{"gene":"GLDC","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2006,"finding":"GLDC encodes the P-protein (glycine decarboxylase) component of the glycine cleavage multi-enzyme system (GCS); mutations in GLDC cause deficiency of this system leading to glycine accumulation in nonketotic hyperglycinemia (NKH). The cofactor-binding site Lys754 (encoded by exon 19) is critical, as 7 of 32 missense mutations clustered there.","method":"Comprehensive mutation screening and sequencing of all GLDC exons in 69 NKH families; haplotype analysis","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — large multi-family genetic study replicated across multiple labs, consistent with prior biochemical characterization of GCS","pmids":["16450403"],"is_preprint":false},{"year":2000,"finding":"The GLDC gene spans ≥135 kb, consists of 25 exons, and is expressed in liver, kidney, brain, and placenta. A processed pseudogene (psiGLDC) with 97.5% coding-region homology exists, arising ~4–8 million years ago from the GLDC transcript.","method":"Gene structure determination, primer extension for transcription start site, RNA blotting, semi-quantitative PCR using psiGLDC as internal control","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal molecular methods in a single study establishing gene structure and expression","pmids":["10798358"],"is_preprint":false},{"year":2004,"finding":"A homozygous GLDC A802V missense mutation results in ~32% residual glycine cleavage system activity compared to wild type, producing a milder/transient NKH phenotype, demonstrating a direct correlation between residual GLDC enzymatic activity and disease severity.","method":"GCS enzyme activity assay in patient tissue; mutation identification by sequencing","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct enzyme activity measurement linking specific mutation to residual function, single study","pmids":["15236413"],"is_preprint":false},{"year":2005,"finding":"A silent exonic transversion (c.2607C>A) in GLDC exon 22 causes missplicing, producing three aberrantly spliced mRNA species (exon 22 skipping, exon 22–23 skipping, and 87-bp cryptic exon insertion), reducing GLDC mRNA levels and glycine decarboxylase expression; ~4–6% residual normally-spliced mRNA correlated with a milder clinical outcome.","method":"Northern blot, RT-PCR identification of aberrant splice products, homozygosity mapping","journal":"Neurology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal molecular methods (Northern blot, RT-PCR, sequencing) in a well-characterized kindred","pmids":["15851735"],"is_preprint":false},{"year":2006,"finding":"GLDC missense mutations cause loss of GCS P-protein function; pathogenic variants were identified throughout the coding sequence with large deletions (including exon 1) being recurrent across multiple ethnic groups with multiple independent origins.","method":"DHPLC and sequencing of complete GLDC coding sequence in 28 unrelated NKH patients","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 3 — comprehensive mutation survey, pathogenicity of missense variants requires expression confirmation","pmids":["16601880"],"is_preprint":false},{"year":2006,"finding":"Treatment of NKH (caused by a novel homozygous GLDC c.482A>G (Y161C) missense mutation) from birth shows severely reduced GCS activity (2.6% of controls) in placental tissue and markedly elevated CSF glycine at birth, demonstrating prenatal onset of glycine accumulation due to GLDC deficiency.","method":"GCS enzyme activity assay in placental tissue; CSF and blood glycine measurement; mutation sequencing","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct enzyme activity measurement in tissue establishing prenatal functional consequence, single case","pmids":["16404748"],"is_preprint":false},{"year":2017,"finding":"Nineteen GLDC missense variants were functionally assessed by expressing mutant cDNA constructs in COS7 cells; enzymatic assays and Western blot revealed that many loss-of-function mutations cause protein instability rather than direct catalytic disruption, identifying these as potential targets for folding-rescue therapies. Structural modeling of the 3D GCS P-protein provided mechanistic interpretation.","method":"Mutant cDNA expression in COS7 cells, enzymatic activity assay, Western blot for protein stability, molecular modeling of 3D structure","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzymatic assays plus mutagenesis plus structural modeling in a single comprehensive study","pmids":["28244183"],"is_preprint":false},{"year":2019,"finding":"GLDC regulates cellular antiviral innate immune responses: GLDC inhibition (with AOAA) or siRNA knockdown boosted IFNβ and IFN-stimulated gene expression upon poly-I:C stimulation or influenza virus infection, and suppressed H1N1/H7N9 replication; GLDC overexpression attenuated antiviral responses and promoted viral replication.","method":"siRNA knockdown, pharmacological inhibition (AOAA), overexpression, IFN/ISG quantification, viral replication assay in vitro and in vivo (BALB/c mice)","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (siRNA, inhibitor, overexpression) with in vivo validation, single lab","pmids":["30498026"],"is_preprint":false},{"year":2024,"finding":"Triplication of the GLDC gene (as found on a small supernumerary marker chromosome in patients with psychosis) reduces extracellular glycine levels in the dentate gyrus (measured by optical FRET), suppresses long-term potentiation (LTP) specifically at mPP-DG synapses but not CA3-CA1 synapses, and produces schizophrenia-like behavioral deficits in mice, demonstrating that GLDC negatively regulates synaptic glycine availability and hippocampal synaptic plasticity.","method":"Chromosome-engineered allelic series in mice, optical FRET for extracellular glycine, electrophysiological LTP recording, behavioral assays","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (FRET, electrophysiology, behavior) in a genetically engineered allelic series","pmids":["39210012"],"is_preprint":false},{"year":2025,"finding":"Glycine