{"gene":"GLA","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2009,"finding":"Three missense GLA mutations (p.C52Y, p.G183A, p.Y216C) reduce α-galactosidase A (α-Gal A) enzymatic activity without directly involving the active site, causing conformational Fabry disease; the p.G183A and p.Y216C mutant proteins showed increased activity and stabilization upon treatment with the pharmacological chaperone 1-deoxygalactonojirimycin (DGJ), while p.C52Y was not DGJ-responsive, as demonstrated by in vitro expression in COS-1 cells and patient lymphocytes with Western blot and activity assays.","method":"In vitro expression in COS-1 cells, Western blot, enzyme activity assays, 3D structural analysis, pharmacological chaperone (DGJ) treatment in patient lymphocytes","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro expression with activity assay and structural analysis, two orthogonal methods (biochemical + structural), single lab","pmids":["19941952"],"is_preprint":false}],"current_model":"The GLA gene encodes lysosomal α-galactosidase A (α-Gal A); loss-of-function mutations cause Fabry disease through reduced enzyme activity, and select missense mutations cause conformational defects rescuable by the active-site chaperone DGJ, while the mechanistic basis of most GLA mutations remains characterized primarily at the clinical/genetic level in the available literature."},"narrative":{"mechanistic_narrative":"GLA encodes lysosomal α-galactosidase A (α-Gal A), an enzyme whose loss of activity underlies Fabry disease [PMID:19941952]. Select missense mutations distant from the active site (p.C52Y, p.G183A, p.Y216C) reduce α-Gal A activity by destabilizing protein conformation rather than disrupting catalysis directly, defining a conformational class of Fabry-causing variants [PMID:19941952]. The active-site-directed pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) increases activity and stabilizes the p.G183A and p.Y216C mutant proteins, whereas p.C52Y is not DGJ-responsive, indicating that chaperone rescue is mutation-specific [PMID:19941952]. Beyond this characterization of conformational mutants and their chaperone responsiveness, no further mechanistic detail of α-Gal A catalysis or substrate processing has been characterized in the available corpus.","teleology":[{"year":2009,"claim":"It was unknown whether GLA missense mutations outside the active site cause Fabry disease through conformational defects rather than direct catalytic disruption; this work established that such mutations reduce α-Gal A activity by destabilizing protein conformation and that some are rescuable by a pharmacological chaperone.","evidence":"In vitro expression of mutant α-Gal A in COS-1 cells and patient lymphocytes, with Western blot, enzyme activity assays, 3D structural analysis, and DGJ chaperone treatment","pmids":["19941952"],"confidence":"Medium","gaps":["Does not establish why p.C52Y is unresponsive to DGJ at the structural level","Limited to three mutations; the conformational basis of most GLA variants is not defined","No direct measurement of substrate (e.g. globotriaosylceramide) processing by the mutant enzymes"]},{"year":null,"claim":"The catalytic mechanism, native substrate handling, and structural determinants distinguishing chaperone-responsive from non-responsive GLA mutations remain uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanistic model linking specific mutation positions to chaperone responsiveness","No characterization of α-Gal A enzymatic mechanism or substrate kinetics in this corpus","No structural data on the wild-type or mutant enzyme beyond modeling"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHE5","full_name":"N-acetyltransferase 8","aliases":["Acetyltransferase 2","ATase2","Camello-like protein 1","Cysteinyl-conjugate N-acetyltransferase","CCNAT","Protein-lysine N6-acetyltransferase 8"],"length_aa":227,"mass_kda":25.6,"function":"Endoplasmic reticulum (ER)-membrane-bound lysine N-acetyltransferase catalyzing the N6-acetylation of lysine residues in the lumen of the ER in various proteins, including PROM1 and BACE1, using acetyl-CoA as acetyl donor (PubMed:19011241, PubMed:22267734, PubMed:24556617, PubMed:31945187). Thereby, may regulate apoptosis through the acetylation and the regulation of the expression of PROM1 (PubMed:24556617). May also regulate amyloid beta-peptide secretion through acetylation of BACE1 and the regulation of its expression in neurons (PubMed:19011241). N(6)-lysine acetylation in the ER maintains protein homeostasis and regulates reticulophagy (By similarity). Alternatively, acetylates the free alpha-amino group of cysteine S-conjugates to form mercapturic acids (PubMed:20392701). This is the final step in a major route for detoxification of a wide variety of reactive electrophiles which starts with