{"gene":"PILRA","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2000,"finding":"PILRA (FDF03) is a monomeric 44-kDa transmembrane glycoprotein with a single extracellular V-set Ig-like domain and two cytoplasmic ITIM-like sequences. Upon tyrosine phosphorylation (induced by pervanadate treatment in U937 cells), PILRA recruits SHP-2 and, to a lesser extent, SHP-1 via their SH2 domains. Cross-linking of PILRA inhibits calcium mobilization in response to CD32/FcγRII aggregation in transfected U937 cells, demonstrating its function as an inhibitory receptor.","method":"Overexpression in U937 cells, pervanadate stimulation, co-immunoprecipitation of SHP-1/SHP-2, calcium mobilization assay, cross-linking experiment","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional assays (pulldown + calcium mobilization inhibition) with clear mechanistic readout in a single rigorous study","pmids":["10903717"],"is_preprint":false},{"year":2000,"finding":"PILRA (FDF03) expression is restricted to cells of the myelomonocytic lineage (monocytes, macrophages, granulocytes, monocyte-derived dendritic cells, CD11c+ blood and tonsil DC), but not lymphocytes (B, T, NK cells), as determined by flow cytometry and tissue expression analysis.","method":"Flow cytometry, tissue expression profiling","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — direct localization/expression experiment with clear cellular specificity, replicated across multiple cell types","pmids":["10903717"],"is_preprint":false},{"year":2025,"finding":"PILRA knockout in human iPSC-derived microglia (iMG) rescued ApoE4-mediated immunometabolic deficits, prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics and antioxidant activity, enhanced microglial chemotaxis, and attenuated inflammation. These effects were mediated through PPAR and STAT1/3 signaling pathways (identified by pharmacological inhibitor studies). AD mice transplanted with PILRA KO human microglia showed reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand-blocking PILRA antibody phenocopied PILRA KO iMG.","method":"PILRA knockout in iPSC-derived microglia, chimeric AD mouse transplantation, pharmacological inhibitor studies (PPAR, STAT1/3), metabolic assays, amyloid pathology quantification, synaptic marker analysis, antibody blocking experiment","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (KO iMG, chimeric mice, pharmacological pathway dissection, antibody phenocopy) in a single rigorous study","pmids":["41337541"],"is_preprint":false},{"year":2025,"finding":"The synonymous variant rs2405442:T>C in PILRA destroys a ramp of slowly translated codons at the 5' end of the mRNA, directly reducing both PILRA mRNA and protein levels (measured by qPCR and ELISA in CHO cells), providing a translational regulatory mechanism for this AD-associated variant independent of the missense variant rs1859788.","method":"qPCR, ELISA in CHO cells expressing wildtype vs. mutant PILRA constructs","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal methods (qPCR + ELISA) in a single lab, mechanistically defined but not yet replicated independently","pmids":["40149715"],"is_preprint":false}],"current_model":"PILRA is an ITIM-bearing inhibitory immunoreceptor expressed on myeloid cells (monocytes, macrophages, granulocytes, dendritic cells, and microglia) that, upon activation, recruits SHP-1/SHP-2 phosphatases to suppress immune signaling (including calcium mobilization downstream of FcγRII); in microglia, PILRA suppresses immunometabolic fitness and amyloid clearance via PPAR and STAT1/3 pathways, and its expression level is regulated by a 5'-end translational ramp sequence."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing that PILRA is a myeloid-restricted inhibitory receptor resolved the question of whether this orphan Ig-superfamily gene encoded an activating or inhibitory molecule and defined its signaling mechanism through ITIM-mediated SHP-1/SHP-2 recruitment and calcium mobilization suppression.","evidence":"Overexpression in U937 cells, pervanadate-induced co-immunoprecipitation of SHP-1/SHP-2, and cross-linking-based calcium mobilization inhibition assay","pmids":["10903717"],"confidence":"High","gaps":["Endogenous ligand(s) for PILRA were not identified in this study","Downstream signaling consequences beyond calcium suppression not explored","In vivo functional role in tissue-resident myeloid cells not addressed"]},{"year":2025,"claim":"Demonstrating that PILRA knockout in human microglia rescues immunometabolic deficits and reduces amyloid pathology in vivo established PILRA as a tonic brake on microglial protective functions relevant to Alzheimer's disease, acting through PPAR and STAT1/3 pathways.","evidence":"PILRA KO in iPSC-derived microglia, chimeric AD mouse transplantation, pharmacological PPAR/STAT1/3 inhibitor studies, metabolic and amyloid quantification, ligand-blocking antibody phenocopy","pmids":["41337541"],"confidence":"High","gaps":["Precise molecular link between ITIM-proximal SHP phosphatase activity and downstream PPAR/STAT1/3 signaling not delineated","Contribution of individual ligands to microglial PILRA engagement in the AD brain not resolved","Whether PILRA blockade affects non-microglial myeloid populations in the CNS is unknown"]},{"year":2025,"claim":"Identifying a translational ramp mechanism at the PILRA 5′ end explained how the synonymous AD-protective variant rs2405442 reduces PILRA