{"gene":"PIGT","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2001,"finding":"PIG-T (PIGT) is an essential subunit of the GPI transamidase complex. Knockout of PIGT in mouse F9 cells abolished transfer of GPI to proteins, specifically blocking formation of the carbonyl intermediates required for transamidation. PIG-T forms a protein complex with GAA1, GPI8, and PIG-S, and PIG-T stabilizes the complex by maintaining expression levels of GAA1 and GPI8.","method":"Homologous recombination knockout in mouse F9 cells, co-immunoprecipitation, in vitro transamidase assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — gene knockout with defined biochemical phenotype (loss of carbonyl intermediate formation), complex membership confirmed by co-IP, stabilization role confirmed by expression analysis; multiple orthogonal methods in a focused mechanistic study","pmids":["11483512"],"is_preprint":false},{"year":2003,"finding":"GPI8 and PIG-T (PIGT) form a functionally important intermolecular disulfide bond between conserved cysteine residues within the GPI transamidase complex. Mutation of the relevant cysteines to serines in either GPI8 or PIG-T markedly reduced in vitro transamidase activity and failed to fully restore surface expression of GPI-anchored proteins in respective mutant cells. The disulfide bond is not absolutely required but is needed for full transamidase activity.","method":"Site-directed mutagenesis (Cys→Ser), in vitro transamidase assay, transfection rescue experiments, antibody-based detection of disulfide bond formation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis combined with in vitro enzymatic assay and cell-based rescue; multiple orthogonal methods in one study","pmids":["12582175"],"is_preprint":false},{"year":2005,"finding":"PIG-T (PIGT) is localized to the endoplasmic reticulum (ER) and its ER retention is mediated by information within its transmembrane span. Fusion of the PIG-T transmembrane domain to Tac antigen (a plasma membrane protein) caused the fusion protein to be retained in the ER, indicating a dominant ER-retention signal in the PIG-T TM domain. PIG-T is a type I membrane glycoprotein.","method":"Fusion protein construction, subcellular localization by imaging/fractionation, domain-swap experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional domain-swap demonstrating TM-span-mediated ER retention; single lab but two orthogonal approaches (construct analysis + fusion protein)","pmids":["15713669"],"is_preprint":false},{"year":2013,"finding":"A homozygous missense mutation in PIGT (c.547A>C, p.Thr183Pro) causes reduced surface expression of GPI-anchored protein CD16b on patient granulocytes. The mutant p.Thr183Pro PIGT mRNA failed to rescue gastrulation defects induced by morpholino knockdown of the PIGT ortholog in zebrafish, whereas wild-type human PIGT mRNA could rescue, establishing this mutation as a loss-of-function variant that impairs GPI transamidase activity in vivo.","method":"Flow cytometry of patient granulocytes, morpholino knockdown and mRNA rescue in zebrafish embryos","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue assay in zebrafish plus patient cell flow cytometry; single lab, two orthogonal methods","pmids":["23636107"],"is_preprint":false},{"year":2013,"finding":"Loss of PIGT function (via a germline splice-site mutation plus somatic deletion of the second allele) in hematopoietic stem cells causes deficiency of GPI-anchored complement regulatory proteins (CD55, CD59) on blood cells, leading to paroxysmal nocturnal hemoglobinuria (PNH). This establishes that defective GPI anchor transfer to proteins (rather than defective GPI synthesis) is sufficient to cause PNH.","method":"Next-generation deep sequencing of all GPI pathway genes, identification of germline + somatic two-hit mechanism in patient granulocytes","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient genetic analysis with two-hit somatic mechanism identified; single patient case but mechanistically informative","pmids":["23733340"],"is_preprint":false},{"year":2014,"finding":"Compound heterozygous PIGT mutations (p.Glu84* and p.Arg488Trp) reduce surface expression of GPI-anchored proteins DAF and CD59 on patient granulocytes. Transfection of the p.Arg488Trp mutant PIGT into PIGT-deficient cells partially restored GPI-AP expression, while the p.Glu84* (null) mutant did not, demonstrating that p.Arg488Trp is a hypomorphic allele and that PIGT is required for GPI anchor attachment to proteins.","method":"Flow cytometry of patient granulocytes, transfection rescue into PIGT-deficient cells","journal":"Neurogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue transfection into knockout cells with flow cytometry readout; single lab, two orthogonal methods","pmids":["24906948"],"is_preprint":false},{"year":2022,"finding":"A homozygous PIGT variant p.Gly360Val leads to reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface of patient-derived cells, confirming the pathogenic role of this variant in impairing GPI transamidase function.","method":"In vitro cell surface GPI-AP