{"gene":"GLDC","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2000,"finding":"The GLDC gene spans at least 135 kb, consists of 25 exons, and is expressed in human liver, kidney, brain, and placenta. A highly conserved processed pseudogene (psiGLDC) shares 97.5% homology with the coding region and arose ~4-8 million years ago. Loss of GLDC expression (large homozygous deletion of exons 1-3) abolishes glycine cleavage system activity, causing NKH.","method":"RNA blotting, primer extension analysis, PCR, semi-quantitative PCR using pseudogene as internal control","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct expression and structural characterization with multiple methods in a single lab study","pmids":["10798358"],"is_preprint":false},{"year":2006,"finding":"GLDC encodes the P-protein (glycine decarboxylase) component of the glycine cleavage system (GCS); mutations in GLDC account for ~80% of NKH cases. The cofactor-binding site at Lys754 (encoded by exon 19) is a mutational hotspot. A large deletion involving exon 1 was found across multiple ethnic backgrounds with multiple independent origins.","method":"Comprehensive mutation screening by sequencing all 25 GLDC exons in 69 NKH families; haplotype analysis","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — large multi-family cohort, replicated across multiple independent groups, identifies functional domain (cofactor-binding site)","pmids":["16450403"],"is_preprint":false},{"year":2004,"finding":"A homozygous GLDC A802V missense mutation results in 32% residual glycine cleavage system activity compared to wild type; patients with this hypomorphic mutation show transient or absent symptoms and normal developmental outcome, directly linking residual GLDC enzymatic activity level to disease severity.","method":"Enzyme activity assay of glycine cleavage system in patient tissue; mutation identified by sequencing","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzyme activity measurement correlated with genotype and phenotype, single lab","pmids":["15236413"],"is_preprint":false},{"year":2006,"finding":"A novel homozygous GLDC Y161C missense mutation abolishes glycine cleavage system (GCS) activity (2.6% of controls) in placental tissue, causing severe neonatal NKH with markedly elevated CSF glycine at birth, demonstrating that GLDC loss-of-function causes prenatal glycine accumulation.","method":"GCS enzyme activity assay in placental tissue; GLDC mutation sequencing; CSF and plasma glycine measurement","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzyme activity assay plus molecular diagnosis, single case/lab","pmids":["16404748"],"is_preprint":false},{"year":2005,"finding":"A translationally silent GLDC exon 22 transversion (c.2607C>A) causes aberrant splicing (exon 22 skipping, exon 22-23 skipping, and cryptic exon insertion), reducing GLDC mRNA levels. Only 4-6% normally spliced mRNA was retained, accounting for the attenuated clinical phenotype, directly linking splicing efficiency to disease severity.","method":"Northern blot, RT-PCR analysis of lymphoblast GLDC mRNA; identification of three aberrant splice products","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA analysis with multiple orthogonal methods, single lab","pmids":["15851735"],"is_preprint":false},{"year":2005,"finding":"A methionine-to-threonine change in the GLDC initiation codon markedly reduces glycine decarboxylase mRNA levels and abolishes glycine cleavage system activity, establishing that loss of translation initiation causes NKH through mRNA instability/nonsense-mediated decay.","method":"mRNA level analysis; enzyme activity assay; sequencing of GLDC initiation codon","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional enzyme assay and mRNA quantification, single lab","pmids":["15864413"],"is_preprint":false},{"year":2017,"finding":"Functional expression of 19 GLDC missense variants in COS7 cells, combined with enzymatic assays and Western blot, showed that loss-of-function for many variants is associated with protein instability rather than direct catalytic disruption. Structural modeling of the 3D structure identified effects on protein stability and catalytic activity, including hypomorphic variants producing attenuated phenotypes.","method":"Mutant cDNA expression in COS7 cells; enzymatic assay; Western blot for protein stability; molecular modeling of 3D structure","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzyme assay with mutagenesis and structural analysis, single lab, multiple orthogonal methods","pmids":["28244183"],"is_preprint":false},{"year":2019,"finding":"GLDC regulates cellular antiviral innate immune response: GLDC inhibition (by AOAA) or siRNA depletion boosted IFNβ and interferon-stimulated gene (ISG) expression upon poly(I:C) stimulation or influenza virus infection, and suppressed H1N1/H7N9 replication. Conversely, GLDC overexpression attenuated antiviral responses and promoted viral replication. In vivo, GLDC inhibition in H1N1-infected mice amplified antiviral responses and suppressed viral growth.","method":"siRNA knockdown; pharmacological inhibition (AOAA); overexpression; IFNβ/ISG quantification; viral replication assays; in vivo mouse influenza infection model","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function, multiple orthogonal methods (siRNA, inhibitor, overexpression), validated in vivo","pmids":["30498026"],"is_preprint":false},{"year":2024,"finding":"Triplication of the GLDC gene (as found in patients with psychosis) reduces extracellular glycine levels in the dentate gyrus (measured by optical FRET), suppresses long-term potentiation (LTP) specifically at medial perforant path–dentate gyrus (mPP-DG) synapses but not CA3-CA1 synapses, and produces schizophrenia-like behavioral deficits. This establishes GLDC as a negative regulator of glycine availability and synaptic plasticity in the dentate gyrus.","method":"Chromosome-engineered allelic series mouse models; optical FRET for extracellular glycine; electrophysiology (LTP); behavioral assays (PPI, latent inhibition, working memory, sociability)","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (FRET, electrophysiology, behavior), allelic series with dose-response, published in peer-reviewed journal","pmids":["39210012"],"is_preprint":false},{"year":2025,"finding":"Glycine administration (1.3 g/kg in drinking water) reversed startle habituation deficit, spatial working memory deficit, sociability deficit, and latent inhibition deficit in mice with 4 copies of Gldc (which have reduced extracellular glycine), confirming that GLDC-mediated glycine catabolism negatively regulates NMDA receptor co-agonist availability and is mechanistically responsible for these behavioral phenotypes.","method":"Chronic oral glycine supplementation in Gldc copy-number variant mice; behavioral battery (Y-maze, startle habituation, latent inhibition, sociability, dendritic spine density)","journal":"Pharmacology research & perspectives","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment with defined behavioral readouts, single lab","pmids":["41361932"],"is_preprint":false},{"year":2024,"finding":"AAV9-mediated expression of mouse or human GLDC in GLDC-deficient mice restored GLDC mRNA and protein expression in liver and brain, significantly lowered plasma and brain tissue glycine, and normalized the folate one-carbon metabolism profile (including betaine and choline), establishing