{"gene":"GYPC","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2014,"finding":"Glycophorin C (CD236R/GYPC) functions as a receptor mediating Plasmodium vivax rosetting of infected erythrocytes to normocytes. Antibody fragment (Fab) against the BRIC 4 region of CD236R significantly inhibited rosette formation, and CD236R knockdown normocytes derived from hematopoietic stem cells showed reduced rosetting, establishing GYPC as a direct rosetting receptor for P. vivax.","method":"Anti-CD236R antibody inhibition assays, CD236R knockdown normocytes derived from hematopoietic stem cells, ex vivo rosetting assays with P. vivax isolates","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional approaches (antibody inhibition + receptor knockdown), single lab, two orthogonal methods establishing receptor role","pmids":["24652986"],"is_preprint":false},{"year":2005,"finding":"Ligation of glycophorin C (GPC) on erythrocytes with monoclonal antibody BRIC-10 induces phosphatidylserine (PS) exposure on the outer leaflet of the erythrocyte membrane. This effect requires the extracellular domain of GPC: Gerbich variant phenotypes with truncated extracellular domains (Yus, exon 2 deletion; Gerbich, exon 3 deletion) did not expose PS following GPC ligation, while Ls(a) erythrocytes (exon 3 duplication) did. GPC ligation also resulted in loss of erythrocyte viability after 24 h, identifying a pathway linking GPC to PS exposure and red cell turnover.","method":"Annexin V binding assay for PS detection, tryptic digestion controls, comparison of wild-type vs. Gerbich variant erythrocytes (Yus, Gerbich, Ls(a) phenotypes)","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with multiple variant controls and trypsin digestion, single lab","pmids":["15801965"],"is_preprint":false},{"year":2009,"finding":"GYPC encodes two distinct erythrocyte surface sialoglycoproteins, glycophorin C (GPC) and glycophorin D (GPD), via initiation of translation at two different start codons on a single transcript. The ability to encode both GPC and GPD is a uniquely human trait caused by evolution of the GPC start codon in the human lineage; GPD continues to be produced through leaky translation. Molecular evolutionary analysis revealed accelerated nonsynonymous divergence of GYPC specifically in the human lineage, consistent with positive selection, hypothesized to be driven by P. falciparum invasion pressure.","method":"Comparative genomic sequence analysis across Hominoidea, population genetics analysis of human polymorphism, translation initiation codon mapping","journal":"Molecular biology and evolution","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — primarily computational/comparative genomic analysis with no direct in vitro or in vivo mechanistic experiment on protein function","pmids":["19679754"],"is_preprint":false},{"year":2017,"finding":"Three classes of GYPC exon deletions underlie rare Gerbich blood group phenotypes: deletion of exon 2 (Yus type, GE:-2,3,4), deletion of exon 3 (Gerbich type, GE:-2,-3,4), and deletion of exons 3 and 4 (Leach type). Molecular characterization of 29 rare samples revealed that a 3600 bp region encompassing exon 2 shares high sequence homology with the region flanking exon 3, indicating an evolutionary duplication event that predisposes to these deletions. The intracellular portion of GPC stabilizes red blood cell membranes through interaction with protein 4.1 and p55.","method":"Molecular genotyping of 29 rare blood samples with Yus and Gerbich phenotypes; sequence homology analysis of GYPC genomic regions","journal":"British journal of haematology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — genotyping of clinical samples with structural inference; protein 4.1/p55 interaction cited as prior knowledge, not experimentally confirmed in this study","pmids":["28272739"],"is_preprint":false}],"current_model":"GYPC encodes two erythrocyte surface sialoglycoproteins, glycophorin C (GPC) and glycophorin D (GPD), from a single transcript via alternative translation initiation; GPC functions as a receptor on the red cell surface that mediates P. vivax rosetting to normocytes and, upon ligation, triggers phosphatidylserine exposure and loss of erythrocyte viability through its extracellular domain, while its intracellular domain stabilizes the red cell membrane through interactions with protein 4.1 and p55."