administration (1.3 g/kg in drinking water) reversed startle habituation, spatial working memory, sociability, and latent inhibition deficits in mice with 4 copies of Gldc, confirming that behavioral phenotypes from GLDC triplication are caused by reduced extracellular glycine and consequent NMDA receptor hypofunction.","method":"Oral glycine supplementation in 4-copy Gldc transgenic mice; behavioral assays (Y-maze, prepulse inhibition, social interaction, latent inhibition)","journal":"Pharmacology research & perspectives","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis/rescue approach with multiple behavioral endpoints, single lab","pmids":["41361932"],"is_preprint":false},{"year":2016,"finding":"Epigenetic silencing of GLDC via promoter hypermethylation in gastric cancer cells leads to reduced GLDC expression; GLDC knockdown increased cell proliferation, migration, invasion, and colony formation while reducing apoptosis, identifying GLDC as a putative tumor suppressor in gastric cancer.","method":"Promoter methylation analysis, GLDC knockdown in GC cell lines, proliferation/migration/invasion/apoptosis assays","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple phenotypic assays but limited mechanistic pathway placement","pmids":["26722042"],"is_preprint":false},{"year":2023,"finding":"GLDC promotes colorectal cancer cell invasion and migration by inhibiting the Hippo signaling pathway and thereby promoting epithelial-mesenchymal transition (EMT); blocking Hippo signaling with verteporfin reduced GLDC-driven metastasis, and tail vein injection of GLDC-overexpressing cells induced more lung metastasis in vivo.","method":"In vitro invasion/migration assays, Hippo pathway inhibition, in vivo tail vein injection metastasis model","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological epistasis plus in vivo metastasis model, single lab","pmids":["37668829"],"is_preprint":false},{"year":2025,"finding":"GLDC interacts directly with VPS34 (PI3-kinase); GLDC overexpression upregulates VPS34 protein and promotes VPS34 interaction with the Beclin1/ATG14 complex to induce autophagy, thereby suppressing EMT and tumor growth in hepatocellular carcinoma. GLDC acetylation at K514 is required for GLDC–VPS34 interaction; the K514R acetylation-dead mutant abolished binding.","method":"Co-immunoprecipitation, site-directed mutagenesis (K514R), overexpression/knockdown with proliferation/migration assays, in vivo xenograft, autophagy flux assays","journal":"Pharmaceutical science advances","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus mutagenesis validation, single lab","pmids":["41550650"],"is_preprint":false},{"year":2026,"finding":"Upon EGFR activation, SRC phosphorylates FBXL3 at Y306, enabling FBXL3 to interact with nuclear GLDC and catalyze K63-linked polyubiquitination of GLDC at K636; K63-ubiquitinated GLDC then interacts with SMARCE1/DMAP1 to inhibit STAT1-driven transcription of MHC-I genes, promoting tumor immune evasion from CD8+ T cells.","method":"Co-immunoprecipitation, site-directed mutagenesis (FBXL3 Y306, GLDC K636), ubiquitination assays (K63-linkage specific), MHC-I expression analysis, CD8+ T cell killing assays, SRC inhibitor treatment","journal":"Cell insight","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods with mutagenesis, single lab","pmids":["41728086"],"is_preprint":false},{"year":2025,"finding":"GLDC overexpression in proximal tubular cells protects against cisplatin-induced apoptosis, cellular senescence, and ROS production via upregulation of mitochondrial uncoupling protein UCP1; UCP1 knockdown reversed the protective effects of GLDC overexpression, placing UCP1 downstream of GLDC in this pathway.","method":"GLDC overexpression and knockdown in HK-2 cells, UCP1 knockdown epistasis, apoptosis/senescence/ROS assays, cisplatin-induced AKI mouse model with AOAA inhibitor","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (GLDC OE + UCP1 KD rescue) plus in vivo pharmacological confirmation, single lab","pmids":["40010632"],"is_preprint":false},{"year":2024,"finding":"AAV9-mediated expression of mouse or human GLDC in GLDC-deficient mice restored GLDC mRNA and protein, significantly lowered plasma and brain tissue glycine, and normalized the folate one-carbon metabolism profile (including betaine and choline), demonstrating that GLDC is the rate-limiting enzyme for glycine catabolism and glycine-derived one-carbon supply to folate metabolism in vivo.","method":"AAV9 gene therapy in GLDC-deficient mice, RT-PCR and Western blot for GLDC expression, plasma/tissue glycine measurement, folate metabolite profiling","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 2 — in vivo rescue experiment with multiple biochemical readouts, demonstrates functional restoration","pmids":["38761651"],"is_preprint":false},{"year":2025,"finding":"In attenuated NKH mutant mice with a 1.5-fold increase in brain glycine, GLDC protein is reduced >5-fold, accompanied by decline in GCSH (mitochondrial lipoyl-transfer protein) and reduced lipoylation of the pyruvate dehydrogenase (PDH) complex, with concomitant increase in astrocyte mitochondrial β-oxidation of fatty acids and activation of neuronal PDH, suggesting GLDC remodels mitochondrial energy metabolism in the brain.","method":"Biochemical pathway analysis in mouse brain tissue, protein quantification (Western blot), metabolomics in NKH mouse models","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, mechanistic model based on correlative biochemical measurements","pmids":["bio_10.1101_2025.07.12.664515"],"is_preprint":true},{"year":2025,"finding":"GLDC downregulation in cardiomyocytes attenuates hypoxia/reperfusion injury by activating Akt signaling and inactivating NF-κB signaling, reducing apoptosis and inflammatory responses; GLDC levels were elevated in I/R mouse hearts and H/R-exposed cardiomyocytes.","method":"GLDC knockdown in H9C2 cells, Akt and NF-κB pathway analysis by Western blot, in vivo mouse I/R model with AOAA inhibitor, apoptosis and