that GLDC is functionally required for glycine-derived one-carbon supply to folate metabolism.","method":"AAV9 gene therapy in GLDC-deficient mouse model; RT-PCR and Western blot for GLDC expression; plasma and tissue glycine measurement; folate metabolite profiling","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo gene replacement with multiple orthogonal biochemical readouts confirming functional rescue","pmids":["38761651"],"is_preprint":false},{"year":2016,"finding":"Promoter hypermethylation of GLDC leads to transcriptional silencing in gastric cancer cell lines and tissues. Knockdown of GLDC increased cell proliferation, migration, invasion, and colony formation and reduced apoptosis, indicating GLDC functions as a tumor suppressor in gastric cancer.","method":"Methylation analysis; GLDC knockdown; cell proliferation, migration, invasion, and colony formation assays; apoptosis assay","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with multiple cellular phenotypic readouts, but no direct molecular mechanism identified, single lab","pmids":["26722042"],"is_preprint":false},{"year":2023,"finding":"GLDC promotes colorectal cancer metastasis by inhibiting the Hippo signaling pathway, leading to EMT. Blocking the Hippo pathway with Verteporfin reduced GLDC's pro-metastatic effect. In vivo, GLDC-overexpressing cells produced more lung metastases after tail vein injection.","method":"In vitro invasion/migration assays; Hippo pathway inhibition (Verteporfin); in vivo tail vein metastasis model; EMT marker analysis","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway inhibitor rescue plus in vivo validation, single lab","pmids":["37668829"],"is_preprint":false},{"year":2025,"finding":"GLDC interacts with VPS34 and promotes association of VPS34 with the Beclin1/ATG14 complex, inducing autophagy and inhibiting EMT in hepatocellular carcinoma. GLDC acetylation at K514 is required for GLDC-VPS34 interaction; the acetylation-dead K514R mutant abolished binding. This establishes a direct mechanistic link between GLDC acetylation, VPS34-dependent autophagy induction, and tumor suppression in HCC.","method":"Co-immunoprecipitation; VPS34/Beclin1/ATG14 complex pulldown; acetylation-dead mutant (K514R); in vitro and in vivo tumor growth/migration assays","journal":"Pharmaceutical science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis, in vitro and in vivo validation, single lab","pmids":["41550650"],"is_preprint":false},{"year":2026,"finding":"GLDC is polyubiquitinated at K636 (K63-linked) by FBXL3 following EGFR activation. EGFR activation triggers SRC-mediated FBXL3 phosphorylation at Y306, enabling FBXL3 interaction with nuclear GLDC. K63-polyubiquitinated GLDC interacts with SMARCE1/DMAP1 to inhibit STAT1-triggered transcriptional activation of MHC-I genes, enabling immune evasion from CD8+ T cells. SRC inhibition restored MHC-I levels and enhanced anti-PD-1 therapy efficacy.","method":"Ubiquitination assays (K63-linkage); Co-immunoprecipitation (GLDC-FBXL3, GLDC-SMARCE1/DMAP1, FBXL3-GLDC); phosphorylation analysis (FBXL3 Y306); K636R and K514 mutant analysis; MHC-I expression assays; CD8+ T cell functional assays; in vivo tumor models with SRC inhibitor + anti-PD-1","journal":"Cell insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs, site-specific mutagenesis, in vitro and in vivo validation, single lab","pmids":["41728086"],"is_preprint":false},{"year":2025,"finding":"GLDC overexpression in renal proximal tubular cells attenuated cisplatin-induced apoptosis, cellular senescence, and ROS production, while knockdown aggravated these effects. Mechanistically, GLDC effects were mediated via upregulation of mitochondrial uncoupling protein 1 (UCP1); UCP1 knockdown reversed GLDC-mediated protection. In vivo, GLDC inhibition worsened AKI, establishing a GLDC-UCP1 protective axis in the kidney.","method":"GLDC overexpression/knockdown in HK-2 cells; UCP1 knockdown rescue experiment; apoptosis, senescence, ROS assays; in vivo cisplatin-AKI mouse model with AOAA inhibitor","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via UCP1 knockdown rescue, multiple cellular readouts, in vitro and in vivo, single lab","pmids":["40010632"],"is_preprint":false},{"year":2025,"finding":"GLDC deficiency in cardiomyocytes (H9C2 cells) subjected to hypoxia/reperfusion attenuated apoptosis and inflammation by activating Akt signaling and inactivating NF-κB signaling (reduced p-NF-κB p65, Bax, cleaved caspase-3; increased p-Akt, Bcl-2). This places GLDC upstream of Akt/NF-κB pathway regulation in ischemia-reperfusion injury.","method":"GLDC knockdown in H9C2 cardiomyocytes; H/R injury model; Western blot for Akt, NF-κB, apoptosis markers; in vivo mouse I/R model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with pathway marker analysis, in vitro and in vivo, single lab","pmids":["39747134"],"is_preprint":false},{"year":2025,"finding":"GLDC overexpression promotes PTBP1 degradation through the autophagy pathway, thereby inhibiting macrophage recruitment and P2RY6-mediated macrophage activation, and reducing liver ischemia-reperfusion injury. This identifies a GLDC-autophagy-PTBP1-P2RY6 axis regulating macrophage-mediated inflammatory injury.","method":"GLDC overexpression/knockdown; autophagy pathway analysis; PTBP1 protein degradation assay; macrophage recruitment and activation assays; in vivo LIRI model","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway proposed with supporting data but limited orthogonal validation, single lab, no full reconstitution","pmids":["40617371"],"is_preprint":false},{"year":2025,"finding":"In attenuated NKH mutant mice with only 1.5-fold elevation in brain glycine but >5-fold reduction in GLDC protein, there is a decline in both the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase (PDH) complex, with a concomitant rise in astrocyte mitochondrial β-oxidation signatures and activation of neuronal PDH, suggesting GLDC remodels mitochondrial energy metabolism in the brain.","method":"Mouse NKH model biochemical analysis; GLDC and GCSH protein quantification; PDH lipoylation assay; β-oxidation pathway analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, novel mechanistic hypothesis supported by biochemical correlations, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.07.12.664515"],"is_preprint":true},{"year":2025,"finding":"AAV9-mediated GLDC gene therapy (rAAV9-GLDC, single intraperitoneal dose) in CRISPR-edited humanized NKH mice provided 100% protection against disease and death, boosted astrogenesis without triggering neuroinflammation, and showed sustained systemic efficacy over 10 months, establishing GLDC restoration in the liver and brain as sufficient to rescue the lethal NKH phenotype.","method":"rAAV9-GLDC delivery in humanized Gldc-mutant mice; GFP reporter tracking for brain access; survival analysis; astrogenesis and neuroinflammation histology","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint, in vivo gene replacement with survival and histological endpoints, single lab","pmids":["bio_10.1101_2025.03.26.645560"],"is_preprint":true},{"year":2023,"finding":"GLDC overexpression in non-small-cell lung cancer context activates the p53 signaling pathway; GLDC depletion in OSCC cells retarded progression by activating p53 signaling. p300 co-functioned with TFAP2A to induce acetylation of GLDC, resulting in GLDC upregulation in OSCC.","method":"GLDC knockdown; xenograft