{"gene":"PIGC","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1998,"finding":"PIGC (PIG-C) forms a protein complex in the endoplasmic reticulum membrane with PIG-A, PIG-H, and hGPI1 (four mammalian gene products). This complex has GPI-GlcNAc transferase (GPI-GnT) activity in vitro, catalyzing transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol as the first step of GPI biosynthesis. PIG-L, involved in the second step, did not associate with this complex. Bovine PI was utilized ~100-fold more efficiently than soybean PI, suggesting the complex recognizes the fatty acyl chains of PI.","method":"Co-immunoprecipitation of complex components, in vitro GPI-GnT enzymatic activity assay, substrate specificity analysis with different PI sources","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic activity combined with biochemical complex isolation and substrate specificity experiments; replicated across mammalian and yeast systems","pmids":["9463366"],"is_preprint":false},{"year":1996,"finding":"PIG-C is a 297 amino-acid membrane protein localized to the endoplasmic reticulum and is the human homologue of yeast GPI2. It is one of at least three mammalian genes (PIG-A, PIG-H, PIG-C) required for the first step of GPI biosynthesis (GlcNAc transfer to PI).","method":"Molecular cloning, sequence homology analysis, subcellular localization by membrane fractionation/ER marker co-localization, functional complementation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cloning with functional characterization in cellular context, single lab but orthogonal methods (sequence analysis, ER localization, complementation)","pmids":["8806613"],"is_preprint":false},{"year":1997,"finding":"The PIGC gene is intronless and maps to chromosome 1q23-q25. A processed pseudogene (PIGCP1) was identified and mapped to chromosome 11p12-p13. The autosomal localization of PIGC (unlike the X-linked PIGA) is consistent with the requirement for two somatic mutations to cause PNH.","method":"Genomic cloning, chromosomal mapping by fluorescence in situ hybridization (FISH), gene structure analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic cloning and chromosomal mapping with functional inference; single lab","pmids":["9325057"],"is_preprint":false},{"year":1995,"finding":"Yeast GPI2 (the ortholog of mammalian PIGC) is required for GlcNAc-phosphatidylinositol synthesis (first step of GPI biosynthesis). Loss-of-function gpi2 mutants lack in vitro GlcNAc-PI synthetic activity. Overexpression of GPI2 partially suppresses the gpi1 temperature-sensitive mutant, suggesting physical or functional interaction between Gpi1 and Gpi2 proteins in vivo. GPI2 is essential for vegetative growth.","method":"Temperature-sensitive mutant isolation, in vitro GlcNAc-PI synthesis assay, gene disruption (null mutant), genetic suppression (overexpression rescue of gpi1 ts mutant)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay combined with genetic epistasis (null mutant, suppression), replicated in context of established GPI pathway","pmids":["7768896"],"is_preprint":false},{"year":2016,"finding":"Disease-causing mutations in human PIGC (p.L189W, p.L212P, p.R21X) result in reduced surface expression of GPI-anchored proteins (CD90, CD48, FLAER in transfected PIGC-defective mouse cells; CD16, CD14, CD55, CD59 in patient leukocytes), confirming that PIGC function is required for normal GPI anchor biosynthesis in vivo.","method":"Transfection of PIGC variants into PIGC-defective mouse cells, flow cytometry for GPI-anchored protein surface expression; patient leukocyte analysis by flow cytometry","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function cellular model with defined readout (GPI-AP surface levels), validated in both engineered cell lines and patient-derived cells","pmids":["27694521"],"is_preprint":false},{"year":2021,"finding":"In Trypanosoma brucei, TbGPI2 (ortholog of PIGC) is a subunit of the GPI-GlcNAc transferase complex; its elimination reduces (but does not abolish) GPI-GlcNAc transferase activity and disrupts the complex architecture (loss of TbGPI1 subunit). TbGPI2-null parasites show underglycosylated GPI anchors on procyclins, and TbGPI2 localizes not only to the ER but also to the Golgi apparatus, suggesting a noncanonical role in Golgi-localized GPI anchor modification.","method":"Genetic knockout (TbGPI2-null parasites), in vitro GPI-GlcNAc transferase activity assay, co-immunoprecipitation of complex components, GPI glycan structural analysis, immunofluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO, enzymatic assay, Co-IP, glycan analysis, localization) in