inflammation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with pathway readouts, in vitro and in vivo, single lab","pmids":["39747134"],"is_preprint":false},{"year":2025,"finding":"GLDC promotes PTBP1 degradation via the autophagy pathway; reduced GLDC expression in liver ischemia-reperfusion injury promotes macrophage infiltration through a PTBP1/P2RY6 axis; GLDC overexpression inhibits macrophage recruitment and activation, reducing liver injury.","method":"GLDC overexpression in vivo (mouse LIRI model), macrophage infiltration assays, autophagy pathway analysis for PTBP1 degradation, Co-IP for PTBP1/P2RY6 interaction","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mechanism partly correlative, PTBP1 autophagy degradation not directly demonstrated by reconstitution","pmids":["40617371"],"is_preprint":false},{"year":2017,"finding":"H293T cells transfected with GLDC missense mutants (c.3006C>G p.C1002W and c.1256C>G p.S419X) showed downregulated glycine decarboxylase activity, directly confirming the pathogenicity of these mutations through loss of enzymatic function.","method":"Transfection of mutant GLDC constructs in H293T cells, glycine decarboxylase activity assay","journal":"Zhongguo dang dai er ke za zhi","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct in vitro enzymatic activity assay with patient mutations, single lab","pmids":["29046206"],"is_preprint":false},{"year":2005,"finding":"A single nucleotide substitution abolishing the initiator methionine codon of GLDC leads to markedly reduced GLDC mRNA levels and complete abolition of glycine cleavage system activity in patient lymphoblasts, establishing that translation initiation is essential for GLDC function.","method":"mRNA quantification, GCS enzyme activity measurement in lymphoblasts, mutation sequencing","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct enzyme activity plus mRNA quantification linking specific mutation to loss of function","pmids":["15864413"],"is_preprint":false},{"year":2025,"finding":"rAAV9-mediated delivery of GLDC in a humanized CRISPR-Cas9 NKH mouse model confers 100% protection against disease and death, restores astrogenesis without inflammatory response, and demonstrates long-term systemic efficacy over 5–10 months.","method":"rAAV9-GLDC gene therapy in humanized CRISPR-edited NKH mice, GFP tracking, astrocyte/glial cell quantification, survival analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gene therapy rescue with functional and histological readouts, preprint","pmids":["bio_10.1101_2025.03.26.645560"],"is_preprint":true}],"current_model":"GLDC encodes glycine decarboxylase (P-protein), the rate-limiting component of the mitochondrial glycine cleavage system (GCS) that catabolizes glycine and supplies one-carbon units to folate metabolism; loss-of-function mutations cause glycine accumulation and nonketotic hyperglycinemia, while copy-number gains reduce extracellular glycine in the dentate gyrus and suppress NMDA receptor-dependent LTP, contributing to psychosis-like phenotypes. Beyond its metabolic role, GLDC regulates antiviral innate immune signaling (IFNβ/ISG pathway), modulates autophagy via direct interaction with VPS34 (requiring K514 acetylation), and in the nucleus undergoes EGFR-SRC-FBXL3-mediated K63-linked polyubiquitination at K636 to suppress MHC-I transcription and promote immune evasion."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing the genomic architecture and tissue expression of GLDC resolved the structural basis for subsequent mutation analysis, revealing a 25-exon gene with a processed pseudogene of high homology.","evidence":"Gene structure determination, primer extension, RNA blotting, and semi-quantitative PCR in human tissues","pmids":["10798358"],"confidence":"High","gaps":["Regulatory elements controlling tissue-specific expression were not mapped","Pseudogene interference in diagnostic sequencing not fully addressed"]},{"year":2005,"claim":"Demonstration that both coding and silent GLDC mutations abolish enzyme activity through distinct mechanisms (translation initiation loss vs. aberrant splicing) established that GLDC deficiency arises through diverse molecular routes beyond missense disruption.","evidence":"GCS enzyme activity assays in patient lymphoblasts and tissue, RT-PCR of aberrant splice products, mRNA quantification","pmids":["15851735","15864413"],"confidence":"High","gaps":["Quantitative relationship between residual splice product levels and clinical severity not systematically defined"]},{"year":2006,"claim":"Comprehensive mutation screening across dozens of NKH families identified the cofactor-binding Lys754 region as a mutation hotspot and established GLDC as the major disease gene for NKH, with residual activity directly correlating with phenotype severity.","evidence":"Sequencing of all GLDC exons in 69 NKH families; GCS enzyme activity in placental tissue; haplotype analysis","pmids":["16450403","16404748","16601880"],"confidence":"High","gaps":["Structural basis for cofactor-binding site sensitivity not resolved at atomic level","Genotype-phenotype correlation not established for all variant classes"]},{"year":2017,"claim":"Systematic functional assessment of 19 missense variants revealed that many NKH-causing mutations act by destabilizing GLDC protein rather than directly impairing catalysis, identifying protein misfolding as a predominant disease mechanism and potential therapeutic target.","evidence":"COS7 cell expression of mutant GLDC cDNA, enzymatic activity assays, Western blot for protein levels, 3D structural modeling","pmids":["28244183","29046206"],"confidence":"High","gaps":["No pharmacological chaperone rescue demonstrated","Crystal structure of human GLDC holoenzyme not available"]},{"year":2019,"claim":"Discovery that GLDC suppresses IFNβ and interferon-stimulated gene induction revealed an unexpected role for glycine metabolism in regulating antiviral innate immunity, extending GLDC function beyond amino acid catabolism.","evidence":"siRNA knockdown, AOAA inhibition, overexpression in