tumor growth; p53 pathway marker analysis; p300/TFAP2A co-functional analysis; acetylation assay","journal":"Environmental toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway analysis with knockdown and acetylation, single lab, limited orthogonal validation","pmids":["39415627"],"is_preprint":false},{"year":2023,"finding":"GLDC enhances aerobic glycolysis in prostate cancer cells (increased glucose uptake, lactate production, LDH activity) through its enzyme activity, and GLDC expression is directly regulated by HIF1-α, which also regulates downstream LDHA expression. GLDC and its enzyme activity promote migration and invasion in vivo and in vitro.","method":"Metabolomic microarray; glucose uptake and lactate production assays; LDH activity assay; HIF1-α regulation analysis; in vitro migration/invasion assays; in vivo experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — enzyme activity-dependent metabolic phenotyping, HIF1-α regulatory link, in vitro and in vivo validation, single lab","pmids":["37781511"],"is_preprint":false}],"current_model":"GLDC encodes glycine decarboxylase, the P-protein subunit of the mitochondrial glycine cleavage system (GCS), which catalyzes glycine degradation and supplies one-carbon units to folate metabolism; loss-of-function mutations cause non-ketotic hyperglycinemia (NKH) with glycine accumulation in brain and plasma, while GLDC copy-number gain reduces extracellular glycine in the dentate gyrus, suppresses LTP at mPP-DG synapses, and produces psychosis-like behavioral deficits via NMDA receptor co-agonist depletion; beyond its metabolic role, GLDC is subject to post-translational regulation (K636 K63-linked polyubiquitination by FBXL3 downstream of EGFR-SRC, K514 acetylation promoting VPS34 interaction), and modulates antiviral innate immunity, autophagy, and cancer-relevant signaling pathways (Hippo/EMT, Akt/NF-κB, p53, MHC-I transcription) in a context-dependent manner."},"narrative":{"mechanistic_narrative":"GLDC encodes glycine decarboxylase, the P-protein subunit of the mitochondrial glycine cleavage system (GCS), which degrades glycine and supplies glycine-derived one-carbon units to folate metabolism [PMID:10798358, PMID:38761651]. Loss-of-function GLDC mutations abolish GCS activity and cause non-ketotic hyperglycinemia (NKH), with mutations in GLDC accounting for the large majority of cases; disease-causing alleles act through diverse mechanisms including large deletions, missense substitutions at the cofactor-binding hotspot Lys754, splicing defects, and loss of translation initiation, and residual enzymatic activity tracks closely with clinical severity [PMID:16450403, PMID:15236413, PMID:15864413, PMID:28244183]. Functional rescue confirms the metabolic requirement: AAV9-mediated GLDC delivery restores hepatic and brain GLDC expression, lowers plasma and brain glycine, and normalizes folate one-carbon and betaine/choline profiles in deficient mice, and rescues the lethal phenotype in humanized NKH models [PMID:38761651, PMID:bio_10.1101_2025.03.26.645560]. Beyond systemic glycine balance, GLDC controls extracellular glycine availability in the dentate gyrus, where GLDC copy-number gain depletes glycine, suppresses LTP at medial perforant path–dentate gyrus synapses, and produces schizophrenia-like behavioral deficits reversible by glycine supplementation—implicating GLDC-mediated glycine catabolism in NMDA receptor co-agonist availability and synaptic plasticity [PMID:39210012, PMID:41361932]. GLDC additionally restrains antiviral innate immunity, with its inhibition or depletion amplifying IFNβ/ISG responses and suppressing influenza replication in vivo [PMID:30498026]. In cancer and ischemic injury contexts GLDC is subject to post-translational regulation—K514 acetylation drives a VPS34/Beclin1/ATG14 interaction promoting autophagy, and EGFR–SRC–FBXL3–dependent K63-linked polyubiquitination of K636 directs nuclear GLDC to repress STAT1-driven MHC-I transcription and enable immune evasion—and it modulates Hippo/EMT, aerobic glycolysis, Akt/NF-κB, and UCP1-dependent stress responses in a tissue-dependent manner [PMID:41550650, PMID:41728086, PMID:37781511].","teleology":[{"year":2000,"claim":"Establishing GLDC's genomic structure, tissue expression, and that homozygous deletion abolishes glycine cleavage activity defined GLDC as the genetic basis of the P-protein deficiency form of NKH.","evidence":"RNA blotting, primer extension, and PCR with pseudogene-controlled assays in human tissues","pmids":["10798358"],"confidence":"Medium","gaps":["Pseudogene homology complicates expression quantification","Did not resolve the catalytic mechanism of the P-protein"]},{"year":2006,"claim":"Comprehensive mutation screening across NKH families established GLDC as the major causative gene and located a functional cofactor-binding hotspot at Lys754, linking specific residues to enzyme function.","evidence":"Sequencing of all 25 exons in 69 NKH families with haplotype analysis","pmids":["16450403"],"confidence":"High","gaps":["Does not establish how each variant affects catalysis versus stability","Founder deletion origins inferred from haplotype, not functional assay"]},{"year":2006,"claim":"Genotype-phenotype correlations from enzyme activity assays showed that residual GCS activity (e.g. 32% for A802V vs 2.6% for Y161C) determines clinical severity, including prenatal glycine accumulation.","evidence":"GCS enzyme activity assays in patient placental tissue with CSF/plasma glycine measurement","pmids":["15236413","16404748"],"confidence":"Medium","gaps":["Activity measured in limited tissues","Quantitative threshold for symptom onset not generalized"]},{"year":2017,"claim":"Functional expression of missense variants revealed that many GLDC loss-of-function alleles act through protein instability rather than direct catalytic disruption, refining how variants cause disease.","evidence":"Expression of 19 variants in COS7 cells with enzymatic assay, Western blot, and 3D structural modeling","pmids":["28244183"],"confidence":"Medium","gaps":["No experimentally solved human GLDC structure","Stability assessed in heterologous cells, not patient mitochondria"]},{"year":2019,"claim":"Reciprocal gain/loss-of-function work uncovered a non-metabolic role: GLDC negatively regulates antiviral innate immunity, restraining IFNβ/ISG induction and permitting viral replication.","evidence":"siRNA, AOAA inhibition, and overexpression with IFNβ/ISG and viral replication readouts plus in vivo influenza model","pmids":["30498026"],"confidence":"High","gaps":["Molecular link between glycine catabolism and IFN signaling not defined","Whether enzymatic activity per se is required is unresolved"]},{"year":2024,"claim":"Gene-replacement and copy-number models established causality in both directions for glycine homeostasis: GLDC restoration lowers glycine and normalizes one-carbon metabolism, while GLDC gain depletes dentate gyrus glycine and impairs synaptic plasticity and behavior.","evidence":"AAV9 GLDC gene therapy with metabolite profiling, and chromosome-engineered allelic series with FRET glycine imaging, LTP electrophysiology, and behavior","pmids":["38761651","39210012"],"confidence":"High","gaps":["Cell-type-specific contributions to brain glycine pool not dissected","Link from synaptic glycine to specific NMDA receptor populations inferred"]},{"year":2025,"claim":"Glycine supplementation rescued behavioral deficits in