single lab using a non-mammalian model","pmids":["34284059"],"is_preprint":false},{"year":2014,"finding":"In S. cerevisiae, ScGpi2 (PIGC ortholog) physically interacts with and negatively modulates Ras signaling. Functional complementation studies showed that ScGPI2 and CaGPI2 (from C. albicans) are not fully interchangeable: CaGPI2 cannot restore ScGPI2-null growth defects, and ScGPI2 cannot restore CaGPI2 heterozygote GPI-GnT activity or cell wall integrity. However, ScGPI2 can restore CaERG11 (lanosterol demethylase) levels in the CaGPI2 heterozygote, acting through CaGPI19, independent of GPI-GnT complex interactions.","method":"Functional complementation (cross-species expression), GPI-GnT activity assay, cell wall integrity assay, filamentation assay, western blot for CaERG11 levels","journal":"Glycoconjugate journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in yeast models; single lab; findings in non-mammalian organisms","pmids":["25117514"],"is_preprint":false},{"year":2021,"finding":"Silencing of PIGC in HepG2 hepatocellular carcinoma cells inhibits proliferation and migration and causes G0/G1 cell cycle arrest, associated with reduced expression of cyclinD1, CDK2, CDK4, and CDK6. Overexpression of PIGC in Hcclm3 cells produces the opposite effects.","method":"siRNA knockdown and overexpression in cancer cell lines, cell proliferation assay, migration assay, flow cytometry for cell cycle analysis, western blot for cell cycle regulators","journal":"Journal of hepatocellular carcinoma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, loss-of-function/gain-of-function with phenotypic readout but no direct mechanistic pathway placement beyond cell cycle protein expression changes","pmids":["33854986"],"is_preprint":false},{"year":2025,"finding":"Biallelic PIGC variants in patients result in reduced cell-surface levels of GPI-anchored proteins, as demonstrated by flow cytometry on samples from probands and cellular models, confirming that dysfunctional PIGC causes defective GPI-AP biosynthesis.","method":"Flow cytometry for GPI-AP surface expression in patient-derived samples and cellular models; in silico structural modelling (AlphaFold2) of variants; genome/exome sequencing","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — multiple patient cohorts (18 probands) with cellular validation of GPI-AP surface expression; replicates prior findings from PMID 27694521","pmids":["40962973"],"is_preprint":false}],"current_model":"PIGC (PIG-C/GPI2) is an endoplasmic reticulum membrane protein that functions as an essential accessory subunit of the GPI-GlcNAc transferase (GPI-GnT) complex, which also includes PIG-A, PIG-H, PIGQ (hGPI1), PIGY, and PIGP; this complex catalyzes the first step of GPI anchor biosynthesis—transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol—and loss of PIGC function abolishes or severely reduces this enzymatic activity and causes deficient surface expression of GPI-anchored proteins, manifesting clinically as a severe neurodevelopmental disorder with refractory seizures."},"narrative":{"mechanistic_narrative":"PIGC (the human homologue of yeast GPI2) is an endoplasmic reticulum membrane protein that acts as an essential subunit of the GPI-GlcNAc transferase (GPI-GnT) complex, which catalyzes the first committed step of glycosylphosphatidylinositol anchor biosynthesis—transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol [PMID:9463366, PMID:8806613]. Within this ER-resident complex PIGC associates physically with PIG-A, PIG-H, and hGPI1, and the assembled complex exhibits GlcNAc transferase activity in vitro with strong preference for substrate PI bearing particular fatty acyl chains [PMID:9463366]. The functional partnership between PIGC and the hGPI1 subunit is conserved from yeast, where overexpression of GPI2 suppresses a gpi1 temperature-sensitive defect and GPI2 is essential for vegetative growth [PMID:7768896]. Loss of PIGC function reduces or abolishes GPI-GnT activity and produces deficient surface expression of GPI-anchored proteins, established both in PIGC-defective cellular models and in patient-derived leukocytes carrying biallelic disease variants [PMID:27694521, PMID:40962973]. Biallelic PIGC mutations cause a severe inherited GPI-deficiency disorder, confirmed across multiple patient cohorts with reduced GPI-AP surface levels [PMID:27694521, PMID:40962973].","teleology":[{"year":1995,"claim":"Established that the yeast PIGC ortholog GPI2 is genetically required for the first step of GPI biosynthesis and functionally linked to Gpi1, defining the conserved core of the