human cells; IFN/ISG quantification; influenza viral replication assays in vitro and in BALB/c mice","pmids":["30498026"],"confidence":"High","gaps":["Molecular mechanism connecting glycine metabolism to IFN signaling not identified","Whether the immune effect is glycine-dependent or reflects a moonlighting function is unknown"]},{"year":2024,"claim":"AAV9-mediated GLDC restoration in deficient mice normalized plasma and brain glycine and corrected folate one-carbon metabolism, providing direct in vivo proof that GLDC is rate-limiting for glycine catabolism and one-carbon supply, and establishing gene therapy feasibility for NKH.","evidence":"AAV9-GLDC gene therapy in GLDC-deficient mice with plasma/tissue glycine and folate metabolite profiling","pmids":["38761651"],"confidence":"High","gaps":["Long-term durability and neurodevelopmental rescue not fully characterized","Therapeutic window relative to disease onset not defined"]},{"year":2024,"claim":"Chromosome-engineered mice with GLDC triplication demonstrated that excess GLDC reduces extracellular glycine in the dentate gyrus and selectively suppresses NMDA receptor-dependent LTP, linking GLDC gene dosage to synaptic plasticity and psychosis-like phenotypes.","evidence":"Allelic series in mice with optical FRET glycine measurement, electrophysiological LTP recordings, behavioral assays","pmids":["39210012"],"confidence":"High","gaps":["Whether human GLDC CNVs produce equivalent glycine reduction is not demonstrated","Cell-type specificity of GLDC overexpression effects in hippocampus not resolved"]},{"year":2025,"claim":"Glycine supplementation rescued all major behavioral deficits in GLDC-triplication mice, confirming the causal chain from excess GLDC → glycine depletion → NMDA hypofunction → psychosis-related behaviors.","evidence":"Oral glycine supplementation in 4-copy Gldc transgenic mice with Y-maze, PPI, social interaction, and latent inhibition assays","pmids":["41361932"],"confidence":"Medium","gaps":["Dose-response relationship not established","Translation to human GLDC CNV carriers not tested"]},{"year":2025,"claim":"Identification of GLDC as a direct VPS34-binding partner that promotes autophagy via Beclin1/ATG14 complex formation — dependent on GLDC acetylation at K514 — established a non-metabolic moonlighting function in autophagy regulation.","evidence":"Reciprocal Co-IP, K514R mutagenesis, autophagy flux assays, xenograft models in hepatocellular carcinoma","pmids":["41550650"],"confidence":"Medium","gaps":["Acetyltransferase responsible for K514 acetylation not identified","Whether this interaction occurs outside cancer cells is unknown","Structural basis of GLDC–VPS34 interaction not resolved"]},{"year":2026,"claim":"Discovery that EGFR-SRC signaling triggers FBXL3-mediated K63-linked polyubiquitination of nuclear GLDC at K636, enabling GLDC to recruit SMARCE1/DMAP1 and suppress STAT1-driven MHC-I transcription, revealed a non-canonical nuclear signaling role for GLDC in tumor immune evasion.","evidence":"Co-IP, K63-linkage-specific ubiquitination assays, FBXL3 Y306 and GLDC K636 mutagenesis, MHC-I expression analysis, CD8+ T cell killing assays","pmids":["41728086"],"confidence":"Medium","gaps":["Mechanism of GLDC nuclear import not defined","Whether nuclear GLDC retains decarboxylase activity is unknown","Independent replication by another lab not yet reported"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of human GLDC, the molecular pathway linking glycine metabolism to IFN signaling, the acetyltransferase controlling K514, the mechanism of GLDC nuclear translocation, and whether the autophagy and immune-evasion functions of GLDC operate independently of its decarboxylase activity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution crystal or cryo-EM structure of human GLDC","Metabolic vs. moonlighting functions not genetically separated","In vivo relevance of K636 ubiquitination in immunotherapy resistance not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[0,2,6,15,19]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,15,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,6,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,3,5]}],"complexes":["glycine cleavage system (GCS)"],"partners":["VPS34","FBXL3","SMARCE1","DMAP1","GCSH","BECN1"],"other_free_text":[]},"mechanistic_narrative":"GLDC encodes glycine decarboxylase (P-protein), the rate-limiting component of the mitochondrial glycine cleavage system (GCS) that catalyzes the oxidative decarboxylation of glycine and supplies one-carbon units to folate metabolism [PMID:16450403, PMID:38761651]. Loss-of-function mutations in GLDC cause nonketotic hyperglycinemia (NKH), with disease severity correlating directly with residual enzymatic activity; many pathogenic missense variants impair protein stability rather than catalytic function per se [PMID:15236413, PMID:28244183]. GLDC copy-number gains reduce extracellular glycine in the hippocampal dentate gyrus, suppress NMDA receptor-dependent long-term potentiation, and produce schizophrenia-like behavioral deficits reversible by glycine supplementation [PMID:39210012, PMID:41361932]. Beyond glycine catabolism, GLDC modulates antiviral innate immune signaling by suppressing IFNβ/ISG induction [PMID:30498026], promotes autophagy through acetylation-dependent interaction with VPS34 [PMID:41550650], and undergoes EGFR-SRC-FBXL3-mediated K63-linked polyubiquitination at K636 in the nucleus to repress MHC-I transcription and facilitate tumor immune evasion [PMID:41728086]."},"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":"3086432","id":"PMC_3086432","title":"The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes.","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3086432","citation_count":1095,"is_preprint":false},{"pmid":"1695113","id":"PMC_1695113","title":"Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH-1; 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The cofactor-binding site Lys754 (encoded by exon 19) is critical, as 7 of 32 missense mutations clustered there.