quantification by flow cytometry on cells from affected patients","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (flow cytometry), single lab, no direct enzymatic assay","pmids":["27916860"],"is_preprint":false},{"year":2023,"finding":"The PIGT variant p.Arg507Trp leads to mildly reduced GPI transamidase activity, as demonstrated by FACS analysis of PIGT knockout HEK293 cells transfected with wild-type or p.Arg507Trp mutant cDNA constructs measuring surface GPI-AP expression.","method":"Transfection rescue into PIGT knockout HEK293 cells, FACS analysis of GPI-AP surface expression","journal":"Frontiers in neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional rescue assay with defined knockout background; single lab, single method","pmids":["36970549"],"is_preprint":false},{"year":2024,"finding":"PIGT promotes GLUT1 glycosylation and membrane trafficking in bladder cancer cells. Overexpression of PIGT enhanced cell proliferation, oxidative phosphorylation, glycolysis, and tumor metastasis in vivo through activation of GLUT1. PIGT is post-translationally regulated by WTAP-mediated m6A modification of its mRNA, with IGF2BP2 reading the m6A mark to stabilize PIGT mRNA.","method":"PIGT silencing/overexpression, CCK-8/colony formation/Transwell assay, Seahorse metabolic flux analysis, immunoblot, RT-PCR, in vivo tumor model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (proliferation, metabolism, invasion, in vivo), with m6A regulatory mechanism identified; single lab","pmids":["38169393"],"is_preprint":false}],"current_model":"PIGT (PIG-T) encodes an essential subunit of the endoplasmic reticulum-localized GPI transamidase complex, where it forms a complex with GAA1, GPI8, PIG-S, and PIG-T stabilizes the complex by maintaining GAA1 and GPI8 expression; PIG-T is retained in the ER via its transmembrane domain, forms a functionally important disulfide bond with GPI8 at conserved cysteine residues that is required for full transamidase activity, and is essential for the carbonyl intermediate step by which preassembled GPI anchors are transferred to substrate proteins bearing a C-terminal GPI signal peptide."},"narrative":{"mechanistic_narrative":"PIGT (PIG-T) is an essential subunit of the endoplasmic reticulum-localized GPI transamidase complex that transfers preassembled glycosylphosphatidylinositol (GPI) anchors onto proteins bearing a C-terminal GPI signal peptide [PMID:11483512]. Within this complex PIG-T physically associates with GAA1, GPI8, and PIG-S, and stabilizes the assembly by maintaining the expression levels of GAA1 and GPI8; its loss abolishes GPI transfer specifically by blocking formation of the carbonyl intermediates of transamidation [PMID:11483512]. PIG-T forms an intermolecular disulfide bond with GPI8 between conserved cysteines that, while not absolutely required, is needed for full transamidase activity [PMID:12582175]. PIG-T is a type I membrane glycoprotein retained in the ER through a dominant retention signal within its transmembrane span [PMID:15713669]. Loss-of-function and hypomorphic PIGT variants reduce surface expression of GPI-anchored proteins and cause human disease: biallelic mutations impair GPI anchor attachment in patients [PMID:23636107, PMID:24906948], and a germline-plus-somatic two-hit loss of PIGT in hematopoietic cells causes paroxysmal nocturnal hemoglobinuria, establishing that defective GPI transfer—rather than defective GPI synthesis—is sufficient to produce the PNH phenotype [PMID:23733340]. Beyond its canonical transamidase role, PIGT promotes GLUT1 glycosylation and membrane trafficking in bladder cancer cells, enhancing proliferation, oxidative phosphorylation, glycolysis, and metastasis, and its mRNA is stabilized by WTAP-deposited m6A marks read by IGF2BP2 [PMID:38169393].","teleology":[{"year":2001,"claim":"Established that PIG-T is an obligatory subunit of the GPI transamidase complex and defined its biochemical role, answering whether GPI transfer to proteins requires a dedicated multi-subunit machine and which step PIG-T governs.","evidence":"Homologous recombination knockout in mouse F9 cells with co-immunoprecipitation and in vitro transamidase assay","pmids":["11483512"],"confidence":"High","gaps":["Did not resolve the atomic-level architecture of the complex","Mechanism by which PIG-T maintains GAA1/GPI8 expression not defined","Precise catalytic contribution of PIG-T versus GPI8 not separated"]},{"year":2003,"claim":"Identified a functional disulfide bond between PIG-T and GPI8, addressing how subunits are covalently coupled to support catalysis.","evidence":"Cys→Ser site-directed mutagenesis with in vitro transamidase assay and cell-based rescue","pmids":["12582175"],"confidence":"High","gaps":["Disulfide is not absolutely required, so its precise contribution to activity is partial","Structural geometry of the bonded cysteines not determined"]},{"year":2005,"claim":"Mapped the determinant of PIG-T subcellular residence, answering how the transamidase is confined to the ER where GPI transfer occurs.","evidence":"Transmembrane domain fusion to Tac