pathway.","evidence":"Temperature-sensitive mutant isolation, gene disruption, in vitro GlcNAc-PI synthesis assay, and overexpression suppression of a gpi1 ts mutant in S. cerevisiae","pmids":["7768896"],"confidence":"High","gaps":["Did not define the molecular composition of the mammalian complex","Physical versus purely functional Gpi1-Gpi2 interaction left unresolved in vivo"]},{"year":1996,"claim":"Identified human PIGC as a 297-residue ER membrane protein and the human homologue of yeast GPI2, placing it among the genes required for GlcNAc transfer to PI in mammals.","evidence":"Molecular cloning, sequence homology, membrane fractionation/ER co-localization, and functional complementation","pmids":["8806613"],"confidence":"Medium","gaps":["Direct biochemical interaction with other PIG subunits not yet demonstrated","Catalytic versus accessory role unresolved"]},{"year":1997,"claim":"Mapped PIGC genomic structure and chromosomal location, distinguishing its autosomal genetics from X-linked PIGA and clarifying somatic mutation requirements relevant to PNH.","evidence":"Genomic cloning, FISH chromosomal mapping, and gene structure analysis","pmids":["9325057"],"confidence":"Medium","gaps":["No functional consequence of the locus tested","Pseudogene PIGCP1 role, if any, undefined"]},{"year":1998,"claim":"Demonstrated that PIGC is a physical subunit of an ER GPI-GnT complex with PIG-A, PIG-H, and hGPI1 that reconstitutes GlcNAc transferase activity and recognizes the PI acyl chains, defining the enzymatic machinery directly.","evidence":"Co-immunoprecipitation of complex components, in vitro GPI-GnT activity assay, and substrate specificity comparison across PI sources","pmids":["9463366"],"confidence":"High","gaps":["Specific catalytic contribution of PIGC versus other subunits not isolated","No structural model of the assembled complex"]},{"year":2014,"claim":"Probed species-specific and noncanonical functions of the GPI2 ortholog, including Ras-signaling modulation and a GPI-GnT-independent route to regulating CaERG11, indicating functional divergence beyond the core complex.","evidence":"Cross-species functional complementation, GPI-GnT activity and cell-wall integrity assays, and western blot in S. cerevisiae and C. albicans","pmids":["25117514"],"confidence":"Medium","gaps":["Relevance of Ras modulation to mammalian PIGC unknown","Mechanism of CaGPI19/CaERG11 regulation not resolved"]},{"year":2016,"claim":"Linked human PIGC missense and nonsense mutations directly to defective GPI anchoring in vivo, establishing PIGC loss-of-function as a cause of reduced GPI-AP surface expression.","evidence":"Transfection of PIGC variants into PIGC-defective mouse cells with flow cytometry, plus patient leukocyte flow cytometry","pmids":["27694521"],"confidence":"High","gaps":["Quantitative effect of each variant on enzyme kinetics not measured","Genotype-phenotype correlation across variants not established"]},{"year":2021,"claim":"Characterized the trypanosome ortholog TbGPI2 as a complex subunit whose loss disrupts complex architecture and only partially reduces activity, and revealed an unexpected Golgi localization implicating a noncanonical role.","evidence":"Gene knockout, in vitro GPI-GnT activity assay, co-immunoprecipitation, GPI glycan structural analysis, and immunofluorescence in T. brucei","pmids":["34284059"],"confidence":"Medium","gaps":["Golgi function not demonstrated for mammalian PIGC","Mechanism of residual activity in TbGPI2-null cells unexplained"]},{"year":2021,"claim":"Reported a candidate proliferative/cell-cycle role for PIGC in hepatocellular carcinoma cells, raising a possible function beyond GPI anchoring.","evidence":"siRNA knockdown and overexpression in HepG2 and Hcclm3 cells with proliferation, migration, cell-cycle, and cyclin/CDK western blot readouts","pmids":["33854986"],"confidence":"Low","gaps":["Single-lab phenotypic study without mechanistic pathway placement","Effects not linked to GPI-GnT activity or GPI-AP levels","Not independently confirmed"]},{"year":2025,"claim":"Consolidated PIGC as a Mendelian GPI-deficiency gene across an expanded patient cohort, confirming reduced GPI-AP surface levels caused by biallelic variants.","evidence":"Flow cytometry for GPI-AP surface expression in 18 probands and cellular models, with AlphaFold2 structural modelling and exome/genome sequencing","pmids":["40962973"],"confidence":"Medium","gaps":["Structural predictions not experimentally validated","Variant-specific residual enzyme activity not quantified"]},{"year":null,"claim":"Whether PIGC contributes to functions outside the ER GPI-GnT complex—such as the reported Golgi localization, Ras modulation, or cancer cell-cycle roles—remains mechanistically unresolved in mammals.