expression independently of the linked missense variant, adding a post-transcriptional regulatory layer to PILRA biology.","evidence":"qPCR and ELISA quantification of wildtype vs. variant PILRA constructs in CHO cells","pmids":["40149715"],"confidence":"Medium","gaps":["Not yet independently replicated or validated in primary myeloid or microglial cells","Whether reduced PILRA protein from this variant is sufficient to alter microglial function in vivo is untested","Structural basis for ramp-dependent translational regulation not resolved"]},{"year":null,"claim":"It remains unknown how PILRA's proximal ITIM/SHP signaling mechanistically connects to the PPAR and STAT1/3 pathways that govern its metabolic and inflammatory effects in microglia, and the full repertoire of physiological ligands driving PILRA engagement in healthy and diseased tissues is incompletely defined.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted biochemical pathway from ITIM phosphorylation to PPAR/STAT transcriptional output","Structural basis for PILRA ligand recognition and selectivity not fully characterized","Role of PILRA in non-CNS myeloid biology (e.g., infection, autoimmunity) largely unexplored in mechanistic terms"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["PTPN6","PTPN11"],"other_free_text":[]},"mechanistic_narrative":"PILRA is an ITIM-bearing inhibitory immunoreceptor expressed on myelomonocytic cells—including monocytes, macrophages, granulocytes, dendritic cells, and microglia—that recruits SHP-1 and SHP-2 phosphatases upon tyrosine phosphorylation to suppress activating immune signals such as calcium mobilization downstream of FcγRII [PMID:10903717]. In microglia, PILRA suppresses immunometabolic fitness, lipid storage, mitochondrial bioenergetics, and amyloid clearance through PPAR and STAT1/3 signaling pathways; genetic deletion or antibody-mediated blockade of PILRA in iPSC-derived microglia rescues these deficits, and transplantation of PILRA-knockout human microglia into Alzheimer's disease model mice reduces amyloid pathology and restores synaptic markers [PMID:41337541]. PILRA expression is regulated at the translational level by a 5′-end ramp of slowly translated codons, and the synonymous Alzheimer's-protective variant rs2405442:T>C disrupts this ramp to reduce both mRNA and protein levels [PMID:40149715]."},"prefetch_data":{"uniprot":{"accession":"Q9UKJ1","full_name":"Paired immunoglobulin-like type 2 receptor alpha","aliases":["Cell surface receptor FDF03","Inhibitory receptor PILR-alpha"],"length_aa":303,"mass_kda":34.0,"function":"Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRA is thought to act as a cellular signaling inhibitory receptor by recruiting cytoplasmic phosphatases like PTPN6/SHP-1 and PTPN11/SHP-2 via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules. Receptor for PIANP (Microbial infection) Acts as an entry co-receptor for herpes simplex virus 1","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UKJ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PILRA","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PILRA","total_profiled":1310},"omim":[{"mim_id":"616065","title":"PILR-ALPHA-ASSOCIATED NEURAL PROTEIN; PIANP","url":"https://www.omim.org/entry/616065"},{"mim_id":"605342","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, BETA; PILRB","url":"https://www.omim.org/entry/605342"},{"mim_id":"605341","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, ALPHA; PILRA","url":"https://www.omim.org/entry/605341"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PILRA"},"hgnc":{"alias_symbol":["FDF03"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKJ1","domains":[{"cath_id":"2.60.40.10","chopping":"41-151","consensus_level":"medium","plddt":95.5938,"start":41,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ1-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PILRA","jax_strain_url":"https://www.jax.org/strain/search?query=PILRA"},"sequence":{"accession":"Q9UKJ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKJ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKJ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ1"}},"corpus_meta":[{"pmid":"10903717","id":"PMC_10903717","title":"FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10903717","citation_count":88,"is_preprint":false},{"pmid":"29181857","id":"PMC_29181857","title":"Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.","date":"2018","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29181857","citation_count":36,"is_preprint":false},{"pmid":"35918447","id":"PMC_35918447","title":"PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer's disease risk.