Gldc copy-number mice, confirming that GLDC-mediated glycine catabolism is mechanistically responsible for NMDA co-agonist depletion phenotypes.","evidence":"Chronic oral glycine supplementation with behavioral battery and spine density in Gldc 4-copy mice","pmids":["41361932"],"confidence":"Medium","gaps":["Single lab","Does not pinpoint the receptor subtype or circuit mediating rescue"]},{"year":2025,"claim":"Post-translational regulation of GLDC was defined: K514 acetylation drives a VPS34/Beclin1/ATG14 interaction inducing autophagy and suppressing EMT in HCC.","evidence":"Co-IP, VPS34/Beclin1/ATG14 pulldown, K514R acetylation-dead mutant, and in vitro/in vivo tumor assays","pmids":["41550650"],"confidence":"Medium","gaps":["Acetyltransferase responsible for K514 not identified here","Whether autophagy role requires catalytic activity unknown"]},{"year":2026,"claim":"An EGFR–SRC–FBXL3 axis was shown to K63-polyubiquitinate GLDC at K636, directing nuclear GLDC to repress STAT1-driven MHC-I transcription and enable immune evasion, defining a druggable signaling node.","evidence":"K63-linkage ubiquitination assays, multiple Co-IPs, FBXL3 Y306 phosphorylation analysis, K636R mutants, MHC-I/CD8+ T cell assays, and in vivo SRC inhibitor + anti-PD-1","pmids":["41728086"],"confidence":"Medium","gaps":["Nuclear localization mechanism of GLDC not detailed","Single lab, reciprocal validation across models pending"]},{"year":2023,"claim":"Context-dependent cancer roles emerged: GLDC inhibits Hippo signaling to drive colorectal metastasis/EMT and, via enzyme activity under HIF1-α control, enhances aerobic glycolysis in prostate cancer.","evidence":"Hippo inhibitor (Verteporfin) rescue with tail-vein metastasis, and metabolomics with glucose/lactate/LDH assays and HIF1-α regulation analysis","pmids":["37668829","37781511"],"confidence":"Medium","gaps":["Direction of GLDC effect differs across tumor types, mechanism of context-dependence unresolved","Direct molecular link to Hippo components not established"]},{"year":null,"claim":"It remains unresolved how GLDC's mitochondrial enzymatic function is mechanistically connected to its diverse non-canonical roles in innate immunity, autophagy, MHC-I transcription, and stress signaling, and whether these require catalytic activity, glycine flux, or moonlighting protein interactions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying mechanism linking metabolic and signaling functions","Catalytic dependence of non-metabolic roles untested in most contexts","Subcellular pool (mitochondrial vs nuclear) driving each function not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[0,2,10]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[18]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,17]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,9]}],"complexes":["glycine cleavage system"],"partners":["VPS34","BECLIN1","ATG14","FBXL3","SMARCE1","DMAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23378","full_name":"Glycine dehydrogenase (decarboxylating), mitochondrial","aliases":["Glycine cleavage system P protein","Glycine decarboxylase","Glycine dehydrogenase (aminomethyl-transferring)"],"length_aa":1020,"mass_kda":112.7,"function":"The glycine cleavage system catalyzes the degradation of glycine. The P protein (GLDC) binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor; CO(2) is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protein (GCSH)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/P23378/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GLDC","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GLDC","total_profiled":1310},"omim":[{"mim_id":"614462","title":"HYPERGLYCINEMIA, LACTIC ACIDOSIS, AND SEIZURES; HGCLAS","url":"https://www.omim.org/entry/614462"},{"mim_id":"605899","title":"GLYCINE ENCEPHALOPATHY 1; GCE1","url":"https://www.omim.org/entry/605899"},{"mim_id":"238330","title":"GLYCINE CLEAVAGE SYSTEM H PROTEIN; GCSH","url":"https://www.omim.org/entry/238330"},{"mim_id":"238310","title":"AMINOMETHYLTRANSFERASE; AMT","url":"https://www.omim.org/entry/238310"},{"mim_id":"238300","title":"GLYCINE DECARBOXYLASE; GLDC","url":"https://www.omim.org/entry/238300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":172.7}],"url":"https://www.proteinatlas.org/search/GLDC"},"hgnc":{"alias_symbol":["GCSP","NKH"],"prev_symbol":[]},"alphafold":{"accession":"P23378","domains":[{"cath_id":"3.40.640.10","chopping":"609-808","consensus_level":"medium","plddt":97.8785,"start":609,"end":808},{"cath_id":"3.90.1150","chopping":"863-988","consensus_level":"high","plddt":98.2034,"start":863,"end":988}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23378","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23378-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23378-F1-predicted_aligned_error_v6.png","plddt_mean":94.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GLDC","jax_strain_url":"https://www.jax.org/strain/search?query=GLDC"},"sequence":{"accession":"P23378","fasta_url":"https://rest.uniprot.org/uniprotkb/P23378.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23378/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23378"}},"corpus_meta":[{"pmid":"21107318","id":"PMC_21107318","title":"Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics.","date":"2010","source":"Clinical pharmacology and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/21107318","citation_count":119,"is_preprint":false},{"pmid":"16450403","id":"PMC_16450403","title":"Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia.","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16450403","citation_count":80,"is_preprint":false},{"pmid":"27362913","id":"PMC_27362913","title":"The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.","date":"2016","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27362913","citation_count":77,"is_preprint":false},{"pmid":"10648514","id":"PMC_10648514","title":"Cloning and characterization of the Flavobacterium johnsoniae gliding-motility genes gldB and gldC.","date":"2000","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/10648514","citation_count":58,"is_preprint":false},{"pmid":"16404748","id":"PMC_16404748","title":"Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation.","date":"2006","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16404748","citation_count":42,"is_preprint":false},{"pmid":"15236413","id":"PMC_15236413","title":"Persistent NKH with transient or absent symptoms and a homozygous GLDC mutation.","date":"2004","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15236413","citation_count":40,"is_preprint":false},{"pmid":"10798358","id":"PMC_10798358","title":"Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (psiGLDC): their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia.","date":"2000","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10798358","citation_count":32,"is_preprint":false},{"pmid":"16601880","id":"PMC_16601880","title":"Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy.","date":"2006","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/16601880","citation_count":30,"is_preprint":false},{"pmid":"26722042","id":"PMC_26722042","title":"Epigenetic Silencing of the Putative Tumor Suppressor Gene GLDC (Glycine Dehydrogenase) in Gastric Carcinoma.","date":"2016","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26722042","citation_count":26,"is_preprint":false},{"pmid":"15851735","id":"PMC_15851735","title":"Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice 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medical primatology","url":"https://pubmed.ncbi.nlm.nih.gov/27325422","citation_count":4,"is_preprint":false},{"pmid":"27617160","id":"PMC_27617160","title":"Two Novel GLDC Mutations in a Neonate with Nonketotic Hyperglycinemia.","date":"2016","source":"Journal of pediatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27617160","citation_count":4,"is_preprint":false},{"pmid":"24407464","id":"PMC_24407464","title":"Diagnosis of glycine encephalopathy in a pediatric patient by detection of a GLDC mutation during initial next generation DNA sequencing.","date":"2014","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/24407464","citation_count":4,"is_preprint":false},{"pmid":"29046206","id":"PMC_29046206","title":"[Clinical and genetic analyses of a family with atypical nonketotic hyperglycinemia caused by compound heterozygous mutations in the GLDC gene].","date":"2017","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/29046206","citation_count":4,"is_preprint":false},{"pmid":"40010632","id":"PMC_40010632","title":"GLDC alleviates cisplatin-induced apoptosis, cellular senescence, and production of reactive oxygen species via regulating UCP1 in the kidney.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40010632","citation_count":3,"is_preprint":false},{"pmid":"34513771","id":"PMC_34513771","title":"Novel GLDC Compound Heterozygous Variant Leading to Nonketotic Hyperglycinemia: Case Report and Literature Review.","date":"2021","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34513771","citation_count":3,"is_preprint":false},{"pmid":"31349202","id":"PMC_31349202","title":"Generation and characterization of a human iPSC line (UAMi005-A) from a patient with nonketotic hyperglycinemia due to mutations in the GLDC gene.","date":"2019","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31349202","citation_count":3,"is_preprint":false},{"pmid":"39747134","id":"PMC_39747134","title":"Downregulation of Gldc attenuates myocardial ischemia reperfusion injury in vitro by modulating Akt and NF-κB signalings.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39747134","citation_count":2,"is_preprint":false},{"pmid":"36817643","id":"PMC_36817643","title":"Novel homozygous GLDC variant causing late-onset glycine encephalopathy: A case report and updated review of the literature.","date":"2023","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/36817643","citation_count":2,"is_preprint":false},{"pmid":"18581728","id":"PMC_18581728","title":"Non-ketotic hyperglycinemia with a novel GLDC mutation in a Taiwanese child.","date":"2008","source":"Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za 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journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40717329","citation_count":1,"is_preprint":false},{"pmid":"40617371","id":"PMC_40617371","title":"GLDC attenuates liver ischemia-reperfusion injury by inhibiting macrophage recruitment and activation via PTBP1/P2RY6.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40617371","citation_count":0,"is_preprint":false},{"pmid":"37398055","id":"PMC_37398055","title":"A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398055","citation_count":0,"is_preprint":false},{"pmid":"38572626","id":"PMC_38572626","title":"Homozygosity for disease-causing variants in AMT and GLDC in a patient with severe nonketotic hyperglycinemia.","date":"2024","source":"American journal of medical genetics. 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A highly conserved processed pseudogene (psiGLDC) shares 97.5% homology with the coding region and arose ~4-8 million years ago. Loss of GLDC expression (large homozygous deletion of exons 1-3) abolishes glycine cleavage system activity, causing NKH.\",\n      \"method\": \"RNA blotting, primer extension analysis, PCR, semi-quantitative PCR using pseudogene as internal control\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct expression and structural characterization with multiple methods in a single lab study\",\n      \"pmids\": [\"10798358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GLDC encodes the P-protein (glycine decarboxylase) component of the glycine cleavage system (GCS); mutations in GLDC account for ~80% of NKH cases. The cofactor-binding site at Lys754 (encoded by exon 19) is a mutational hotspot. A large deletion involving exon 1 was found across multiple ethnic backgrounds with multiple independent origins.\",\n      \"method\": \"Comprehensive mutation screening by sequencing all 25 GLDC exons in 69 NKH families; haplotype analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large multi-family cohort, replicated across multiple independent groups, identifies functional domain (cofactor-binding site)\",\n      \"pmids\": [\"16450403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A homozygous GLDC A802V missense mutation results in 32% residual glycine cleavage system activity compared to wild type; patients with this hypomorphic mutation show transient or absent symptoms and normal developmental outcome, directly linking residual GLDC enzymatic activity level to disease severity.\",\n      \"method\": \"Enzyme activity assay of glycine cleavage system in patient tissue; mutation identified by sequencing\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzyme activity measurement correlated with genotype and phenotype, single lab\",\n      \"pmids\": [\"15236413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A novel homozygous GLDC Y161C missense mutation abolishes glycine cleavage system (GCS) activity (2.6% of controls) in placental tissue, causing severe neonatal NKH with markedly elevated CSF glycine at birth, demonstrating that GLDC loss-of-function causes prenatal glycine accumulation.\",\n      \"method\": \"GCS enzyme activity assay in placental tissue; GLDC mutation sequencing; CSF and plasma glycine measurement\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzyme activity assay plus molecular diagnosis, single case/lab\",\n      \"pmids\": [\"16404748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A translationally silent GLDC exon 22 transversion (c.2607C>A) causes aberrant splicing (exon 22 skipping, exon 22-23 skipping, and cryptic exon insertion), reducing GLDC mRNA levels. Only 4-6% normally spliced mRNA was retained, accounting for the attenuated clinical phenotype, directly linking splicing efficiency to disease severity.\",\n      \"method\": \"Northern blot, RT-PCR analysis of lymphoblast GLDC mRNA; identification of three aberrant splice products\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA analysis with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"15851735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A methionine-to-threonine change in the GLDC initiation codon markedly reduces glycine decarboxylase mRNA levels and abolishes glycine cleavage system activity, establishing that loss of translation initiation causes NKH through mRNA instability/nonsense-mediated decay.