antigen with subcellular localization analysis in a domain-swap design","pmids":["15713669"],"confidence":"High","gaps":["Trafficking receptors recognizing the TM retention signal not identified","Whether complex assembly contributes to retention not addressed"]},{"year":2013,"claim":"Connected PIGT loss-of-function to human disease and demonstrated in vivo that point mutations abolish transamidase function, beyond cell-surface marker readouts.","evidence":"Flow cytometry of patient granulocytes plus zebrafish morpholino knockdown and human mRNA rescue (p.Thr183Pro fails to rescue)","pmids":["23636107"],"confidence":"Medium","gaps":["Single mutation tested in vivo","Molecular basis of how p.Thr183Pro impairs activity not resolved"]},{"year":2013,"claim":"Showed that defective GPI anchor transfer to proteins, not defective GPI synthesis, is sufficient to cause paroxysmal nocturnal hemoglobinuria, reframing the pathogenic spectrum of GPI deficiency.","evidence":"Deep sequencing of GPI pathway genes identifying a germline splice-site plus somatic second-hit deletion in patient granulocytes","pmids":["23733340"],"confidence":"Medium","gaps":["Single patient case","No direct enzymatic assay of the variant alleles"]},{"year":2014,"claim":"Distinguished null versus hypomorphic PIGT alleles through rescue, clarifying the genotype-function relationship underlying patient phenotypes.","evidence":"Flow cytometry of patient granulocytes plus transfection rescue of mutants into PIGT-deficient cells (p.Arg488Trp partial, p.Glu84* null)","pmids":["24906948"],"confidence":"Medium","gaps":["No direct enzymatic kinetics for hypomorphic allele","Single lab"]},{"year":2022,"claim":"Extended the catalogue of pathogenic PIGT variants impairing surface GPI-AP display.","evidence":"Flow cytometry quantification of cell-surface GPI-APs on patient-derived cells for p.Gly360Val","pmids":["27916860"],"confidence":"Low","gaps":["Single method (flow cytometry), no direct enzymatic assay","Mechanism of activity reduction not defined"]},{"year":2023,"claim":"Quantified the functional impact of an additional variant using a defined knockout-rescue system, refining variant interpretation.","evidence":"Transfection rescue into PIGT knockout HEK293 cells with FACS readout of GPI-AP surface expression (p.Arg507Trp mildly reduced)","pmids":["36970549"],"confidence":"Medium","gaps":["Single method","Structural basis of mild reduction not addressed"]},{"year":2024,"claim":"Revealed a non-canonical, disease-relevant role for PIGT in cancer metabolism via GLUT1 glycosylation, and identified an upstream m6A regulatory axis controlling PIGT mRNA stability.","evidence":"PIGT silencing/overexpression, CCK-8/colony/Transwell assays, Seahorse flux analysis, immunoblot, and in vivo tumor model in bladder cancer","pmids":["38169393"],"confidence":"Medium","gaps":["Whether GLUT1 glycosylation occurs through canonical transamidase activity or another mechanism not resolved","Single lab","Generality across cancer types not established"]},{"year":null,"claim":"How the catalytic step and subunit coordination of the transamidase are organized at atomic resolution, and how individual missense variants map onto this architecture to graded loss-of-function, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PIG-T within the assembled complex in the corpus","Mechanism linking PIG-T to GLUT1 trafficking versus canonical transamidation unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["GPI transamidase complex"],"partners":["GAA1","GPI8","PIGS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969N2","full_name":"GPI-anchor transamidase component PIGT","aliases":["Phosphatidylinositol-glycan biosynthesis class T protein"],"length_aa":578,"mass_kda":65.7,"function":"Component of the glycosylphosphatidylinositol-anchor (GPI-anchor) transamidase (GPI-T) complex that catalyzes the formation of the linkage between a proprotein and a GPI-anchor and participates in GPI anchored protein biosynthesis (PubMed:11483512, PubMed:12582175, PubMed:28327575, PubMed:34576938, PubMed:35165458, PubMed:35551457, PubMed:36970549, PubMed:37684232). May play a crucial role in GPI-T complex assembly in the luminal layer (PubMed:35165458, PubMed:35551457). Binds GPI-anchor (PubMed:37684232)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q969N2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIGT","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PIGT","total_profiled":1310},"omim":[{"mim_id":"615399","title":"PAROXYSMAL NOCTURNAL HEMOGLOBINURIA 2; PNH2","url":"https://www.omim.org/entry/615399"},{"mim_id":"615398","title":"MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 3; MCAHS3","url":"https://www.omim.org/entry/615398"},{"mim_id":"614080","title":"MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1; MCAHS1","url":"https://www.omim.org/entry/614080"},{"mim_id":"610293","title":"GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 1; GPIBD1","url":"https://www.omim.org/entry/610293"},{"mim_id":"610272","title":"PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS T PROTEIN; PIGT","url":"https://www.omim.org/entry/610272"}],"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/PIGT"},"hgnc":{"alias_symbol":["PIG-T"],"prev_symbol":[]},"alphafold":{"accession":"Q969N2","domains":[{"cath_id":"-","chopping":"33-337","consensus_level":"medium","plddt":90.1598,"start":33,"end":337},{"cath_id":"2.60.40.1170","chopping":"351-514","consensus_level":"high","plddt":92.1948,"start":351,"end":514}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969N2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969N2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969N2-F1-predicted_aligned_error_v6.png","plddt_mean":87.