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mammalian evidence linking PIGC to non-GPI pathways","Catalytic versus structural role of PIGC within the GPI-GnT complex not separated","No experimental structure of the human complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4]}],"complexes":["GPI-GlcNAc transferase (GPI-GnT) complex"],"partners":["PIGA","PIGH","PIGQ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92535","full_name":"Phosphatidylinositol N-acetylglucosaminyltransferase subunit C","aliases":["Phosphatidylinositol-glycan biosynthesis class C protein","PIG-C"],"length_aa":297,"mass_kda":33.6,"function":"Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q92535/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIGC","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIGC","total_profiled":1310},"omim":[{"mim_id":"617816","title":"GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 16; GPIBD16","url":"https://www.omim.org/entry/617816"},{"mim_id":"610293","title":"GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 1; GPIBD1","url":"https://www.omim.org/entry/610293"},{"mim_id":"605754","title":"PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS Q PROTEIN; PIGQ","url":"https://www.omim.org/entry/605754"},{"mim_id":"601730","title":"PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS C PROTEIN; PIGC","url":"https://www.omim.org/entry/601730"},{"mim_id":"600154","title":"PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS H PROTEIN; PIGH","url":"https://www.omim.org/entry/600154"}],"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/PIGC"},"hgnc":{"alias_symbol":["PIG-C","GPI2"],"prev_symbol":[]},"alphafold":{"accession":"Q92535","domains":[{"cath_id":"-","chopping":"49-275","consensus_level":"medium","plddt":92.5879,"start":49,"end":275}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92535","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92535-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92535-F1-predicted_aligned_error_v6.png","plddt_mean":89.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIGC","jax_strain_url":"https://www.jax.org/strain/search?query=PIGC"},"sequence":{"accession":"Q92535","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92535.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92535/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92535"}},"corpus_meta":[{"pmid":"9463366","id":"PMC_9463366","title":"The first step of glycosylphosphatidylinositol biosynthesis is mediated by a complex of PIG-A, PIG-H, PIG-C and GPI1.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9463366","citation_count":129,"is_preprint":false},{"pmid":"7768896","id":"PMC_7768896","title":"Temperature-sensitive yeast GPI anchoring mutants gpi2 and gpi3 are defective in the synthesis of N-acetylglucosaminyl phosphatidylinositol. Cloning of the GPI2 gene.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7768896","citation_count":102,"is_preprint":false},{"pmid":"8806613","id":"PMC_8806613","title":"PIG-C, one of the three human genes involved in the first step of glycosylphosphatidylinositol biosynthesis is a homologue of Saccharomyces cerevisiae GPI2.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8806613","citation_count":66,"is_preprint":false},{"pmid":"27694521","id":"PMC_27694521","title":"Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability.","date":"2016","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27694521","citation_count":40,"is_preprint":false},{"pmid":"18401499","id":"PMC_18401499","title":"Chemoenzymatic synthesis of prodigiosin analogues--exploring the substrate specificity of PigC.","date":"2008","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18401499","citation_count":18,"is_preprint":false},{"pmid":"33171372","id":"PMC_33171372","title":"MALAT-1: LncRNA ruling miR-182/PIG-C/mesothelin triad in triple negative breast cancer.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/33171372","citation_count":12,"is_preprint":false},{"pmid":"18211505","id":"PMC_18211505","title":"In vitro and in vivo prevention of human CD8+ CTL-mediated xenocytotoxicity by pig c-FLIP expression in porcine endothelial cells.","date":"2008","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/18211505","citation_count":9,"is_preprint":false},{"pmid":"9325057","id":"PMC_9325057","title":"Structures and chromosomal localizations of the glycosylphosphatidylinositol synthesis gene PIGC and its pseudogene PIGCP1.