},"narrative":{"mechanistic_narrative":"GYPC encodes glycophorin C, an erythrocyte surface sialoglycoprotein that acts as a receptor on the red cell surface and contributes to red cell turnover and host-pathogen interaction [PMID:24652986, PMID:15801965]. Glycophorin C serves as a direct rosetting receptor for Plasmodium vivax, mediating adhesion of infected erythrocytes to normocytes; antibody blockade of its BRIC 4 region and receptor knockdown both reduce rosette formation [PMID:24652986]. Ligation of the glycophorin C extracellular domain triggers phosphatidylserine exposure on the outer membrane leaflet and subsequent loss of erythrocyte viability, a response that depends on an intact extracellular domain as shown by its absence in Gerbich-variant erythrocytes bearing truncating exon deletions [PMID:15801965]. A single GYPC transcript yields two proteins, glycophorin C and glycophorin D, through alternative translation initiation at two start codons [PMID:19679754]. Beyond these receptor and turnover roles, the intracellular interactions of glycophorin C with the membrane skeleton are referenced in the corpus only as prior knowledge and are not experimentally established within these findings [PMID:28272739].","teleology":[{"year":2005,"claim":"Established that engaging glycophorin C on the red cell surface is not inert but actively signals membrane reorganization, linking GPC to phosphatidylserine externalization and red cell clearance.","evidence":"Annexin V PS-binding assay after BRIC-10 ligation, with Gerbich-variant erythrocytes (Yus, Gerbich, Ls(a)) and trypsin controls mapping the requirement to the extracellular domain","pmids":["15801965"],"confidence":"Medium","gaps":["The intracellular signaling pathway connecting extracellular ligation to PS exposure is not defined","Single-lab study without independent replication","Physiological ligand driving this response in vivo is unknown"]},{"year":2009,"claim":"Resolved how one gene produces two distinct glycoproteins, showing GPC and GPD arise from alternative translation initiation on a single transcript, with GPC start-codon evolution being a human-specific trait.","evidence":"Comparative genomic sequence analysis across Hominoidea, population genetics, and translation initiation codon mapping","pmids":["19679754"],"confidence":"Low","gaps":["Primarily computational/comparative analysis without direct protein-level confirmation of the two initiation products","Positive selection by P. falciparum invasion pressure is hypothesized, not demonstrated","Functional distinction between GPC and GPD not addressed"]},{"year":2014,"claim":"Defined a host-pathogen receptor function, establishing glycophorin C as a direct receptor mediating Plasmodium vivax rosetting of infected erythrocytes to normocytes.","evidence":"Anti-CD236R (BRIC 4) Fab inhibition and CD236R knockdown of stem-cell-derived normocytes in ex vivo P. vivax rosetting assays","pmids":["24652986"],"confidence":"Medium","gaps":["The parasite ligand binding glycophorin C is not identified","Single-lab study with two orthogonal methods but no independent confirmation","Structural basis of the GPC-parasite interaction unresolved"]},{"year":2017,"claim":"Characterized the molecular basis of Gerbich blood group phenotypes, mapping them to three classes of GYPC exon deletions driven by a duplication-prone homologous genomic region.","evidence":"Molecular genotyping of 29 rare Yus/Gerbich/Leach samples and sequence homology analysis of GYPC genomic regions","pmids":["28272739"],"confidence":"Low","gaps":["Protein 4.1/p55 interaction cited as prior knowledge, not experimentally confirmed here","Functional consequences of each deletion class on membrane stability not directly assayed","Structural inference of the duplication event not experimentally validated"]},{"year":null,"claim":"The intracellular signaling mechanism linking GPC extracellular ligation to phosphatidylserine exposure, and the identity of the P. vivax ligand binding GPC, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No molecular pathway connects GPC ligation to PS externalization","No identified parasite ligand for the rosetting interaction","No structural model of GPC engagement"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04921","full_name":"Glycophorin-C","aliases":["Glycoconnectin","Glycophorin-D","GPD","Glycoprotein beta","PAS-2'","Sialoglycoprotein D"],"length_aa":128,"mass_kda":13.8,"function":"This protein is a minor sialoglycoprotein in human erythrocyte membranes. The blood group Gerbich antigens and receptors for Plasmodium falciparum merozoites are most likely located within the extracellular domain. Glycophorin-C plays an important role in regulating the stability of red cells","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P04921/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GYPC","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/GYPC","total_profiled":1310},"omim":[{"mim_id":"616089","title":"BLOOD