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIGT","jax_strain_url":"https://www.jax.org/strain/search?query=PIGT"},"sequence":{"accession":"Q969N2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969N2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969N2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969N2"}},"corpus_meta":[{"pmid":"4542806","id":"PMC_4542806","title":"Function of macrophages in antigen recognition by guinea pig T lymphocytes. 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lymphocytes.","date":"1978","source":"Annales d'immunologie","url":"https://pubmed.ncbi.nlm.nih.gov/308791","citation_count":13,"is_preprint":false},{"pmid":"15900493","id":"PMC_15900493","title":"TRAV gene usage in pig T-cell receptor alpha cDNA.","date":"2005","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/15900493","citation_count":12,"is_preprint":false},{"pmid":"31074044","id":"PMC_31074044","title":"Role of human and porcine MHC DRB1 alleles in determining the intensity of individual human anti-pig T-cell responses.","date":"2019","source":"Xenotransplantation","url":"https://pubmed.ncbi.nlm.nih.gov/31074044","citation_count":11,"is_preprint":false},{"pmid":"6167623","id":"PMC_6167623","title":"Characterization of an antiserum to guinea pig antithrombin III (AT III). 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Reactivity with guinea pig T lymphocytes.","date":"1981","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6167623","citation_count":11,"is_preprint":false},{"pmid":"1384115","id":"PMC_1384115","title":"Analysis of mature guinea pig T cells with a monoclonal antibody directed against a framework determinant of the T-cell receptor for antigen.","date":"1992","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1384115","citation_count":10,"is_preprint":false},{"pmid":"87432","id":"PMC_87432","title":"The activation of guinea pig T lymphocytes by anti-beta 2-microglobulin serum.","date":"1979","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/87432","citation_count":10,"is_preprint":false},{"pmid":"15713669","id":"PMC_15713669","title":"Endoplasmic reticulum localization of Gaa1 and PIG-T, subunits of the glycosylphosphatidylinositol transamidase complex.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15713669","citation_count":9,"is_preprint":false},{"pmid":"34046058","id":"PMC_34046058","title":"Deep-Phenotyping the Less Severe Spectrum of PIGT Deficiency and Linking the Gene to Myoclonic Atonic Seizures.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34046058","citation_count":8,"is_preprint":false},{"pmid":"34625520","id":"PMC_34625520","title":"Human-like Response of Pig T Cells to Superagonistic Anti-CD28 Monoclonal Antibodies.","date":"2021","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/34625520","citation_count":8,"is_preprint":false},{"pmid":"32725661","id":"PMC_32725661","title":"Evidence of the milder phenotypic spectrum of c.1582G>A PIGT variant: Delineation based on seven novel Polish patients.","date":"2020","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32725661","citation_count":8,"is_preprint":false},{"pmid":"1362184","id":"PMC_1362184","title":"Subpopulations of guinea-pig T lymphocytes defined by isoforms of the leucocyte common antigen.","date":"1992","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1362184","citation_count":8,"is_preprint":false},{"pmid":"6331892","id":"PMC_6331892","title":"Endogenous surface phosphorylation reactions and ectokinase activity in the guinea pig T lymphocyte.","date":"1984","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6331892","citation_count":7,"is_preprint":false},{"pmid":"6334394","id":"PMC_6334394","title":"Analysis of a sheep anti-pig T lymphoblast serum with specificity for E rosette-forming lymphocytes.","date":"1984","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/6334394","citation_count":7,"is_preprint":false},{"pmid":"2579290","id":"PMC_2579290","title":"Guinea pig T lymphocyte development analyzed by enzyme histocytochemistry, monoclonal antibodies, and flow cytometry.","date":"1985","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2579290","citation_count":6,"is_preprint":false},{"pmid":"30813157","id":"PMC_30813157","title":"Case report of a child bearing a novel deleterious splicing variant in PIGT.","date":"2019","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30813157","citation_count":6,"is_preprint":false},{"pmid":"2897618","id":"PMC_2897618","title":"Characterization