\",\n      \"method\": \"Comprehensive mutation screening and sequencing of all GLDC exons in 69 NKH families; haplotype analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large multi-family genetic study replicated across multiple labs, consistent with prior biochemical characterization of GCS\",\n      \"pmids\": [\"16450403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The GLDC gene spans ≥135 kb, consists of 25 exons, and is expressed in liver, kidney, brain, and placenta. A processed pseudogene (psiGLDC) with 97.5% coding-region homology exists, arising ~4–8 million years ago from the GLDC transcript.\",\n      \"method\": \"Gene structure determination, primer extension for transcription start site, RNA blotting, semi-quantitative PCR using psiGLDC as internal control\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal molecular methods in a single study establishing gene structure and expression\",\n      \"pmids\": [\"10798358\"],\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, producing a milder/transient NKH phenotype, demonstrating a direct correlation between residual GLDC enzymatic activity and disease severity.\",\n      \"method\": \"GCS enzyme activity assay in patient tissue; mutation identification by sequencing\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct enzyme activity measurement linking specific mutation to residual function, single study\",\n      \"pmids\": [\"15236413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A silent exonic transversion (c.2607C>A) in GLDC exon 22 causes missplicing, producing three aberrantly spliced mRNA species (exon 22 skipping, exon 22–23 skipping, and 87-bp cryptic exon insertion), reducing GLDC mRNA levels and glycine decarboxylase expression; ~4–6% residual normally-spliced mRNA correlated with a milder clinical outcome.\",\n      \"method\": \"Northern blot, RT-PCR identification of aberrant splice products, homozygosity mapping\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal molecular methods (Northern blot, RT-PCR, sequencing) in a well-characterized kindred\",\n      \"pmids\": [\"15851735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GLDC missense mutations cause loss of GCS P-protein function; pathogenic variants were identified throughout the coding sequence with large deletions (including exon 1) being recurrent across multiple ethnic groups with multiple independent origins.\",\n      \"method\": \"DHPLC and sequencing of complete GLDC coding sequence in 28 unrelated NKH patients\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — comprehensive mutation survey, pathogenicity of missense variants requires expression confirmation\",\n      \"pmids\": [\"16601880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Treatment of NKH (caused by a novel homozygous GLDC c.482A>G (Y161C) missense mutation) from birth shows severely reduced GCS activity (2.6% of controls) in placental tissue and markedly elevated CSF glycine at birth, demonstrating prenatal onset of glycine accumulation due to GLDC deficiency.\",\n      \"method\": \"GCS enzyme activity assay in placental tissue; CSF and blood glycine measurement; mutation sequencing\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct enzyme activity measurement in tissue establishing prenatal functional consequence, single case\",\n      \"pmids\": [\"16404748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nineteen GLDC missense variants were functionally assessed by expressing mutant cDNA constructs in COS7 cells; enzymatic assays and Western blot revealed that many loss-of-function mutations cause protein instability rather than direct catalytic disruption, identifying these as potential targets for folding-rescue therapies. Structural modeling of the 3D GCS P-protein provided mechanistic interpretation.\",\n      \"method\": \"Mutant cDNA expression in COS7 cells, enzymatic activity assay, Western blot for protein stability, molecular modeling of 3D structure\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic assays plus mutagenesis plus structural modeling in a single comprehensive study\",\n      \"pmids\": [\"28244183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GLDC regulates cellular antiviral innate immune responses: GLDC inhibition (with AOAA) or siRNA knockdown boosted IFNβ and IFN-stimulated gene expression upon poly-I:C stimulation or influenza virus infection, and suppressed H1N1/H7N9 replication; GLDC overexpression attenuated antiviral responses and promoted viral replication.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition (AOAA), overexpression, IFN/ISG quantification, viral replication assay in vitro and in vivo (BALB/c mice)\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (siRNA, inhibitor, overexpression) with in vivo validation, single lab\",\n      \"pmids\": [\"30498026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Triplication of the GLDC gene (as found on a small supernumerary marker chromosome in patients with psychosis) reduces extracellular glycine levels in the dentate gyrus (measured by optical FRET), suppresses long-term potentiation (LTP) specifically at mPP-DG synapses but not CA3-CA1 synapses, and produces schizophrenia-like behavioral deficits in mice, demonstrating that GLDC negatively regulates synaptic glycine availability and hippocampal synaptic plasticity.\",\n      \"method\": \"Chromosome-engineered allelic series in mice, optical FRET for extracellular glycine, electrophysiological LTP recording, behavioral assays\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (FRET, electrophysiology, behavior) in a genetically engineered allelic series\",\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, spatial working memory, sociability, and latent inhibition deficits in mice with 4 copies of Gldc, confirming that behavioral phenotypes from GLDC triplication are caused by reduced extracellular glycine and consequent NMDA receptor hypofunction.