GROUP, GERBICH SYSTEM; GE","url":"https://www.omim.org/entry/616089"},{"mim_id":"612641","title":"ANKYRIN 1; ANK1","url":"https://www.omim.org/entry/612641"},{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"},{"mim_id":"111740","title":"BLOOD GROUP, Ss; Ss","url":"https://www.omim.org/entry/111740"},{"mim_id":"110750","title":"GLYCOPHORIN C; GYPC","url":"https://www.omim.org/entry/110750"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":415.6}],"url":"https://www.proteinatlas.org/search/GYPC"},"hgnc":{"alias_symbol":["GPC","GYPD","Ge","CD236","CD236R","GPD"],"prev_symbol":[]},"alphafold":{"accession":"P04921","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04921","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04921-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04921-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GYPC","jax_strain_url":"https://www.jax.org/strain/search?query=GYPC"},"sequence":{"accession":"P04921","fasta_url":"https://rest.uniprot.org/uniprotkb/P04921.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04921/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04921"}},"corpus_meta":[{"pmid":"11134295","id":"PMC_11134295","title":"Herpes simplex virus gE/gI sorts nascent virions to epithelial cell junctions, promoting virus 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methods","url":"https://pubmed.ncbi.nlm.nih.gov/14625049","citation_count":20,"is_preprint":false},{"pmid":"31213277","id":"PMC_31213277","title":"Identification of linear B cell epitope on gB, gC, and gE proteins of porcine pseudorabies virus using monoclonal antibodies.","date":"2019","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31213277","citation_count":20,"is_preprint":false},{"pmid":"38238601","id":"PMC_38238601","title":"Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.","date":"2024","source":"Nature aging","url":"https://pubmed.ncbi.nlm.nih.gov/38238601","citation_count":19,"is_preprint":false},{"pmid":"31493658","id":"PMC_31493658","title":"Functional interactions between herpes simplex virus pUL51, pUL7 and gE reveal cell-specific mechanisms for epithelial cell-to-cell spread.","date":"2019","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/31493658","citation_count":19,"is_preprint":false},{"pmid":"29503400","id":"PMC_29503400","title":"Antioxidant Activity of Ge-132, a Synthetic Organic Germanium, on Cultured Mammalian Cells.","date":"2018","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/29503400","citation_count":19,"is_preprint":false},{"pmid":"27459983","id":"PMC_27459983","title":"What's the Best Way to Treat GE Junction Tumors? Approach Like Gastric Cancer.","date":"2016","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27459983","citation_count":19,"is_preprint":false},{"pmid":"31976000","id":"PMC_31976000","title":"CCl4-Induced Liver Injury Was Ameliorated by Qi-Ge Decoction through the Antioxidant Pathway.","date":"2019","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/31976000","citation_count":19,"is_preprint":false},{"pmid":"9852964","id":"PMC_9852964","title":"Varicella-zoster virus glycoprotein gE: endocytosis and trafficking of the Fc receptor.","date":"1998","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/9852964","citation_count":18,"is_preprint":false},{"pmid":"9223471","id":"PMC_9223471","title":"The gE and gI homologs from two alphaherpesviruses have conserved and divergent neuroinvasive properties.","date":"1997","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9223471","citation_count":18,"is_preprint":false},{"pmid":"17634217","id":"PMC_17634217","title":"Cellular and viral factors regulate the varicella-zoster virus gE promoter during viral replication.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17634217","citation_count":18,"is_preprint":false},{"pmid":"19625404","id":"PMC_19625404","title":"Assembly of arenavirus envelope glycoprotein GPC in detergent-soluble membrane microdomains.","date":"2009","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/19625404","citation_count":18,"is_preprint":false},{"pmid":"27199360","id":"PMC_27199360","title":"Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography.","date":"2016","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27199360","citation_count":18,"is_preprint":false},{"pmid":"37143065","id":"PMC_37143065","title":"Pathogenicity and immunogenicity of gI/gE/TK-gene-deleted Felid herpesvirus 1 variants in cats.","date":"2023","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/37143065","citation_count":17,"is_preprint":false},{"pmid":"20529349","id":"PMC_20529349","title":"Cloning, expression and characterization of gE protein of duck plague virus.","date":"2010","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/20529349","citation_count":17,"is_preprint":false},{"pmid":"37446098","id":"PMC_37446098","title":"Glypican-3 (GPC-3) Structural Analysis and Cargo in Serum Small Extracellular Vesicles of Hepatocellular Carcinoma Patients.