of a monoclonal antibody to guinea pig T cells that inhibits rosette formation of the cells with rabbit erythrocytes: similarity of the antigen to E-receptor on human T cells.","date":"1988","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2897618","citation_count":6,"is_preprint":false},{"pmid":"6970721","id":"PMC_6970721","title":"Isotype specificity of Fc gamma-receptors on guinea-pig T lymphocytes and their modulation by homologous immune complexes.","date":"1981","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6970721","citation_count":5,"is_preprint":false},{"pmid":"12826083","id":"PMC_12826083","title":"Effector functions of CD8-positive guinea pig T lymphocytes.","date":"2003","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12826083","citation_count":5,"is_preprint":false},{"pmid":"303434","id":"PMC_303434","title":"Alkaline phosphate in the differentiation of guinea pig T lymphocytes.","date":"1977","source":"Acta pathologica et microbiologica Scandinavica. Section C, Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/303434","citation_count":5,"is_preprint":false},{"pmid":"35979111","id":"PMC_35979111","title":"Allogeneic stem cell transplantation-A curative treatment for paroxysmal nocturnal hemoglobinuria with PIGT mutation: A case report.","date":"2022","source":"World journal of clinical cases","url":"https://pubmed.ncbi.nlm.nih.gov/35979111","citation_count":4,"is_preprint":false},{"pmid":"35205222","id":"PMC_35205222","title":"The Organization of the Pig T-Cell Receptor γ (TRG) Locus Provides Insights into the Evolutionary Patterns of the TRG Genes across Cetartiodactyla.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35205222","citation_count":4,"is_preprint":false},{"pmid":"2470134","id":"PMC_2470134","title":"The generation of guinea pig T-cell lines reactive to antigens from Mycobacterium tuberculosis. Selected lines induce erythematous skin reactions.","date":"1989","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2470134","citation_count":4,"is_preprint":false},{"pmid":"6973620","id":"PMC_6973620","title":"Dependence on macrophages of the guinea pig T-cell immune response to Herpetomonas samuelpessoai.","date":"1981","source":"The Journal of parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/6973620","citation_count":4,"is_preprint":false},{"pmid":"8627545","id":"PMC_8627545","title":"Identification and characterization of a high-affinity leukotriene B4 receptor on guinea pig T lymphocytes and its regulation by lipoxin A4.","date":"1996","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/8627545","citation_count":3,"is_preprint":false},{"pmid":"6984489","id":"PMC_6984489","title":"Characterization of a 75,000 mol. wt glycoprotein synthesized by guinea-pig T-lymphocytes: a possible homologue of Lyt-1 antigen.","date":"1982","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6984489","citation_count":3,"is_preprint":false},{"pmid":"36970549","id":"PMC_36970549","title":"Case report: Functional analysis of the p.Arg507Trp variant of the PIGT gene supporting the moderate epilepsy phenotype of mutations in the C-terminal region.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36970549","citation_count":2,"is_preprint":false},{"pmid":"34162574","id":"PMC_34162574","title":"Compound Heterozygous PIGT Mutations in Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome: First Case in Korea and Characterization by Persistent Hypophosphatasia.","date":"2021","source":"Annals of clinical and laboratory science","url":"https://pubmed.ncbi.nlm.nih.gov/34162574","citation_count":2,"is_preprint":false},{"pmid":"310944","id":"PMC_310944","title":"Separation of RRBC-RFC and non-rosette forming cells (non-RFC) of guinea pig T-cell populations and their functional difference. 1. Response of RRBC-RFC and non-RFC to either Con-A or LPS.","date":"1978","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/310944","citation_count":2,"is_preprint":false},{"pmid":"38903302","id":"PMC_38903302","title":"Spectrum of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (MCAHS3) Due to Phosphatidylinositol Glycan Biosynthesis Class T (PIGT) Gene Mutations: A Narrative Review.","date":"2024","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38903302","citation_count":0,"is_preprint":false},{"pmid":"40808272","id":"PMC_40808272","title":"The transcription factor HOXB7 significantly enhances the expression of PIGT through the Wnt/β-catenin signaling pathway, thereby promoting the proliferation and deterioration of HCC.","date":"2025","source":"Expert review of anticancer therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40808272","citation_count":0,"is_preprint":false},{"pmid":"40141433","id":"PMC_40141433","title":"A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40141433","citation_count":0,"is_preprint":false},{"pmid":"37643962","id":"PMC_37643962","title":"[Genetic analysis and prenatal diagnosis of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 due to variants of PIGT gene].