\",\n      \"method\": \"Oral glycine supplementation in 4-copy Gldc transgenic mice; behavioral assays (Y-maze, prepulse inhibition, social interaction, latent inhibition)\",\n      \"journal\": \"Pharmacology research & perspectives\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis/rescue approach with multiple behavioral endpoints, single lab\",\n      \"pmids\": [\"41361932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Epigenetic silencing of GLDC via promoter hypermethylation in gastric cancer cells leads to reduced GLDC expression; GLDC knockdown increased cell proliferation, migration, invasion, and colony formation while reducing apoptosis, identifying GLDC as a putative tumor suppressor in gastric cancer.\",\n      \"method\": \"Promoter methylation analysis, GLDC knockdown in GC cell lines, proliferation/migration/invasion/apoptosis assays\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple phenotypic assays but limited mechanistic pathway placement\",\n      \"pmids\": [\"26722042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GLDC promotes colorectal cancer cell invasion and migration by inhibiting the Hippo signaling pathway and thereby promoting epithelial-mesenchymal transition (EMT); blocking Hippo signaling with verteporfin reduced GLDC-driven metastasis, and tail vein injection of GLDC-overexpressing cells induced more lung metastasis in vivo.\",\n      \"method\": \"In vitro invasion/migration assays, Hippo pathway inhibition, in vivo tail vein injection metastasis model\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological epistasis plus in vivo metastasis model, single lab\",\n      \"pmids\": [\"37668829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC interacts directly with VPS34 (PI3-kinase); GLDC overexpression upregulates VPS34 protein and promotes VPS34 interaction with the Beclin1/ATG14 complex to induce autophagy, thereby suppressing EMT and tumor growth in hepatocellular carcinoma. GLDC acetylation at K514 is required for GLDC–VPS34 interaction; the K514R acetylation-dead mutant abolished binding.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K514R), overexpression/knockdown with proliferation/migration assays, in vivo xenograft, autophagy flux assays\",\n      \"journal\": \"Pharmaceutical science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus mutagenesis validation, single lab\",\n      \"pmids\": [\"41550650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Upon EGFR activation, SRC phosphorylates FBXL3 at Y306, enabling FBXL3 to interact with nuclear GLDC and catalyze K63-linked polyubiquitination of GLDC at K636; K63-ubiquitinated GLDC then interacts with SMARCE1/DMAP1 to inhibit STAT1-driven transcription of MHC-I genes, promoting tumor immune evasion from CD8+ T cells.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (FBXL3 Y306, GLDC K636), ubiquitination assays (K63-linkage specific), MHC-I expression analysis, CD8+ T cell killing assays, SRC inhibitor treatment\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods with mutagenesis, single lab\",\n      \"pmids\": [\"41728086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC overexpression in proximal tubular cells protects against cisplatin-induced apoptosis, cellular senescence, and ROS production via upregulation of mitochondrial uncoupling protein UCP1; UCP1 knockdown reversed the protective effects of GLDC overexpression, placing UCP1 downstream of GLDC in this pathway.\",\n      \"method\": \"GLDC overexpression and knockdown in HK-2 cells, UCP1 knockdown epistasis, apoptosis/senescence/ROS assays, cisplatin-induced AKI mouse model with AOAA inhibitor\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (GLDC OE + UCP1 KD rescue) plus in vivo pharmacological confirmation, single lab\",\n      \"pmids\": [\"40010632\"],\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, significantly lowered plasma and brain tissue glycine, and normalized the folate one-carbon metabolism profile (including betaine and choline), demonstrating that GLDC is the rate-limiting enzyme for glycine catabolism and glycine-derived one-carbon supply to folate metabolism in vivo.\",\n      \"method\": \"AAV9 gene therapy in GLDC-deficient mice, RT-PCR and Western blot for GLDC expression, plasma/tissue glycine measurement, folate metabolite profiling\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo rescue experiment with multiple biochemical readouts, demonstrates functional restoration\",\n      \"pmids\": [\"38761651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In attenuated NKH mutant mice with a 1.5-fold increase in brain glycine, GLDC protein is reduced >5-fold, accompanied by decline in GCSH (mitochondrial lipoyl-transfer protein) and reduced lipoylation of the pyruvate dehydrogenase (PDH) complex, with concomitant increase in astrocyte mitochondrial β-oxidation of fatty acids and activation of neuronal PDH, suggesting GLDC remodels mitochondrial energy metabolism in the brain.\",\n      \"method\": \"Biochemical pathway analysis in mouse brain tissue, protein quantification (Western blot), metabolomics in NKH mouse models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, mechanistic model based on correlative biochemical measurements\",\n      \"pmids\": [\"bio_10.1101_2025.07.12.664515\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC downregulation in cardiomyocytes attenuates hypoxia/reperfusion injury by activating Akt signaling and inactivating NF-κB signaling, reducing apoptosis and inflammatory responses; GLDC levels were elevated in I/R mouse hearts and H/R-exposed cardiomyocytes.\",\n      \"method\": \"GLDC knockdown in H9C2 cells, Akt and NF-κB pathway analysis by Western blot, in vivo mouse I/R model with AOAA inhibitor, apoptosis and inflammation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with pathway readouts, in vitro and in vivo, single lab\",\n      \"pmids\": [\"39747134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLDC promotes PTBP1 degradation via the autophagy pathway; reduced GLDC expression in liver ischemia-reperfusion injury promotes macrophage infiltration through a PTBP1/P2RY6 axis; GLDC overexpression inhibits macrophage recruitment and activation, reducing liver injury.