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35918447","citation_count":18,"is_preprint":false},{"pmid":"37396579","id":"PMC_37396579","title":"PILRA is associated with immune cells infiltration in atrial fibrillation based on bioinformatics and experiment validation.","date":"2023","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37396579","citation_count":15,"is_preprint":false},{"pmid":"31297637","id":"PMC_31297637","title":"The PILRA G78R Variant Correlates with Higher HSV-1-Specific IgG Titers in Alzheimer's Disease.","date":"2019","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31297637","citation_count":15,"is_preprint":false},{"pmid":"34206597","id":"PMC_34206597","title":"A Possible Role for HSV-1-Specific Humoral Response and PILRA rs1859788 Polymorphism in the Pathogenesis of Parkinson's Disease.","date":"2021","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/34206597","citation_count":10,"is_preprint":false},{"pmid":"40149715","id":"PMC_40149715","title":"Ramp Sequence May Explain Synonymous Variant Association with Alzheimer's Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA).","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40149715","citation_count":4,"is_preprint":false},{"pmid":"41337541","id":"PMC_41337541","title":"Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41337541","citation_count":2,"is_preprint":false},{"pmid":"26399532","id":"PMC_26399532","title":"Cloning and identification of splice variants of the porcine PILRA gene.","date":"2015","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/26399532","citation_count":1,"is_preprint":false},{"pmid":"39149451","id":"PMC_39149451","title":"The paired immunoglobulin-like type 2 receptor alpha (PILRA) gene polymorphism rs1859788 reduces risk of Alzheimer's Disease in men homozygous for the ApoE ε4 allele.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/39149451","citation_count":1,"is_preprint":false},{"pmid":"39829933","id":"PMC_39829933","title":"Ramp sequence may explain synonymous variant association with Alzheimer's disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA).","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39829933","citation_count":1,"is_preprint":false},{"pmid":"38408113","id":"PMC_38408113","title":"New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes.","date":"2024","source":"Medwave","url":"https://pubmed.ncbi.nlm.nih.gov/38408113","citation_count":0,"is_preprint":false},{"pmid":"41546015","id":"PMC_41546015","title":"Decoding the diabetes-pancreatic adenocarcinoma connection: the critical role of PILRA in intermediate monocyte activity.","date":"2026","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41546015","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.06.631528","title":"Ramp sequence may explain synonymous variant association with Alzheimer’s disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (<i>PILRA</i>)","date":"2025-01-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.06.631528","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.07.25321860","title":"Proteome-wide Mendelian randomization analyses to identify potential therapeutic targets for lung function and respiratory disease","date":"2025-02-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.07.25321860","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9734,"output_tokens":1242,"usd":0.023916},"stage2":{"model":"claude-opus-4-6","input_tokens":4450,"output_tokens":1440,"usd":0.087375},"total_usd":0.111291,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"PILRA (FDF03) is a monomeric 44-kDa transmembrane glycoprotein with a single extracellular V-set Ig-like domain and two cytoplasmic ITIM-like sequences. Upon tyrosine phosphorylation (induced by pervanadate treatment in U937 cells), PILRA recruits SHP-2 and, to a lesser extent, SHP-1 via their SH2 domains. Cross-linking of PILRA inhibits calcium mobilization in response to CD32/FcγRII aggregation in transfected U937 cells, demonstrating its function as an inhibitory receptor.\",\n      \"method\": \"Overexpression in U937 cells, pervanadate stimulation, co-immunoprecipitation of SHP-1/SHP-2, calcium mobilization assay, cross-linking experiment\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional assays (pulldown + calcium mobilization inhibition) with clear mechanistic readout in a single rigorous study\",\n      \"pmids\": [\"10903717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PILRA (FDF03) expression is restricted to cells of the myelomonocytic lineage (monocytes, macrophages, granulocytes, monocyte-derived dendritic cells, CD11c+ blood and tonsil DC), but not lymphocytes (B, T, NK cells), as determined by flow cytometry and tissue expression analysis.\",\n      \"method\": \"Flow cytometry, tissue expression profiling\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization/expression experiment with clear cellular specificity, replicated across multiple cell types\",\n      \"pmids\": [\"10903717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PILRA knockout in human iPSC-derived microglia (iMG) rescued ApoE4-mediated immunometabolic deficits, prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics and antioxidant activity, enhanced microglial chemotaxis, and attenuated inflammation. These effects were mediated through PPAR and STAT1/3 signaling pathways (identified by pharmacological inhibitor studies). AD mice transplanted with PILRA KO human microglia showed reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand-blocking PILRA antibody phenocopied PILRA KO iMG.\",\n      \"method\": \"PILRA knockout in iPSC-derived microglia, chimeric AD mouse transplantation, pharmacological inhibitor studies (PPAR, STAT1/3), metabolic assays, amyloid pathology quantification, synaptic marker analysis, antibody blocking experiment\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (KO iMG, chimeric mice, pharmacological pathway dissection, antibody phenocopy) in a single rigorous study\",\n      \"pmids\": [\"41337541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The synonymous variant rs2405442:T>C in PILRA destroys a ramp of slowly translated codons at the 5' end of the mRNA, directly reducing both PILRA mRNA and protein levels (measured by qPCR and ELISA in CHO cells), providing a translational regulatory mechanism for this AD-associated variant independent of the missense variant rs1859788.