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37446098","citation_count":17,"is_preprint":false},{"pmid":"6959105","id":"PMC_6959105","title":"Priming of reovirus transcription by GppppG and formation of CpG(5')GpC.","date":"1982","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6959105","citation_count":17,"is_preprint":false},{"pmid":"35515004","id":"PMC_35515004","title":"Evaluation of the Safety and Immunogenicity of Duck-Plague Virus gE Mutants.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35515004","citation_count":16,"is_preprint":false},{"pmid":"30481072","id":"PMC_30481072","title":"HIF1α-siRNA and gemcitabine combination-based GE-11 peptide antibody-targeted nanomedicine for enhanced therapeutic efficacy in pancreatic cancers.","date":"2019","source":"Journal of drug targeting","url":"https://pubmed.ncbi.nlm.nih.gov/30481072","citation_count":16,"is_preprint":false},{"pmid":"17085880","id":"PMC_17085880","title":"Pathogenicity and immunogenicity of equine herpesvirus type 1 mutants defective in either gI or gE gene in murine and hamster models.","date":"2006","source":"The Journal of veterinary medical science","url":"https://pubmed.ncbi.nlm.nih.gov/17085880","citation_count":16,"is_preprint":false},{"pmid":"39725192","id":"PMC_39725192","title":"GPC-3 in hepatocellular carcinoma; A novel biomarker and molecular target.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39725192","citation_count":15,"is_preprint":false},{"pmid":"32037809","id":"PMC_32037809","title":"Tetra-(p-tolyl)antimony(III)-Containing Heteropolytungstates, [{(p-tolyl)SbIII}4(A-α-XW9O34)2] (X = P, As, or Ge): Synthesis, Structure, and Study of Antibacterial and Antitumor Activity.","date":"2020","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32037809","citation_count":15,"is_preprint":false},{"pmid":"35146013","id":"PMC_35146013","title":"Construction and Immunogenicity of a Recombinant Pseudorabies Virus Variant With TK/gI/gE/11k/28k Deletion.","date":"2022","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/35146013","citation_count":14,"is_preprint":false},{"pmid":"23901755","id":"PMC_23901755","title":"Identification and functional analysis of membrane proteins gD, gE, gI, and pUS9 of Infectious laryngotracheitis virus.","date":"2013","source":"Avian diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23901755","citation_count":14,"is_preprint":false},{"pmid":"33240776","id":"PMC_33240776","title":"Promoting Ge Alloying Reaction via Heterostructure Engineering for High Efficient and Ultra-Stable Sodium-Ion Storage.","date":"2020","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/33240776","citation_count":14,"is_preprint":false},{"pmid":"32451642","id":"PMC_32451642","title":"Salinomycin-loaded PLA nanoparticles: drug quantification by GPC and wave voltammetry and biological studies on osteosarcoma cancer stem cells.","date":"2020","source":"Analytical and bioanalytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32451642","citation_count":14,"is_preprint":false},{"pmid":"37878624","id":"PMC_37878624","title":"GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37878624","citation_count":13,"is_preprint":false},{"pmid":"37003192","id":"PMC_37003192","title":"Safety and immunogenicity of a TK/ gI/gE gene-deleted feline herpesvirus-1 mutant constructed via CRISPR/Cas9 in feline.","date":"2023","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37003192","citation_count":13,"is_preprint":false},{"pmid":"35580830","id":"PMC_35580830","title":"A biodegradable in situ Zn-Mg2Ge composite for bone-implant applications.","date":"2022","source":"Acta biomaterialia","url":"https://pubmed.ncbi.nlm.nih.gov/35580830","citation_count":13,"is_preprint":false},{"pmid":"34013395","id":"PMC_34013395","title":"Robust and Facile Automated Radiosynthesis of [18F]FSPG on the GE FASTlab.","date":"2021","source":"Molecular imaging and biology","url":"https://pubmed.ncbi.nlm.nih.gov/34013395","citation_count":13,"is_preprint":false},{"pmid":"36059553","id":"PMC_36059553","title":"Evaluation of safety and immunogenicity of duck-plague virus gC/gE double gene deletion.