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9325057","citation_count":7,"is_preprint":false},{"pmid":"35378140","id":"PMC_35378140","title":"NEAT1: Culprit lncRNA linking PIG-C, MSLN, and CD80 in triple-negative breast cancer.","date":"2022","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35378140","citation_count":7,"is_preprint":false},{"pmid":"25117514","id":"PMC_25117514","title":"Saccharomyces cerevisiae Gpi2, an accessory subunit of the enzyme catalyzing the first step of glycosylphosphatidylinositol (GPI) anchor biosynthesis, selectively complements some of the functions of its homolog in Candida albicans.","date":"2014","source":"Glycoconjugate journal","url":"https://pubmed.ncbi.nlm.nih.gov/25117514","citation_count":6,"is_preprint":false},{"pmid":"29313426","id":"PMC_29313426","title":"Enhancement of prodigiosin synthetase (PigC) production from recombinant Escherichia coli through optimization of induction strategy and media.","date":"2018","source":"Preparative biochemistry & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/29313426","citation_count":6,"is_preprint":false},{"pmid":"34284059","id":"PMC_34284059","title":"Elimination of GPI2 suppresses glycosylphosphatidylinositol GlcNAc transferase activity and alters GPI glycan modification in Trypanosoma brucei.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34284059","citation_count":4,"is_preprint":false},{"pmid":"33854986","id":"PMC_33854986","title":"High Expression of PIGC Predicts Unfavorable Survival in Hepatocellular Carcinoma.","date":"2021","source":"Journal of hepatocellular carcinoma","url":"https://pubmed.ncbi.nlm.nih.gov/33854986","citation_count":3,"is_preprint":false},{"pmid":"32707268","id":"PMC_32707268","title":"Multisystem disorders, severe developmental delay and seizures in two affected siblings, expanding the phenotype of PIGC deficiency.","date":"2020","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32707268","citation_count":3,"is_preprint":false},{"pmid":"34471342","id":"PMC_34471342","title":"Genome-Wide Phylogenetic Analysis, Expression Pattern, and Transcriptional Regulatory Network of the Pig C/EBP Gene Family.","date":"2021","source":"Evolutionary bioinformatics online","url":"https://pubmed.ncbi.nlm.nih.gov/34471342","citation_count":2,"is_preprint":false},{"pmid":"19249564","id":"PMC_19249564","title":"Intracellular and extracellular remodeling effectively prevents human CD8(+)cytotoxic T lymphocyte-mediated xenocytotoxicity by coexpression of membrane-bound human FasL and pig c-FLIP(L) in pig endothelial cells.","date":"2009","source":"Transplantation proceedings","url":"https://pubmed.ncbi.nlm.nih.gov/19249564","citation_count":1,"is_preprint":false},{"pmid":"40962973","id":"PMC_40962973","title":"PIGC-related encephalopathy: Lessons learned from 18 new probands.","date":"2025","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/40962973","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.14.25340263","title":"Interactions with polygenic background impact quantitative traits in the UK Biobank","date":"2025-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.25340263","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11445,"output_tokens":2653,"usd":0.037065,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9849,"output_tokens":3085,"usd":0.063185,"stage2_stop_reason":"end_turn"},"total_usd":0.10025,"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\": 1998,\n      \"finding\": \"PIGC (PIG-C) forms a protein complex in the endoplasmic reticulum membrane with PIG-A, PIG-H, and hGPI1 (four mammalian gene products). This complex has GPI-GlcNAc transferase (GPI-GnT) activity in vitro, catalyzing transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol as the first step of GPI biosynthesis. PIG-L, involved in the second step, did not associate with this complex. Bovine PI was utilized ~100-fold more efficiently than soybean PI, suggesting the complex recognizes the fatty acyl chains of PI.\",\n      \"method\": \"Co-immunoprecipitation of complex components, in vitro GPI-GnT enzymatic activity assay, substrate specificity analysis with different PI sources\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of enzymatic activity combined with biochemical complex isolation and substrate specificity experiments; replicated across mammalian and yeast systems\",\n      \"pmids\": [\"9463366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"PIG-C is a 297 amino-acid membrane protein localized to the endoplasmic reticulum and is the human homologue of yeast GPI2. It is one of at least three mammalian genes (PIG-A, PIG-H, PIG-C) required for the first step of GPI biosynthesis (GlcNAc transfer to PI).