\",\n      \"method\": \"qPCR, ELISA in CHO cells expressing wildtype vs. mutant PILRA constructs\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal methods (qPCR + ELISA) in a single lab, mechanistically defined but not yet replicated independently\",\n      \"pmids\": [\"40149715\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PILRA is an ITIM-bearing inhibitory immunoreceptor expressed on myeloid cells (monocytes, macrophages, granulocytes, dendritic cells, and microglia) that, upon activation, recruits SHP-1/SHP-2 phosphatases to suppress immune signaling (including calcium mobilization downstream of FcγRII); in microglia, PILRA suppresses immunometabolic fitness and amyloid clearance via PPAR and STAT1/3 pathways, and its expression level is regulated by a 5'-end translational ramp sequence.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PILRA is an ITIM-bearing inhibitory immunoreceptor expressed on myelomonocytic cells—including monocytes, macrophages, granulocytes, dendritic cells, and microglia—that recruits SHP-1 and SHP-2 phosphatases upon tyrosine phosphorylation to suppress activating immune signals such as calcium mobilization downstream of FcγRII [PMID:10903717]. In microglia, PILRA suppresses immunometabolic fitness, lipid storage, mitochondrial bioenergetics, and amyloid clearance through PPAR and STAT1/3 signaling pathways; genetic deletion or antibody-mediated blockade of PILRA in iPSC-derived microglia rescues these deficits, and transplantation of PILRA-knockout human microglia into Alzheimer's disease model mice reduces amyloid pathology and restores synaptic markers [PMID:41337541]. PILRA expression is regulated at the translational level by a 5′-end ramp of slowly translated codons, and the synonymous Alzheimer's-protective variant rs2405442:T>C disrupts this ramp to reduce both mRNA and protein levels [PMID:40149715].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that PILRA is a myeloid-restricted inhibitory receptor resolved the question of whether this orphan Ig-superfamily gene encoded an activating or inhibitory molecule and defined its signaling mechanism through ITIM-mediated SHP-1/SHP-2 recruitment and calcium mobilization suppression.\",\n      \"evidence\": \"Overexpression in U937 cells, pervanadate-induced co-immunoprecipitation of SHP-1/SHP-2, and cross-linking-based calcium mobilization inhibition assay\",\n      \"pmids\": [\"10903717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous ligand(s) for PILRA were not identified in this study\",\n        \"Downstream signaling consequences beyond calcium suppression not explored\",\n        \"In vivo functional role in tissue-resident myeloid cells not addressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that PILRA knockout in human microglia rescues immunometabolic deficits and reduces amyloid pathology in vivo established PILRA as a tonic brake on microglial protective functions relevant to Alzheimer's disease, acting through PPAR and STAT1/3 pathways.\",\n      \"evidence\": \"PILRA KO in iPSC-derived microglia, chimeric AD mouse transplantation, pharmacological PPAR/STAT1/3 inhibitor studies, metabolic and amyloid quantification, ligand-blocking antibody phenocopy\",\n      \"pmids\": [\"41337541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise molecular link between ITIM-proximal SHP phosphatase activity and downstream PPAR/STAT1/3 signaling not delineated\",\n        \"Contribution of individual ligands to microglial PILRA engagement in the AD brain not resolved\",\n        \"Whether PILRA blockade affects non-microglial myeloid populations in the CNS is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying a translational ramp mechanism at the PILRA 5′ end explained how the synonymous AD-protective variant rs2405442 reduces PILRA expression independently of the linked missense variant, adding a post-transcriptional regulatory layer to PILRA biology.\",\n      \"evidence\": \"qPCR and ELISA quantification of wildtype vs. variant PILRA constructs in CHO cells\",\n      \"pmids\": [\"40149715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not yet independently replicated or validated in primary myeloid or microglial cells\",\n        \"Whether reduced PILRA protein from this variant is sufficient to alter microglial function in vivo is untested\",\n        \"Structural basis for ramp-dependent translational regulation not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how PILRA's proximal ITIM/SHP signaling mechanistically connects to the PPAR and STAT1/3 pathways that govern its metabolic and inflammatory effects in microglia, and the full repertoire of physiological ligands driving PILRA engagement in healthy and diseased tissues is incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No reconstituted biochemical pathway from ITIM phosphorylation to PPAR/STAT transcriptional output\",\n        \"Structural basis for PILRA ligand recognition and selectivity not fully characterized\",\n        \"Role of PILRA in non-CNS myeloid biology (e.g., infection, autoimmunity) largely unexplored in mechanistic terms\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PTPN6\",\n      \"PTPN11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}