\",\n      \"method\": \"GLDC overexpression in vivo (mouse LIRI model), macrophage infiltration assays, autophagy pathway analysis for PTBP1 degradation, Co-IP for PTBP1/P2RY6 interaction\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanism partly correlative, PTBP1 autophagy degradation not directly demonstrated by reconstitution\",\n      \"pmids\": [\"40617371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"H293T cells transfected with GLDC missense mutants (c.3006C>G p.C1002W and c.1256C>G p.S419X) showed downregulated glycine decarboxylase activity, directly confirming the pathogenicity of these mutations through loss of enzymatic function.\",\n      \"method\": \"Transfection of mutant GLDC constructs in H293T cells, glycine decarboxylase activity assay\",\n      \"journal\": \"Zhongguo dang dai er ke za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct in vitro enzymatic activity assay with patient mutations, single lab\",\n      \"pmids\": [\"29046206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A single nucleotide substitution abolishing the initiator methionine codon of GLDC leads to markedly reduced GLDC mRNA levels and complete abolition of glycine cleavage system activity in patient lymphoblasts, establishing that translation initiation is essential for GLDC function.\",\n      \"method\": \"mRNA quantification, GCS enzyme activity measurement in lymphoblasts, mutation sequencing\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct enzyme activity plus mRNA quantification linking specific mutation to loss of function\",\n      \"pmids\": [\"15864413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"rAAV9-mediated delivery of GLDC in a humanized CRISPR-Cas9 NKH mouse model confers 100% protection against disease and death, restores astrogenesis without inflammatory response, and demonstrates long-term systemic efficacy over 5–10 months.\",\n      \"method\": \"rAAV9-GLDC gene therapy in humanized CRISPR-edited NKH mice, GFP tracking, astrocyte/glial cell quantification, survival analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gene therapy rescue with functional and histological readouts, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.03.26.645560\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GLDC encodes glycine decarboxylase (P-protein), the rate-limiting component of the mitochondrial glycine cleavage system (GCS) that catabolizes glycine and supplies one-carbon units to folate metabolism; loss-of-function mutations cause glycine accumulation and nonketotic hyperglycinemia, while copy-number gains reduce extracellular glycine in the dentate gyrus and suppress NMDA receptor-dependent LTP, contributing to psychosis-like phenotypes. Beyond its metabolic role, GLDC regulates antiviral innate immune signaling (IFNβ/ISG pathway), modulates autophagy via direct interaction with VPS34 (requiring K514 acetylation), and in the nucleus undergoes EGFR-SRC-FBXL3-mediated K63-linked polyubiquitination at K636 to suppress MHC-I transcription and promote immune evasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GLDC encodes glycine decarboxylase (P-protein), the rate-limiting component of the mitochondrial glycine cleavage system (GCS) that catalyzes the oxidative decarboxylation of glycine and supplies one-carbon units to folate metabolism [PMID:16450403, PMID:38761651]. Loss-of-function mutations in GLDC cause nonketotic hyperglycinemia (NKH), with disease severity correlating directly with residual enzymatic activity; many pathogenic missense variants impair protein stability rather than catalytic function per se [PMID:15236413, PMID:28244183]. GLDC copy-number gains reduce extracellular glycine in the hippocampal dentate gyrus, suppress NMDA receptor-dependent long-term potentiation, and produce schizophrenia-like behavioral deficits reversible by glycine supplementation [PMID:39210012, PMID:41361932]. Beyond glycine catabolism, GLDC modulates antiviral innate immune signaling by suppressing IFNβ/ISG induction [PMID:30498026], promotes autophagy through acetylation-dependent interaction with VPS34 [PMID:41550650], and undergoes EGFR-SRC-FBXL3-mediated K63-linked polyubiquitination at K636 in the nucleus to repress MHC-I transcription and facilitate tumor immune evasion [PMID:41728086].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the genomic architecture and tissue expression of GLDC resolved the structural basis for subsequent mutation analysis, revealing a 25-exon gene with a processed pseudogene of high homology.\",\n      \"evidence\": \"Gene structure determination, primer extension, RNA blotting, and semi-quantitative PCR in human tissues\",\n      \"pmids\": [\"10798358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulatory elements controlling tissue-specific expression were not mapped\", \"Pseudogene interference in diagnostic sequencing not fully addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that both coding and silent GLDC mutations abolish enzyme activity through distinct mechanisms (translation initiation loss vs. aberrant splicing) established that GLDC deficiency arises through diverse molecular routes beyond missense disruption.\",\n      \"evidence\": \"GCS enzyme activity assays in patient lymphoblasts and tissue, RT-PCR of aberrant splice products, mRNA quantification\",\n      \"pmids\": [\"15851735\", \"15864413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative relationship between residual splice product levels and clinical severity not systematically defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Comprehensive mutation screening across dozens of NKH families identified the cofactor-binding Lys754 region as a mutation hotspot and established GLDC as the major disease gene for NKH, with residual activity directly correlating with phenotype severity.