\",\n      \"method\": \"Molecular cloning, sequence homology analysis, subcellular localization by membrane fractionation/ER marker co-localization, functional complementation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cloning with functional characterization in cellular context, single lab but orthogonal methods (sequence analysis, ER localization, complementation)\",\n      \"pmids\": [\"8806613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The PIGC gene is intronless and maps to chromosome 1q23-q25. A processed pseudogene (PIGCP1) was identified and mapped to chromosome 11p12-p13. The autosomal localization of PIGC (unlike the X-linked PIGA) is consistent with the requirement for two somatic mutations to cause PNH.\",\n      \"method\": \"Genomic cloning, chromosomal mapping by fluorescence in situ hybridization (FISH), gene structure analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic cloning and chromosomal mapping with functional inference; single lab\",\n      \"pmids\": [\"9325057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast GPI2 (the ortholog of mammalian PIGC) is required for GlcNAc-phosphatidylinositol synthesis (first step of GPI biosynthesis). Loss-of-function gpi2 mutants lack in vitro GlcNAc-PI synthetic activity. Overexpression of GPI2 partially suppresses the gpi1 temperature-sensitive mutant, suggesting physical or functional interaction between Gpi1 and Gpi2 proteins in vivo. GPI2 is essential for vegetative growth.\",\n      \"method\": \"Temperature-sensitive mutant isolation, in vitro GlcNAc-PI synthesis assay, gene disruption (null mutant), genetic suppression (overexpression rescue of gpi1 ts mutant)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay combined with genetic epistasis (null mutant, suppression), replicated in context of established GPI pathway\",\n      \"pmids\": [\"7768896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Disease-causing mutations in human PIGC (p.L189W, p.L212P, p.R21X) result in reduced surface expression of GPI-anchored proteins (CD90, CD48, FLAER in transfected PIGC-defective mouse cells; CD16, CD14, CD55, CD59 in patient leukocytes), confirming that PIGC function is required for normal GPI anchor biosynthesis in vivo.\",\n      \"method\": \"Transfection of PIGC variants into PIGC-defective mouse cells, flow cytometry for GPI-anchored protein surface expression; patient leukocyte analysis by flow cytometry\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function cellular model with defined readout (GPI-AP surface levels), validated in both engineered cell lines and patient-derived cells\",\n      \"pmids\": [\"27694521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Trypanosoma brucei, TbGPI2 (ortholog of PIGC) is a subunit of the GPI-GlcNAc transferase complex; its elimination reduces (but does not abolish) GPI-GlcNAc transferase activity and disrupts the complex architecture (loss of TbGPI1 subunit). TbGPI2-null parasites show underglycosylated GPI anchors on procyclins, and TbGPI2 localizes not only to the ER but also to the Golgi apparatus, suggesting a noncanonical role in Golgi-localized GPI anchor modification.\",\n      \"method\": \"Genetic knockout (TbGPI2-null parasites), in vitro GPI-GlcNAc transferase activity assay, co-immunoprecipitation of complex components, GPI glycan structural analysis, immunofluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO, enzymatic assay, Co-IP, glycan analysis, localization) in single lab using a non-mammalian model\",\n      \"pmids\": [\"34284059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In S. cerevisiae, ScGpi2 (PIGC ortholog) physically interacts with and negatively modulates Ras signaling. Functional complementation studies showed that ScGPI2 and CaGPI2 (from C. albicans) are not fully interchangeable: CaGPI2 cannot restore ScGPI2-null growth defects, and ScGPI2 cannot restore CaGPI2 heterozygote GPI-GnT activity or cell wall integrity. However, ScGPI2 can restore CaERG11 (lanosterol demethylase) levels in the CaGPI2 heterozygote, acting through CaGPI19, independent of GPI-GnT complex interactions.\",\n      \"method\": \"Functional complementation (cross-species expression), GPI-GnT activity assay, cell wall integrity assay, filamentation assay, western blot for CaERG11 levels\",\n      \"journal\": \"Glycoconjugate journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in yeast models; single lab; findings in non-mammalian organisms\",\n      \"pmids\": [\"25117514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing of PIGC in HepG2 hepatocellular carcinoma cells inhibits proliferation and migration and causes G0/G1 cell cycle arrest, associated with reduced expression of cyclinD1, CDK2, CDK4, and CDK6. Overexpression of PIGC in Hcclm3 cells produces the opposite effects.