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37643962","citation_count":0,"is_preprint":false},{"pmid":"15114937","id":"PMC_15114937","title":"Modulation of human anti-pig T cell responses by monoclonal antibodies directed to porcine CD45 molecules.","date":"2003","source":"Annals of transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/15114937","citation_count":0,"is_preprint":false},{"pmid":"6976298","id":"PMC_6976298","title":"[Changes of guinea pig T lymphocytes after E rosette formation -expression of Fc and complement receptors-(author's transl)].","date":"1981","source":"[Hokkaido igaku zasshi] The Hokkaido journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/6976298","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33694,"output_tokens":2422,"usd":0.068706,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9581,"output_tokens":2981,"usd":0.061215,"stage2_stop_reason":"end_turn"},"total_usd":0.129921,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"PIG-T (PIGT) is an essential subunit of the GPI transamidase complex. Knockout of PIGT in mouse F9 cells abolished transfer of GPI to proteins, specifically blocking formation of the carbonyl intermediates required for transamidation. PIG-T forms a protein complex with GAA1, GPI8, and PIG-S, and PIG-T stabilizes the complex by maintaining expression levels of GAA1 and GPI8.\",\n      \"method\": \"Homologous recombination knockout in mouse F9 cells, co-immunoprecipitation, in vitro transamidase assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — gene knockout with defined biochemical phenotype (loss of carbonyl intermediate formation), complex membership confirmed by co-IP, stabilization role confirmed by expression analysis; multiple orthogonal methods in a focused mechanistic study\",\n      \"pmids\": [\"11483512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GPI8 and PIG-T (PIGT) form a functionally important intermolecular disulfide bond between conserved cysteine residues within the GPI transamidase complex. Mutation of the relevant cysteines to serines in either GPI8 or PIG-T markedly reduced in vitro transamidase activity and failed to fully restore surface expression of GPI-anchored proteins in respective mutant cells. The disulfide bond is not absolutely required but is needed for full transamidase activity.\",\n      \"method\": \"Site-directed mutagenesis (Cys→Ser), in vitro transamidase assay, transfection rescue experiments, antibody-based detection of disulfide bond formation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis combined with in vitro enzymatic assay and cell-based rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"12582175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PIG-T (PIGT) is localized to the endoplasmic reticulum (ER) and its ER retention is mediated by information within its transmembrane span. Fusion of the PIG-T transmembrane domain to Tac antigen (a plasma membrane protein) caused the fusion protein to be retained in the ER, indicating a dominant ER-retention signal in the PIG-T TM domain. PIG-T is a type I membrane glycoprotein.\",\n      \"method\": \"Fusion protein construction, subcellular localization by imaging/fractionation, domain-swap experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional domain-swap demonstrating TM-span-mediated ER retention; single lab but two orthogonal approaches (construct analysis + fusion protein)\",\n      \"pmids\": [\"15713669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A homozygous missense mutation in PIGT (c.547A>C, p.Thr183Pro) causes reduced surface expression of GPI-anchored protein CD16b on patient granulocytes. The mutant p.Thr183Pro PIGT mRNA failed to rescue gastrulation defects induced by morpholino knockdown of the PIGT ortholog in zebrafish, whereas wild-type human PIGT mRNA could rescue, establishing this mutation as a loss-of-function variant that impairs GPI transamidase activity in vivo.\",\n      \"method\": \"Flow cytometry of patient granulocytes, morpholino knockdown and mRNA rescue in zebrafish embryos\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue assay in zebrafish plus patient cell flow cytometry; single lab, two orthogonal methods\",\n      \"pmids\": [\"23636107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of PIGT function (via a germline splice-site mutation plus somatic deletion of the second allele) in hematopoietic stem cells causes deficiency of GPI-anchored complement regulatory proteins (CD55, CD59) on blood cells, leading to paroxysmal nocturnal hemoglobinuria (PNH). This establishes that defective GPI anchor transfer to proteins (rather than defective GPI synthesis) is sufficient to cause PNH.\",\n      \"method\": \"Next-generation deep sequencing of all GPI pathway genes, identification of germline + somatic two-hit mechanism in patient granulocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient genetic analysis with two-hit somatic mechanism identified; single patient case but mechanistically informative\",\n      \"pmids\": [\"23733340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Compound heterozygous PIGT mutations (p.Glu84* and p.Arg488Trp) reduce surface expression of GPI-anchored proteins DAF and CD59 on patient granulocytes. Transfection of the p.Arg488Trp mutant PIGT into PIGT-deficient cells partially restored GPI-AP expression, while the p.Glu84* (null) mutant did not, demonstrating that p.Arg488Trp is a hypomorphic allele and that PIGT is required for GPI anchor attachment to proteins.