\",\n      \"evidence\": \"Sequencing of all GLDC exons in 69 NKH families; GCS enzyme activity in placental tissue; haplotype analysis\",\n      \"pmids\": [\"16450403\", \"16404748\", \"16601880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for cofactor-binding site sensitivity not resolved at atomic level\", \"Genotype-phenotype correlation not established for all variant classes\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Systematic functional assessment of 19 missense variants revealed that many NKH-causing mutations act by destabilizing GLDC protein rather than directly impairing catalysis, identifying protein misfolding as a predominant disease mechanism and potential therapeutic target.\",\n      \"evidence\": \"COS7 cell expression of mutant GLDC cDNA, enzymatic activity assays, Western blot for protein levels, 3D structural modeling\",\n      \"pmids\": [\"28244183\", \"29046206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No pharmacological chaperone rescue demonstrated\", \"Crystal structure of human GLDC holoenzyme not available\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that GLDC suppresses IFNβ and interferon-stimulated gene induction revealed an unexpected role for glycine metabolism in regulating antiviral innate immunity, extending GLDC function beyond amino acid catabolism.\",\n      \"evidence\": \"siRNA knockdown, AOAA inhibition, overexpression in human cells; IFN/ISG quantification; influenza viral replication assays in vitro and in BALB/c mice\",\n      \"pmids\": [\"30498026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting glycine metabolism to IFN signaling not identified\", \"Whether the immune effect is glycine-dependent or reflects a moonlighting function is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"AAV9-mediated GLDC restoration in deficient mice normalized plasma and brain glycine and corrected folate one-carbon metabolism, providing direct in vivo proof that GLDC is rate-limiting for glycine catabolism and one-carbon supply, and establishing gene therapy feasibility for NKH.\",\n      \"evidence\": \"AAV9-GLDC gene therapy in GLDC-deficient mice with plasma/tissue glycine and folate metabolite profiling\",\n      \"pmids\": [\"38761651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term durability and neurodevelopmental rescue not fully characterized\", \"Therapeutic window relative to disease onset not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Chromosome-engineered mice with GLDC triplication demonstrated that excess GLDC reduces extracellular glycine in the dentate gyrus and selectively suppresses NMDA receptor-dependent LTP, linking GLDC gene dosage to synaptic plasticity and psychosis-like phenotypes.\",\n      \"evidence\": \"Allelic series in mice with optical FRET glycine measurement, electrophysiological LTP recordings, behavioral assays\",\n      \"pmids\": [\"39210012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human GLDC CNVs produce equivalent glycine reduction is not demonstrated\", \"Cell-type specificity of GLDC overexpression effects in hippocampus not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Glycine supplementation rescued all major behavioral deficits in GLDC-triplication mice, confirming the causal chain from excess GLDC → glycine depletion → NMDA hypofunction → psychosis-related behaviors.\",\n      \"evidence\": \"Oral glycine supplementation in 4-copy Gldc transgenic mice with Y-maze, PPI, social interaction, and latent inhibition assays\",\n      \"pmids\": [\"41361932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dose-response relationship not established\", \"Translation to human GLDC CNV carriers not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of GLDC as a direct VPS34-binding partner that promotes autophagy via Beclin1/ATG14 complex formation — dependent on GLDC acetylation at K514 — established a non-metabolic moonlighting function in autophagy regulation.\",\n      \"evidence\": \"Reciprocal Co-IP, K514R mutagenesis, autophagy flux assays, xenograft models in hepatocellular carcinoma\",\n      \"pmids\": [\"41550650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetyltransferase responsible for K514 acetylation not identified\", \"Whether this interaction occurs outside cancer cells is unknown\", \"Structural basis of GLDC–VPS34 interaction not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovery that EGFR-SRC signaling triggers FBXL3-mediated K63-linked polyubiquitination of nuclear GLDC at K636, enabling GLDC to recruit SMARCE1/DMAP1 and suppress STAT1-driven MHC-I transcription, revealed a non-canonical nuclear signaling role for GLDC in tumor immune evasion.\",\n      \"evidence\": \"Co-IP, K63-linkage-specific ubiquitination assays, FBXL3 Y306 and GLDC K636 mutagenesis, MHC-I expression analysis, CD8+ T cell killing assays\",\n      \"pmids\": [\"41728086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of GLDC nuclear import not defined\", \"Whether nuclear GLDC retains decarboxylase activity is unknown\", \"Independent replication by another lab not yet reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of human GLDC, the molecular pathway linking glycine metabolism to IFN signaling, the acetyltransferase controlling K514, the mechanism of GLDC nuclear translocation, and whether the autophagy and immune-evasion functions of GLDC operate independently of its decarboxylase activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution crystal or cryo-EM structure of human GLDC\", \"Metabolic vs. moonlighting functions not genetically separated\", \"In vivo relevance of K636 ubiquitination in immunotherapy resistance not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [0, 2, 6, 15, 19]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 15, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 6, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 3, 5]}\n    ],\n    \"complexes\": [\n      \"glycine cleavage system (GCS)\"\n    ],\n    \"partners\": [\n      \"VPS34\",\n      \"FBXL3\",\n      \"SMARCE1\",\n      \"DMAP1\",\n      \"GCSH\",\n      \"BECN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}