\",\n      \"method\": \"mRNA level analysis; enzyme activity assay; sequencing of GLDC initiation codon\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional enzyme assay and mRNA quantification, single lab\",\n      \"pmids\": [\"15864413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Functional expression of 19 GLDC missense variants in COS7 cells, combined with enzymatic assays and Western blot, showed that loss-of-function for many variants is associated with protein instability rather than direct catalytic disruption. Structural modeling of the 3D structure identified effects on protein stability and catalytic activity, including hypomorphic variants producing attenuated phenotypes.\",\n      \"method\": \"Mutant cDNA expression in COS7 cells; enzymatic assay; Western blot for protein stability; molecular modeling of 3D structure\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzyme assay with mutagenesis and structural analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28244183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GLDC regulates cellular antiviral innate immune response: GLDC inhibition (by AOAA) or siRNA depletion boosted IFNβ and interferon-stimulated gene (ISG) expression upon poly(I:C) stimulation or influenza virus infection, and suppressed H1N1/H7N9 replication. Conversely, GLDC overexpression attenuated antiviral responses and promoted viral replication. In vivo, GLDC inhibition in H1N1-infected mice amplified antiviral responses and suppressed viral growth.\",\n      \"method\": \"siRNA knockdown; pharmacological inhibition (AOAA); overexpression; IFNβ/ISG quantification; viral replication assays; in vivo mouse influenza infection model\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function, multiple orthogonal methods (siRNA, inhibitor, overexpression), validated in vivo\",\n      \"pmids\": [\"30498026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Triplication of the GLDC gene (as found in patients with psychosis) reduces extracellular glycine levels in the dentate gyrus (measured by optical FRET), suppresses long-term potentiation (LTP) specifically at medial perforant path–dentate gyrus (mPP-DG) synapses but not CA3-CA1 synapses, and produces schizophrenia-like behavioral deficits. This establishes GLDC as a negative regulator of glycine availability and synaptic plasticity in the dentate gyrus.\",\n      \"method\": \"Chromosome-engineered allelic series mouse models; optical FRET for extracellular glycine; electrophysiology (LTP); behavioral assays (PPI, latent inhibition, working memory, sociability)\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (FRET, electrophysiology, behavior), allelic series with dose-response, published in peer-reviewed journal\",\n      \"pmids\": [\"39210012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glycine administration (1.3 g/kg in drinking water) reversed startle habituation deficit, spatial working memory deficit, sociability deficit, and latent inhibition deficit in mice with 4 copies of Gldc (which have reduced extracellular glycine), confirming that GLDC-mediated glycine catabolism negatively regulates NMDA receptor co-agonist availability and is mechanistically responsible for these behavioral phenotypes.\",\n      \"method\": \"Chronic oral glycine supplementation in Gldc copy-number variant mice; behavioral battery (Y-maze, startle habituation, latent inhibition, sociability, dendritic spine density)\",\n      \"journal\": \"Pharmacology research & perspectives\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment with defined behavioral readouts, single lab\",\n      \"pmids\": [\"41361932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AAV9-mediated expression of mouse or human GLDC in GLDC-deficient mice restored GLDC mRNA and protein expression in liver and brain, significantly lowered plasma and brain tissue glycine, and normalized the folate one-carbon metabolism profile (including betaine and choline), establishing that GLDC is functionally required for glycine-derived one-carbon supply to folate metabolism.\",\n      \"method\": \"AAV9 gene therapy in GLDC-deficient mouse model; RT-PCR and Western blot for GLDC expression; plasma and tissue glycine measurement; folate metabolite profiling\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo gene replacement with multiple orthogonal biochemical readouts confirming functional rescue\",\n      \"pmids\": [\"38761651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Promoter hypermethylation of GLDC leads to transcriptional silencing in gastric cancer cell lines and tissues. Knockdown of GLDC increased cell proliferation, migration, invasion, and colony formation and reduced apoptosis, indicating GLDC functions as a tumor suppressor in gastric cancer.\",\n      \"method\": \"Methylation analysis; GLDC knockdown; cell proliferation, migration, invasion, and colony formation assays; apoptosis assay\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with multiple cellular phenotypic readouts, but no direct molecular mechanism identified, single lab\",\n      \"pmids\": [\"26722042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GLDC promotes colorectal cancer metastasis by inhibiting the Hippo signaling pathway, leading to EMT. Blocking the Hippo pathway with Verteporfin reduced GLDC's pro-metastatic effect. In vivo, GLDC-overexpressing cells produced more lung metastases after tail vein injection.\",\n      \"method\": \"In vitro invasion/migration assays; Hippo pathway inhibition (Verteporfin); in vivo tail vein metastasis model; EMT marker analysis\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway inhibitor rescue plus in vivo validation, single lab\",\n      \"pmids\": [\"37668829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC interacts with VPS34 and promotes association of VPS34 with the Beclin1/ATG14 complex, inducing autophagy and inhibiting EMT in hepatocellular carcinoma. GLDC acetylation at K514 is required for GLDC-VPS34 interaction; the acetylation-dead K514R mutant abolished binding. This establishes a direct mechanistic link between GLDC acetylation, VPS34-dependent autophagy induction, and tumor suppression in HCC.\",\n      \"method\": \"Co-immunoprecipitation; VPS34/Beclin1/ATG14 complex pulldown; acetylation-dead mutant (K514R); in vitro and in vivo tumor growth/migration assays\",\n      \"journal\": \"Pharmaceutical science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"41550650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GLDC is polyubiquitinated at K636 (K63-linked) by FBXL3 following EGFR activation. EGFR activation triggers SRC-mediated FBXL3 phosphorylation at Y306, enabling FBXL3 interaction with nuclear GLDC. K63-polyubiquitinated GLDC interacts with SMARCE1/DMAP1 to inhibit STAT1-triggered transcriptional activation of MHC-I genes, enabling immune evasion from CD8+ T cells. SRC inhibition restored MHC-I levels and enhanced anti-PD-1 therapy efficacy.\",\n      \"method\": \"Ubiquitination assays (K63-linkage); Co-immunoprecipitation (GLDC-FBXL3, GLDC-SMARCE1/DMAP1, FBXL3-GLDC); phosphorylation analysis (FBXL3 Y306); K636R and K514 mutant analysis; MHC-I expression assays; CD8+ T cell functional assays; in vivo tumor models with SRC inhibitor + anti-PD-1\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs, site-specific mutagenesis, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"41728086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC overexpression in renal proximal tubular cells attenuated cisplatin-induced apoptosis, cellular senescence, and ROS production, while knockdown aggravated these effects. Mechanistically, GLDC effects were mediated via upregulation of mitochondrial uncoupling protein 1 (UCP1); UCP1 knockdown reversed GLDC-mediated protection. In vivo, GLDC inhibition worsened AKI, establishing a GLDC-UCP1 protective axis in the kidney.