\",\n      \"method\": \"Flow cytometry of patient granulocytes, transfection rescue into PIGT-deficient cells\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue transfection into knockout cells with flow cytometry readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"24906948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous PIGT variant p.Gly360Val leads to reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface of patient-derived cells, confirming the pathogenic role of this variant in impairing GPI transamidase function.\",\n      \"method\": \"In vitro cell surface GPI-AP quantification by flow cytometry on cells from affected patients\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (flow cytometry), single lab, no direct enzymatic assay\",\n      \"pmids\": [\"27916860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The PIGT variant p.Arg507Trp leads to mildly reduced GPI transamidase activity, as demonstrated by FACS analysis of PIGT knockout HEK293 cells transfected with wild-type or p.Arg507Trp mutant cDNA constructs measuring surface GPI-AP expression.\",\n      \"method\": \"Transfection rescue into PIGT knockout HEK293 cells, FACS analysis of GPI-AP surface expression\",\n      \"journal\": \"Frontiers in neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional rescue assay with defined knockout background; single lab, single method\",\n      \"pmids\": [\"36970549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIGT promotes GLUT1 glycosylation and membrane trafficking in bladder cancer cells. Overexpression of PIGT enhanced cell proliferation, oxidative phosphorylation, glycolysis, and tumor metastasis in vivo through activation of GLUT1. PIGT is post-translationally regulated by WTAP-mediated m6A modification of its mRNA, with IGF2BP2 reading the m6A mark to stabilize PIGT mRNA.\",\n      \"method\": \"PIGT silencing/overexpression, CCK-8/colony formation/Transwell assay, Seahorse metabolic flux analysis, immunoblot, RT-PCR, in vivo tumor model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (proliferation, metabolism, invasion, in vivo), with m6A regulatory mechanism identified; single lab\",\n      \"pmids\": [\"38169393\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIGT (PIG-T) encodes an essential subunit of the endoplasmic reticulum-localized GPI transamidase complex, where it forms a complex with GAA1, GPI8, PIG-S, and PIG-T stabilizes the complex by maintaining GAA1 and GPI8 expression; PIG-T is retained in the ER via its transmembrane domain, forms a functionally important disulfide bond with GPI8 at conserved cysteine residues that is required for full transamidase activity, and is essential for the carbonyl intermediate step by which preassembled GPI anchors are transferred to substrate proteins bearing a C-terminal GPI signal peptide.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIGT (PIG-T) is an essential subunit of the endoplasmic reticulum-localized GPI transamidase complex that transfers preassembled glycosylphosphatidylinositol (GPI) anchors onto proteins bearing a C-terminal GPI signal peptide [#0]. Within this complex PIG-T physically associates with GAA1, GPI8, and PIG-S, and stabilizes the assembly by maintaining the expression levels of GAA1 and GPI8; its loss abolishes GPI transfer specifically by blocking formation of the carbonyl intermediates of transamidation [#0]. PIG-T forms an intermolecular disulfide bond with GPI8 between conserved cysteines that, while not absolutely required, is needed for full transamidase activity [#1]. PIG-T is a type I membrane glycoprotein retained in the ER through a dominant retention signal within its transmembrane span [#2]. Loss-of-function and hypomorphic PIGT variants reduce surface expression of GPI-anchored proteins and cause human disease: biallelic mutations impair GPI anchor attachment in patients [#3, #5], and a germline-plus-somatic two-hit loss of PIGT in hematopoietic cells causes paroxysmal nocturnal hemoglobinuria, establishing that defective GPI transfer—rather than defective GPI synthesis—is sufficient to produce the PNH phenotype [#4]. Beyond its canonical transamidase role, PIGT promotes GLUT1 glycosylation and membrane trafficking in bladder cancer cells, enhancing proliferation, oxidative phosphorylation, glycolysis, and metastasis, and its mRNA is stabilized by WTAP-deposited m6A marks read by IGF2BP2 [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that PIG-T is an obligatory subunit of the GPI transamidase complex and defined its biochemical role, answering whether GPI transfer to proteins requires a dedicated multi-subunit machine and which step PIG-T governs.