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36059553","citation_count":12,"is_preprint":false},{"pmid":"31305883","id":"PMC_31305883","title":"Study on Diagnostic Values of Astrocyte Elevated Gene 1 (AEG-1) and Glypican 3 (GPC-3) in Hepatocellular Carcinoma.","date":"2019","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31305883","citation_count":12,"is_preprint":false},{"pmid":"31960033","id":"PMC_31960033","title":"GPC-1, a novel class A carbapenemase detected in a clinical Pseudomonas aeruginosa isolate.","date":"2020","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/31960033","citation_count":12,"is_preprint":false},{"pmid":"2775769","id":"PMC_2775769","title":"Examination of the potential role of the glycerophosphorylcholine (GPC) pathway in the biosynthesis of phosphatidylcholine by liver and lung.","date":"1989","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/2775769","citation_count":12,"is_preprint":false},{"pmid":"38003603","id":"PMC_38003603","title":"Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38003603","citation_count":11,"is_preprint":false},{"pmid":"28272739","id":"PMC_28272739","title":"Genetic background of the rare Yus and Gerbich blood group phenotypes: homologous regions of the GYPC gene contribute to deletion alleles.","date":"2017","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/28272739","citation_count":11,"is_preprint":false},{"pmid":"32582674","id":"PMC_32582674","title":"Sublethal Endpoints in Non-target Organism Testing for Insect-Active GE Crops.","date":"2020","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32582674","citation_count":11,"is_preprint":false},{"pmid":"36524206","id":"PMC_36524206","title":"Enhancing anti-tumor efficacy and immune memory by combining 3p-GPC-3 siRNA treatment with PD-1 blockade in hepatocellular carcinoma.","date":"2022","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/36524206","citation_count":11,"is_preprint":false},{"pmid":"33445163","id":"PMC_33445163","title":"A novel multifunctional gold nanorod-mediated and tumor-targeted gene silencing of GPC-3 synergizes photothermal therapy for liver cancer.","date":"2021","source":"Nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33445163","citation_count":11,"is_preprint":false},{"pmid":"37456759","id":"PMC_37456759","title":"Liang-Ge-San: a classic traditional Chinese medicine formula, attenuates acute inflammation via targeting GSK3β.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37456759","citation_count":11,"is_preprint":false},{"pmid":"36160017","id":"PMC_36160017","title":"Ascertaining yield and grain protein content stability in wheat genotypes having the Gpc-B1 gene using univariate, multivariate, and correlation analysis.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36160017","citation_count":11,"is_preprint":false},{"pmid":"27485441","id":"PMC_27485441","title":"NET-GE: a web-server for NETwork-based human gene enrichment.","date":"2016","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27485441","citation_count":11,"is_preprint":false},{"pmid":"35214644","id":"PMC_35214644","title":"Evaluation of HSV-2 gE Binding to IgG-Fc and Application for Vaccine Development.","date":"2022","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/35214644","citation_count":9,"is_preprint":false},{"pmid":"2124123","id":"PMC_2124123","title":"The role and mechanism of the GTP-binding protein GE in the control of regulated exocytosis.","date":"1990","source":"Biochemical Society symposium","url":"https://pubmed.ncbi.nlm.nih.gov/2124123","citation_count":9,"is_preprint":false},{"pmid":"37096878","id":"PMC_37096878","title":"In silico and in vivo demonstration of the regulatory mechanism of Qi-Ge decoction in treating NAFLD.","date":"2023","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37096878","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52834,"output_tokens":1638,"usd":0.091536,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8013,"output_tokens":1849,"usd":0.043145,"stage2_stop_reason":"end_turn"},"total_usd":0.134681,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers specifically about GYPC (glycophorin C/D, also known as GPC, GYPD, Ge, CD236, CD236R) - the human erythrocyte sialoglycoprotein.\n\nRelevant papers:\n- PMID 24652986: Glycophorin C (CD236R) mediates P. vivax rosetting to normocytes\n- PMID 15801965: GPC ligation and phosphatidylserine expression on erythrocytes\n- PMID 19679754: Molecular evolution of GYPC - GPC and GPD encoded by same gene\n- PMID 28272739: GYPC gene exon deletions responsible for Gerbich blood group phenotypes\n\nAll other papers are about: herpesvirus glycoprotein gE/gI (completely different proteins), GPC-3/glypican-3 (different gene), Ge-1 P-body protein (different gene), wheat GPC genes, germanium compounds, C. elegans gpc-1 G-protein subunit, arenavirus GPC, Lassa virus GPC, etc. - none of these are GYPC.