\",\n      \"method\": \"GLDC overexpression/knockdown in HK-2 cells; UCP1 knockdown rescue experiment; apoptosis, senescence, ROS assays; in vivo cisplatin-AKI mouse model with AOAA inhibitor\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via UCP1 knockdown rescue, multiple cellular readouts, in vitro and in vivo, single lab\",\n      \"pmids\": [\"40010632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC deficiency in cardiomyocytes (H9C2 cells) subjected to hypoxia/reperfusion attenuated apoptosis and inflammation by activating Akt signaling and inactivating NF-κB signaling (reduced p-NF-κB p65, Bax, cleaved caspase-3; increased p-Akt, Bcl-2). This places GLDC upstream of Akt/NF-κB pathway regulation in ischemia-reperfusion injury.\",\n      \"method\": \"GLDC knockdown in H9C2 cardiomyocytes; H/R injury model; Western blot for Akt, NF-κB, apoptosis markers; in vivo mouse I/R model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with pathway marker analysis, in vitro and in vivo, single lab\",\n      \"pmids\": [\"39747134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC overexpression promotes PTBP1 degradation through the autophagy pathway, thereby inhibiting macrophage recruitment and P2RY6-mediated macrophage activation, and reducing liver ischemia-reperfusion injury. This identifies a GLDC-autophagy-PTBP1-P2RY6 axis regulating macrophage-mediated inflammatory injury.\",\n      \"method\": \"GLDC overexpression/knockdown; autophagy pathway analysis; PTBP1 protein degradation assay; macrophage recruitment and activation assays; in vivo LIRI model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway proposed with supporting data but limited orthogonal validation, single lab, no full reconstitution\",\n      \"pmids\": [\"40617371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In attenuated NKH mutant mice with only 1.5-fold elevation in brain glycine but >5-fold reduction in GLDC protein, there is a decline in both the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase (PDH) complex, with a concomitant rise in astrocyte mitochondrial β-oxidation signatures and activation of neuronal PDH, suggesting GLDC remodels mitochondrial energy metabolism in the brain.\",\n      \"method\": \"Mouse NKH model biochemical analysis; GLDC and GCSH protein quantification; PDH lipoylation assay; β-oxidation pathway analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, novel mechanistic hypothesis supported by biochemical correlations, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.12.664515\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AAV9-mediated GLDC gene therapy (rAAV9-GLDC, single intraperitoneal dose) in CRISPR-edited humanized NKH mice provided 100% protection against disease and death, boosted astrogenesis without triggering neuroinflammation, and showed sustained systemic efficacy over 10 months, establishing GLDC restoration in the liver and brain as sufficient to rescue the lethal NKH phenotype.\",\n      \"method\": \"rAAV9-GLDC delivery in humanized Gldc-mutant mice; GFP reporter tracking for brain access; survival analysis; astrogenesis and neuroinflammation histology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint, in vivo gene replacement with survival and histological endpoints, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.03.26.645560\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GLDC overexpression in non-small-cell lung cancer context activates the p53 signaling pathway; GLDC depletion in OSCC cells retarded progression by activating p53 signaling. p300 co-functioned with TFAP2A to induce acetylation of GLDC, resulting in GLDC upregulation in OSCC.\",\n      \"method\": \"GLDC knockdown; xenograft tumor growth; p53 pathway marker analysis; p300/TFAP2A co-functional analysis; acetylation assay\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway analysis with knockdown and acetylation, single lab, limited orthogonal validation\",\n      \"pmids\": [\"39415627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GLDC enhances aerobic glycolysis in prostate cancer cells (increased glucose uptake, lactate production, LDH activity) through its enzyme activity, and GLDC expression is directly regulated by HIF1-α, which also regulates downstream LDHA expression. GLDC and its enzyme activity promote migration and invasion in vivo and in vitro.\",\n      \"method\": \"Metabolomic microarray; glucose uptake and lactate production assays; LDH activity assay; HIF1-α regulation analysis; in vitro migration/invasion assays; in vivo experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — enzyme activity-dependent metabolic phenotyping, HIF1-α regulatory link, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"37781511\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GLDC encodes glycine decarboxylase, the P-protein subunit of the mitochondrial glycine cleavage system (GCS), which catalyzes glycine degradation and supplies one-carbon units to folate metabolism; loss-of-function mutations cause non-ketotic hyperglycinemia (NKH) with glycine accumulation in brain and plasma, while GLDC copy-number gain reduces extracellular glycine in the dentate gyrus, suppresses LTP at mPP-DG synapses, and produces psychosis-like behavioral deficits via NMDA receptor co-agonist depletion; beyond its metabolic role, GLDC is subject to post-translational regulation (K636 K63-linked polyubiquitination by FBXL3 downstream of EGFR-SRC, K514 acetylation promoting VPS34 interaction), and modulates antiviral innate immunity, autophagy, and cancer-relevant signaling pathways (Hippo/EMT, Akt/NF-κB, p53, MHC-I transcription) in a context-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GLDC encodes glycine decarboxylase, the P-protein subunit of the mitochondrial glycine cleavage system (GCS), which degrades glycine and supplies glycine-derived one-carbon units to folate metabolism [#0, #10]. Loss-of-function GLDC mutations abolish GCS activity and cause non-ketotic hyperglycinemia (NKH), with mutations in GLDC accounting for the large majority of cases; disease-causing alleles act through diverse mechanisms including large deletions, missense substitutions at the cofactor-binding hotspot Lys754, splicing defects, and loss of translation initiation, and residual enzymatic activity tracks closely with clinical severity [#1, #2, #5, #6]. Functional rescue confirms the metabolic requirement: AAV9-mediated GLDC delivery restores hepatic and brain GLDC expression, lowers plasma and brain glycine, and normalizes folate one-carbon and betaine/choline profiles in deficient mice, and rescues the lethal phenotype in humanized NKH models [#10, #19]. Beyond systemic glycine balance, GLDC controls extracellular glycine availability in the dentate gyrus, where GLDC copy-number gain depletes glycine, suppresses LTP at medial perforant path\\u2013dentate gyrus synapses, and produces schizophrenia-like behavioral deficits reversible by glycine supplementation\\u2014implicating GLDC-mediated glycine catabolism in NMDA receptor co-agonist availability and synaptic plasticity [#8, #9]. GLDC additionally restrains antiviral innate immunity, with its inhibition or depletion amplifying IFN\\u03b2/ISG responses and suppressing influenza replication in vivo [#7]. In cancer and ischemic injury contexts GLDC is subject to post-translational regulation\\u2014K514 acetylation drives a VPS34/Beclin1/ATG14 interaction promoting autophagy, and EGFR\\u2013SRC\\u2013FBXL3\\u2013dependent K63-linked polyubiquitination of K636 directs nuclear GLDC to repress STAT1-driven MHC-I transcription and enable immune evasion\\u2014and it modulates Hippo/EMT, aerobic glycolysis, Akt/NF-\\u03baB, and UCP1-dependent stress responses in a tissue-dependent manner [#13, #14, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing GLDC's genomic structure, tissue expression, and that homozygous deletion abolishes glycine cleavage activity defined GLDC as the genetic basis of the P-protein deficiency form of NKH.