulation unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Tissue-specific glycosylation was shown to depend on the expressing cell type rather than the isoform, establishing that post-translational modification diversity of Neuroplastin is host-cell-determined.\",\n      \"evidence\": \"Deglycosylation assays and HEK cell transfection with isoform-specific constructs\",\n      \"pmids\": [\"9662433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequences of differential glycosylation remain unresolved\",\n        \"Single-lab observation without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A body of work revealed that Neuroplastin participates in synaptic regulation through multiple mechanisms: Np65 trans-homophilic binding activates p38 MAPK and drives GluR1 internalization, both isoforms act as monocarboxylate transporter accessories, and both bind GABA-A receptor subunits, placing NPTN at the intersection of excitatory/inhibitory synapse regulation and neuronal metabolism.\",\n      \"evidence\": \"Co-immunoprecipitation, cell adhesion assays, electrophysiology, receptor internalization assays across multiple primary studies (compiled in review)\",\n      \"pmids\": [\"25040546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of Np65 trans-homophilic interaction unknown\",\n        \"Relative contributions of FGFR vs. p38 MAPK arms to synaptic plasticity not dissected\",\n        \"Evidence compiled from review; individual findings vary in rigor\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two parallel discoveries revealed unexpected non-synaptic roles: NPTN was shown to be an obligatory subunit of the Xkr8 phospholipid scramblase complex required for apoptotic PS exposure, and Np55 was found to be essential for outer hair cell stereocilia function and cochlear amplification, broadening the gene's functional scope beyond the nervous system.\",\n      \"evidence\": \"BSG⁻/⁻NPTN⁻/⁻ double-knockout cells with scramblase assays and mutagenesis (Xkr8); ENU mutagenesis screen with in vivo vibrometry and cochlear microphonics (hearing)\",\n      \"pmids\": [\"27503893\", \"27581460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and assembly pathway of the Xkr8–NPTN complex not fully resolved\",\n        \"Whether NPTN versus BSG preferentially partners with Xkr8 in specific tissues is unknown\",\n        \"Molecular basis of tectorial membrane coupling via Np55 not identified\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cryo-EM structure of the hPMCA1–NPTN complex at near-atomic resolution revealed the direct transmembrane interface and established NPTN as an obligatory PMCA subunit that opens the cytoplasmic Ca²⁺ entry pathway, providing the first structural explanation for NPTN-dependent Ca²⁺ clearance.\",\n      \"evidence\": \"Cryo-EM at 4.1 Å resolution with functional Ca²⁺-ATPase activity assays\",\n      \"pmids\": [\"30190470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structures of NPTN with PMCA2, PMCA3, or PMCA4 not determined\",\n        \"How NPTN binding shifts the conformational cycle of PMCAs beyond the E1-Mg²⁺ state is unresolved\",\n        \"Role of NPTN Ig ectodomains in PMCA regulation not addressed structurally\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Isoform-specific knockout mice demonstrated that Np55, not Np65, is the functionally essential isoform for hearing; continued adult expression is required for PMCA2 membrane localization in OHCs, and NPTN haploinsufficiency genetically interacts with the Cdh23ahl deafness allele, directly linking NPTN dosage to hearing loss.\",\n      \"evidence\": \"Isoform-specific knockout mice, ABR thresholds, whole-cell patch-clamp for MET currents, PMCA2 immunofluorescence, genetic interaction with Cdh23ahl\",\n      \"pmids\": [\"35100259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which NPTN maintains PMCA2 at the stereocilia membrane is unknown\",\n        \"Whether NPTN haploinsufficiency contributes to age-related hearing loss in humans is untested\",\n        \"How loss of NPTN impairs MET channel open probability independently of PMCA2 is unexplained\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of Np65 trans-homophilic adhesion, the mechanism by which NPTN maintains PMCA2 at stereocilia membranes in adulthood, and the tissue-specific logic determining whether NPTN or BSG partners with Xkr8 and PMCAs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of Np65 Ig1 domain in trans-homophilic configuration\",\n        \"No reconstitution of NPTN–PMCA2 complex for structural or functional analysis\",\n        \"Functional role of NPTN in immune cells beyond cochlea and brain lacks rigorous primary data\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\n      \"PMCA1–NPTN complex\",\n      \"PMCA2–NPTN complex\",\n      \"Xkr8–NPTN scramblase complex\"\n    ],\n    \"partners\": [\n      \"ATP2B1\",\n      \"ATP2B2\",\n      \"XKR8\",\n      \"BSG\",\n      \"FGFR1\",\n      \"GABRA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}