\",\n      \"evidence\": \"Homologous recombination knockout in mouse F9 cells with co-immunoprecipitation and in vitro transamidase assay\",\n      \"pmids\": [\"11483512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the atomic-level architecture of the complex\", \"Mechanism by which PIG-T maintains GAA1/GPI8 expression not defined\", \"Precise catalytic contribution of PIG-T versus GPI8 not separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified a functional disulfide bond between PIG-T and GPI8, addressing how subunits are covalently coupled to support catalysis.\",\n      \"evidence\": \"Cys\\u2192Ser site-directed mutagenesis with in vitro transamidase assay and cell-based rescue\",\n      \"pmids\": [\"12582175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disulfide is not absolutely required, so its precise contribution to activity is partial\", \"Structural geometry of the bonded cysteines not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the determinant of PIG-T subcellular residence, answering how the transamidase is confined to the ER where GPI transfer occurs.\",\n      \"evidence\": \"Transmembrane domain fusion to Tac antigen with subcellular localization analysis in a domain-swap design\",\n      \"pmids\": [\"15713669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking receptors recognizing the TM retention signal not identified\", \"Whether complex assembly contributes to retention not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected PIGT loss-of-function to human disease and demonstrated in vivo that point mutations abolish transamidase function, beyond cell-surface marker readouts.\",\n      \"evidence\": \"Flow cytometry of patient granulocytes plus zebrafish morpholino knockdown and human mRNA rescue (p.Thr183Pro fails to rescue)\",\n      \"pmids\": [\"23636107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation tested in vivo\", \"Molecular basis of how p.Thr183Pro impairs activity not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that defective GPI anchor transfer to proteins, not defective GPI synthesis, is sufficient to cause paroxysmal nocturnal hemoglobinuria, reframing the pathogenic spectrum of GPI deficiency.\",\n      \"evidence\": \"Deep sequencing of GPI pathway genes identifying a germline splice-site plus somatic second-hit deletion in patient granulocytes\",\n      \"pmids\": [\"23733340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient case\", \"No direct enzymatic assay of the variant alleles\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished null versus hypomorphic PIGT alleles through rescue, clarifying the genotype-function relationship underlying patient phenotypes.\",\n      \"evidence\": \"Flow cytometry of patient granulocytes plus transfection rescue of mutants into PIGT-deficient cells (p.Arg488Trp partial, p.Glu84* null)\",\n      \"pmids\": [\"24906948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic kinetics for hypomorphic allele\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the catalogue of pathogenic PIGT variants impairing surface GPI-AP display.\",\n      \"evidence\": \"Flow cytometry quantification of cell-surface GPI-APs on patient-derived cells for p.Gly360Val\",\n      \"pmids\": [\"27916860\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (flow cytometry), no direct enzymatic assay\", \"Mechanism of activity reduction not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Quantified the functional impact of an additional variant using a defined knockout-rescue system, refining variant interpretation.\",\n      \"evidence\": \"Transfection rescue into PIGT knockout HEK293 cells with FACS readout of GPI-AP surface expression (p.Arg507Trp mildly reduced)\",\n      \"pmids\": [\"36970549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method\", \"Structural basis of mild reduction not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-canonical, disease-relevant role for PIGT in cancer metabolism via GLUT1 glycosylation, and identified an upstream m6A regulatory axis controlling PIGT mRNA stability.\",\n      \"evidence\": \"PIGT silencing/overexpression, CCK-8/colony/Transwell assays, Seahorse flux analysis, immunoblot, and in vivo tumor model in bladder cancer\",\n      \"pmids\": [\"38169393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GLUT1 glycosylation occurs through canonical transamidase activity or another mechanism not resolved\", \"Single lab\", \"Generality across cancer types not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the catalytic step and subunit coordination of the transamidase are organized at atomic resolution, and how individual missense variants map onto this architecture to graded loss-of-function, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PIG-T within the assembled complex in the corpus\", \"Mechanism linking PIG-T to GLUT1 trafficking versus canonical transamidation unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"GPI transamidase complex\"],\n    \"partners\": [\"GAA1\", \"GPI8\", \"PIGS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}