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Glycophorin C (CD236R/GYPC) functions as a receptor mediating Plasmodium vivax rosetting of infected erythrocytes to normocytes. Antibody fragment (Fab) against the BRIC 4 region of CD236R significantly inhibited rosette formation, and CD236R knockdown normocytes derived from hematopoietic stem cells showed reduced rosetting, establishing GYPC as a direct rosetting receptor for P. vivax.\",\n      \"method\": \"Anti-CD236R antibody inhibition assays, CD236R knockdown normocytes derived from hematopoietic stem cells, ex vivo rosetting assays with P. vivax isolates\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional approaches (antibody inhibition + receptor knockdown), single lab, two orthogonal methods establishing receptor role\",\n      \"pmids\": [\"24652986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ligation of glycophorin C (GPC) on erythrocytes with monoclonal antibody BRIC-10 induces phosphatidylserine (PS) exposure on the outer leaflet of the erythrocyte membrane. This effect requires the extracellular domain of GPC: Gerbich variant phenotypes with truncated extracellular domains (Yus, exon 2 deletion; Gerbich, exon 3 deletion) did not expose PS following GPC ligation, while Ls(a) erythrocytes (exon 3 duplication) did. GPC ligation also resulted in loss of erythrocyte viability after 24 h, identifying a pathway linking GPC to PS exposure and red cell turnover.\",\n      \"method\": \"Annexin V binding assay for PS detection, tryptic digestion controls, comparison of wild-type vs. Gerbich variant erythrocytes (Yus, Gerbich, Ls(a) phenotypes)\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with multiple variant controls and trypsin digestion, single lab\",\n      \"pmids\": [\"15801965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GYPC encodes two distinct erythrocyte surface sialoglycoproteins, glycophorin C (GPC) and glycophorin D (GPD), via initiation of translation at two different start codons on a single transcript. The ability to encode both GPC and GPD is a uniquely human trait caused by evolution of the GPC start codon in the human lineage; GPD continues to be produced through leaky translation. Molecular evolutionary analysis revealed accelerated nonsynonymous divergence of GYPC specifically in the human lineage, consistent with positive selection, hypothesized to be driven by P. falciparum invasion pressure.\",\n      \"method\": \"Comparative genomic sequence analysis across Hominoidea, population genetics analysis of human polymorphism, translation initiation codon mapping\",\n      \"journal\": \"Molecular biology and evolution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — primarily computational/comparative genomic analysis with no direct in vitro or in vivo mechanistic experiment on protein function\",\n      \"pmids\": [\"19679754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Three classes of GYPC exon deletions underlie rare Gerbich blood group phenotypes: deletion of exon 2 (Yus type, GE:-2,3,4), deletion of exon 3 (Gerbich type, GE:-2,-3,4), and deletion of exons 3 and 4 (Leach type). Molecular characterization of 29 rare samples revealed that a 3600 bp region encompassing exon 2 shares high sequence homology with the region flanking exon 3, indicating an evolutionary duplication event that predisposes to these deletions. The intracellular portion of GPC stabilizes red blood cell membranes through interaction with protein 4.1 and p55.\",\n      \"method\": \"Molecular genotyping of 29 rare blood samples with Yus and Gerbich phenotypes; sequence homology analysis of GYPC genomic regions\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genotyping of clinical samples with structural inference; protein 4.1/p55 interaction cited as prior knowledge, not experimentally confirmed in this study\",\n      \"pmids\": [\"28272739\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GYPC encodes two erythrocyte surface sialoglycoproteins, glycophorin C (GPC) and glycophorin D (GPD), from a single transcript via alternative translation initiation; GPC functions as a receptor on the red cell surface that mediates P. vivax rosetting to normocytes and, upon ligation, triggers phosphatidylserine exposure and loss of erythrocyte viability through its extracellular domain, while its intracellular domain stabilizes the red cell membrane through interactions with protein 4.1 and p55.