\",\n      \"evidence\": \"RNA blotting, primer extension, and PCR with pseudogene-controlled assays in human tissues\",\n      \"pmids\": [\"10798358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pseudogene homology complicates expression quantification\", \"Did not resolve the catalytic mechanism of the P-protein\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Comprehensive mutation screening across NKH families established GLDC as the major causative gene and located a functional cofactor-binding hotspot at Lys754, linking specific residues to enzyme function.\",\n      \"evidence\": \"Sequencing of all 25 exons in 69 NKH families with haplotype analysis\",\n      \"pmids\": [\"16450403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish how each variant affects catalysis versus stability\", \"Founder deletion origins inferred from haplotype, not functional assay\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genotype-phenotype correlations from enzyme activity assays showed that residual GCS activity (e.g. 32% for A802V vs 2.6% for Y161C) determines clinical severity, including prenatal glycine accumulation.\",\n      \"evidence\": \"GCS enzyme activity assays in patient placental tissue with CSF/plasma glycine measurement\",\n      \"pmids\": [\"15236413\", \"16404748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Activity measured in limited tissues\", \"Quantitative threshold for symptom onset not generalized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Functional expression of missense variants revealed that many GLDC loss-of-function alleles act through protein instability rather than direct catalytic disruption, refining how variants cause disease.\",\n      \"evidence\": \"Expression of 19 variants in COS7 cells with enzymatic assay, Western blot, and 3D structural modeling\",\n      \"pmids\": [\"28244183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimentally solved human GLDC structure\", \"Stability assessed in heterologous cells, not patient mitochondria\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reciprocal gain/loss-of-function work uncovered a non-metabolic role: GLDC negatively regulates antiviral innate immunity, restraining IFN\\u03b2/ISG induction and permitting viral replication.\",\n      \"evidence\": \"siRNA, AOAA inhibition, and overexpression with IFN\\u03b2/ISG and viral replication readouts plus in vivo influenza model\",\n      \"pmids\": [\"30498026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between glycine catabolism and IFN signaling not defined\", \"Whether enzymatic activity per se is required is unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Gene-replacement and copy-number models established causality in both directions for glycine homeostasis: GLDC restoration lowers glycine and normalizes one-carbon metabolism, while GLDC gain depletes dentate gyrus glycine and impairs synaptic plasticity and behavior.\",\n      \"evidence\": \"AAV9 GLDC gene therapy with metabolite profiling, and chromosome-engineered allelic series with FRET glycine imaging, LTP electrophysiology, and behavior\",\n      \"pmids\": [\"38761651\", \"39210012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions to brain glycine pool not dissected\", \"Link from synaptic glycine to specific NMDA receptor populations inferred\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Glycine supplementation rescued behavioral deficits in Gldc copy-number mice, confirming that GLDC-mediated glycine catabolism is mechanistically responsible for NMDA co-agonist depletion phenotypes.\",\n      \"evidence\": \"Chronic oral glycine supplementation with behavioral battery and spine density in Gldc 4-copy mice\",\n      \"pmids\": [\"41361932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not pinpoint the receptor subtype or circuit mediating rescue\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Post-translational regulation of GLDC was defined: K514 acetylation drives a VPS34/Beclin1/ATG14 interaction inducing autophagy and suppressing EMT in HCC.\",\n      \"evidence\": \"Co-IP, VPS34/Beclin1/ATG14 pulldown, K514R acetylation-dead mutant, and in vitro/in vivo tumor assays\",\n      \"pmids\": [\"41550650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetyltransferase responsible for K514 not identified here\", \"Whether autophagy role requires catalytic activity unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"An EGFR\\u2013SRC\\u2013FBXL3 axis was shown to K63-polyubiquitinate GLDC at K636, directing nuclear GLDC to repress STAT1-driven MHC-I transcription and enable immune evasion, defining a druggable signaling node.\",\n      \"evidence\": \"K63-linkage ubiquitination assays, multiple Co-IPs, FBXL3 Y306 phosphorylation analysis, K636R mutants, MHC-I/CD8+ T cell assays, and in vivo SRC inhibitor + anti-PD-1\",\n      \"pmids\": [\"41728086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear localization mechanism of GLDC not detailed\", \"Single lab, reciprocal validation across models pending\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Context-dependent cancer roles emerged: GLDC inhibits Hippo signaling to drive colorectal metastasis/EMT and, via enzyme activity under HIF1-\\u03b1 control, enhances aerobic glycolysis in prostate cancer.\",\n      \"evidence\": \"Hippo inhibitor (Verteporfin) rescue with tail-vein metastasis, and metabolomics with glucose/lactate/LDH assays and HIF1-\\u03b1 regulation analysis\",\n      \"pmids\": [\"37668829\", \"37781511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of GLDC effect differs across tumor types, mechanism of context-dependence unresolved\", \"Direct molecular link to Hippo components not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how GLDC's mitochondrial enzymatic function is mechanistically connected to its diverse non-canonical roles in innate immunity, autophagy, MHC-I transcription, and stress signaling, and whether these require catalytic activity, glycine flux, or moonlighting protein interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism linking metabolic and signaling functions\", \"Catalytic dependence of non-metabolic roles untested in most contexts\", \"Subcellular pool (mitochondrial vs nuclear) driving each function not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016830\", \"supporting_discovery_ids\": [0, 2, 3, 10]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [0, 2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 17]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [\"glycine cleavage system\"],\n    \"partners\": [\"VPS34\", \"Beclin1\", \"ATG14\", \"FBXL3\", \"SMARCE1\", \"DMAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}