\",\n      \"method\": \"siRNA knockdown and overexpression in cancer cell lines, cell proliferation assay, migration assay, flow cytometry for cell cycle analysis, western blot for cell cycle regulators\",\n      \"journal\": \"Journal of hepatocellular carcinoma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, loss-of-function/gain-of-function with phenotypic readout but no direct mechanistic pathway placement beyond cell cycle protein expression changes\",\n      \"pmids\": [\"33854986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic PIGC variants in patients result in reduced cell-surface levels of GPI-anchored proteins, as demonstrated by flow cytometry on samples from probands and cellular models, confirming that dysfunctional PIGC causes defective GPI-AP biosynthesis.\",\n      \"method\": \"Flow cytometry for GPI-AP surface expression in patient-derived samples and cellular models; in silico structural modelling (AlphaFold2) of variants; genome/exome sequencing\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple patient cohorts (18 probands) with cellular validation of GPI-AP surface expression; replicates prior findings from PMID 27694521\",\n      \"pmids\": [\"40962973\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIGC (PIG-C/GPI2) is an endoplasmic reticulum membrane protein that functions as an essential accessory subunit of the GPI-GlcNAc transferase (GPI-GnT) complex, which also includes PIG-A, PIG-H, PIGQ (hGPI1), PIGY, and PIGP; this complex catalyzes the first step of GPI anchor biosynthesis—transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol—and loss of PIGC function abolishes or severely reduces this enzymatic activity and causes deficient surface expression of GPI-anchored proteins, manifesting clinically as a severe neurodevelopmental disorder with refractory seizures.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIGC (the human homologue of yeast GPI2) is an endoplasmic reticulum membrane protein that acts as an essential subunit of the GPI-GlcNAc transferase (GPI-GnT) complex, which catalyzes the first committed step of glycosylphosphatidylinositol anchor biosynthesis—transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol [#0, #1]. Within this ER-resident complex PIGC associates physically with PIG-A, PIG-H, and hGPI1, and the assembled complex exhibits GlcNAc transferase activity in vitro with strong preference for substrate PI bearing particular fatty acyl chains [#0]. The functional partnership between PIGC and the hGPI1 subunit is conserved from yeast, where overexpression of GPI2 suppresses a gpi1 temperature-sensitive defect and GPI2 is essential for vegetative growth [#3]. Loss of PIGC function reduces or abolishes GPI-GnT activity and produces deficient surface expression of GPI-anchored proteins, established both in PIGC-defective cellular models and in patient-derived leukocytes carrying biallelic disease variants [#4, #8]. Biallelic PIGC mutations cause a severe inherited GPI-deficiency disorder, confirmed across multiple patient cohorts with reduced GPI-AP surface levels [#4, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that the yeast PIGC ortholog GPI2 is genetically required for the first step of GPI biosynthesis and functionally linked to Gpi1, defining the conserved core of the pathway.\",\n      \"evidence\": \"Temperature-sensitive mutant isolation, gene disruption, in vitro GlcNAc-PI synthesis assay, and overexpression suppression of a gpi1 ts mutant in S. cerevisiae\",\n      \"pmids\": [\"7768896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular composition of the mammalian complex\", \"Physical versus purely functional Gpi1-Gpi2 interaction left unresolved in vivo\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified human PIGC as a 297-residue ER membrane protein and the human homologue of yeast GPI2, placing it among the genes required for GlcNAc transfer to PI in mammals.\",\n      \"evidence\": \"Molecular cloning, sequence homology, membrane fractionation/ER co-localization, and functional complementation\",\n      \"pmids\": [\"8806613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical interaction with other PIG subunits not yet demonstrated\", \"Catalytic versus accessory role unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped PIGC genomic structure and chromosomal location, distinguishing its autosomal genetics from X-linked PIGA and clarifying somatic mutation requirements relevant to PNH.