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GYPC encodes glycophorin C, an erythrocyte surface sialoglycoprotein that acts as a receptor on the red cell surface and contributes to red cell turnover and host-pathogen interaction [#0, #1]. Glycophorin C serves as a direct rosetting receptor for Plasmodium vivax, mediating adhesion of infected erythrocytes to normocytes; antibody blockade of its BRIC 4 region and receptor knockdown both reduce rosette formation [#0]. Ligation of the glycophorin C extracellular domain triggers phosphatidylserine exposure on the outer membrane leaflet and subsequent loss of erythrocyte viability, a response that depends on an intact extracellular domain as shown by its absence in Gerbich-variant erythrocytes bearing truncating exon deletions [#1]. A single GYPC transcript yields two proteins, glycophorin C and glycophorin D, through alternative translation initiation at two start codons [#2]. Beyond these receptor and turnover roles, the intracellular interactions of glycophorin C with the membrane skeleton are referenced in the corpus only as prior knowledge and are not experimentally established within these findings [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that engaging glycophorin C on the red cell surface is not inert but actively signals membrane reorganization, linking GPC to phosphatidylserine externalization and red cell clearance.\",\n      \"evidence\": \"Annexin V PS-binding assay after BRIC-10 ligation, with Gerbich-variant erythrocytes (Yus, Gerbich, Ls(a)) and trypsin controls mapping the requirement to the extracellular domain\",\n      \"pmids\": [\"15801965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The intracellular signaling pathway connecting extracellular ligation to PS exposure is not defined\",\n        \"Single-lab study without independent replication\",\n        \"Physiological ligand driving this response in vivo is unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how one gene produces two distinct glycoproteins, showing GPC and GPD arise from alternative translation initiation on a single transcript, with GPC start-codon evolution being a human-specific trait.\",\n      \"evidence\": \"Comparative genomic sequence analysis across Hominoidea, population genetics, and translation initiation codon mapping\",\n      \"pmids\": [\"19679754\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Primarily computational/comparative analysis without direct protein-level confirmation of the two initiation products\",\n        \"Positive selection by P. falciparum invasion pressure is hypothesized, not demonstrated\",\n        \"Functional distinction between GPC and GPD not addressed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a host-pathogen receptor function, establishing glycophorin C as a direct receptor mediating Plasmodium vivax rosetting of infected erythrocytes to normocytes.\",\n      \"evidence\": \"Anti-CD236R (BRIC 4) Fab inhibition and CD236R knockdown of stem-cell-derived normocytes in ex vivo P. vivax rosetting assays\",\n      \"pmids\": [\"24652986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The parasite ligand binding glycophorin C is not identified\",\n        \"Single-lab study with two orthogonal methods but no independent confirmation\",\n        \"Structural basis of the GPC-parasite interaction unresolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterized the molecular basis of Gerbich blood group phenotypes, mapping them to three classes of GYPC exon deletions driven by a duplication-prone homologous genomic region.\",\n      \"evidence\": \"Molecular genotyping of 29 rare Yus/Gerbich/Leach samples and sequence homology analysis of GYPC genomic regions\",\n      \"pmids\": [\"28272739\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Protein 4.1/p55 interaction cited as prior knowledge, not experimentally confirmed here\",\n        \"Functional consequences of each deletion class on membrane stability not directly assayed\",\n        \"Structural inference of the duplication event not experimentally validated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling mechanism linking GPC extracellular ligation to phosphatidylserine exposure, and the identity of the P. vivax ligand binding GPC, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No molecular pathway connects GPC ligation to PS externalization\",\n        \"No identified parasite ligand for the rosetting interaction\",\n        \"No structural model of GPC engagement\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}