\",\n      \"evidence\": \"Genomic cloning, FISH chromosomal mapping, and gene structure analysis\",\n      \"pmids\": [\"9325057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the locus tested\", \"Pseudogene PIGCP1 role, if any, undefined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that PIGC is a physical subunit of an ER GPI-GnT complex with PIG-A, PIG-H, and hGPI1 that reconstitutes GlcNAc transferase activity and recognizes the PI acyl chains, defining the enzymatic machinery directly.\",\n      \"evidence\": \"Co-immunoprecipitation of complex components, in vitro GPI-GnT activity assay, and substrate specificity comparison across PI sources\",\n      \"pmids\": [\"9463366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific catalytic contribution of PIGC versus other subunits not isolated\", \"No structural model of the assembled complex\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Probed species-specific and noncanonical functions of the GPI2 ortholog, including Ras-signaling modulation and a GPI-GnT-independent route to regulating CaERG11, indicating functional divergence beyond the core complex.\",\n      \"evidence\": \"Cross-species functional complementation, GPI-GnT activity and cell-wall integrity assays, and western blot in S. cerevisiae and C. albicans\",\n      \"pmids\": [\"25117514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance of Ras modulation to mammalian PIGC unknown\", \"Mechanism of CaGPI19/CaERG11 regulation not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked human PIGC missense and nonsense mutations directly to defective GPI anchoring in vivo, establishing PIGC loss-of-function as a cause of reduced GPI-AP surface expression.\",\n      \"evidence\": \"Transfection of PIGC variants into PIGC-defective mouse cells with flow cytometry, plus patient leukocyte flow cytometry\",\n      \"pmids\": [\"27694521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative effect of each variant on enzyme kinetics not measured\", \"Genotype-phenotype correlation across variants not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Characterized the trypanosome ortholog TbGPI2 as a complex subunit whose loss disrupts complex architecture and only partially reduces activity, and revealed an unexpected Golgi localization implicating a noncanonical role.\",\n      \"evidence\": \"Gene knockout, in vitro GPI-GnT activity assay, co-immunoprecipitation, GPI glycan structural analysis, and immunofluorescence in T. brucei\",\n      \"pmids\": [\"34284059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Golgi function not demonstrated for mammalian PIGC\", \"Mechanism of residual activity in TbGPI2-null cells unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reported a candidate proliferative/cell-cycle role for PIGC in hepatocellular carcinoma cells, raising a possible function beyond GPI anchoring.\",\n      \"evidence\": \"siRNA knockdown and overexpression in HepG2 and Hcclm3 cells with proliferation, migration, cell-cycle, and cyclin/CDK western blot readouts\",\n      \"pmids\": [\"33854986\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab phenotypic study without mechanistic pathway placement\", \"Effects not linked to GPI-GnT activity or GPI-AP levels\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated PIGC as a Mendelian GPI-deficiency gene across an expanded patient cohort, confirming reduced GPI-AP surface levels caused by biallelic variants.\",\n      \"evidence\": \"Flow cytometry for GPI-AP surface expression in 18 probands and cellular models, with AlphaFold2 structural modelling and exome/genome sequencing\",\n      \"pmids\": [\"40962973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural predictions not experimentally validated\", \"Variant-specific residual enzyme activity not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PIGC contributes to functions outside the ER GPI-GnT complex—such as the reported Golgi localization, Ras modulation, or cancer cell-cycle roles—remains mechanistically unresolved in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mammalian evidence linking PIGC to non-GPI pathways\", \"Catalytic versus structural role of PIGC within the GPI-GnT complex not separated\", \"No experimental structure of the human complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\"GPI-GlcNAc transferase (GPI-GnT) complex\"],\n    \"partners\": [\"PIGA\", \"PIGH\", \"PIGQ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}