their incorporation into glutathione S-conjugates. The glutathione S-conjugates are then further processed into cysteine S-conjugates and finally mercapturic acids which are water soluble and can be readily excreted in urine or bile","subcellular_location":"Endoplasmic reticulum-Golgi intermediate compartment membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9UHE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GLA","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GLA","total_profiled":1310},"omim":[{"mim_id":"614441","title":"PHOAR2-ENTEROPATHY SYNDROME; PHOAR2E","url":"https://www.omim.org/entry/614441"},{"mim_id":"614024","title":"PROTEIN Z DEFICIENCY","url":"https://www.omim.org/entry/614024"},{"mim_id":"613874","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 18; CMH18","url":"https://www.omim.org/entry/613874"},{"mim_id":"613872","title":"COAGULATION FACTOR X; F10","url":"https://www.omim.org/entry/613872"},{"mim_id":"612795","title":"POLYUNSATURATED FATTY ACIDS PLASMA LEVEL QUANTITATIVE TRAIT LOCUS 1; PUFAQTL1","url":"https://www.omim.org/entry/612795"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GLA"},"hgnc":{"alias_symbol":["GALA"],"prev_symbol":[]},"alphafold":{"accession":"Q9UHE5","domains":[{"cath_id":"3.40.630.30","chopping":"6-12_99-219","consensus_level":"medium","plddt":94.5727,"start":6,"end":219},{"cath_id":"1.20.58","chopping":"25-90","consensus_level":"medium","plddt":93.8468,"start":25,"end":90}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHE5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHE5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHE5-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GLA","jax_strain_url":"https://www.jax.org/strain/search?query=GLA"},"sequence":{"accession":"Q9UHE5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHE5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHE5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHE5"}},"corpus_meta":[{"pmid":"15066755","id":"PMC_15066755","title":"GALA: 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/30988158","citation_count":30,"is_preprint":false},{"pmid":"32086862","id":"PMC_32086862","title":"Intracellular matrix Gla protein promotes tumor progression by activating JAK2/STAT5 signaling in gastric cancer.","date":"2020","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32086862","citation_count":29,"is_preprint":false},{"pmid":"28487368","id":"PMC_28487368","title":"Matrix Gla protein deficiency impairs nasal septum growth, causing midface hypoplasia.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28487368","citation_count":29,"is_preprint":false},{"pmid":"31185231","id":"PMC_31185231","title":"A study of the endocytosis mechanism and transendothelial activity of lung-targeted GALA-modified liposomes.","date":"2019","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/31185231","citation_count":29,"is_preprint":false},{"pmid":"23110920","id":"PMC_23110920","title":"Matrix Gla protein reinforces angiogenic resolution.","date":"2012","source":"Microvascular research","url":"https://pubmed.ncbi.nlm.nih.gov/23110920","citation_count":28,"is_preprint":false},{"pmid":"31215457","id":"PMC_31215457","title":"Expression analysis of the osteoarthritis genetic susceptibility mapping to the matrix Gla protein gene MGP.","date":"2019","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31215457","citation_count":28,"is_preprint":false},{"pmid":"23475213","id":"PMC_23475213","title":"Calcium oxalate nephrolithiasis and expression of matrix GLA protein in the kidneys.","date":"2013","source":"World journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/23475213","citation_count":27,"is_preprint":false},{"pmid":"12446455","id":"PMC_12446455","title":"Gla domain-mutated human protein C exhibiting enhanced anticoagulant activity and increased phospholipid binding.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12446455","citation_count":27,"is_preprint":false},{"pmid":"26364300","id":"PMC_26364300","title":"Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells.","date":"2015","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/26364300","citation_count":27,"is_preprint":false},{"pmid":"15111593","id":"PMC_15111593","title":"Expression analysis of the matrix GLA protein and VE-cadherin gene promoters in the outflow pathway.","date":"2004","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/15111593","citation_count":26,"is_preprint":false},{"pmid":"21517827","id":"PMC_21517827","title":"Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene.","date":"2011","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21517827","citation_count":26,"is_preprint":false},{"pmid":"28134400","id":"PMC_28134400","title":"The influence of phosphate, calcium and magnesium on matrix Gla-protein and vascular calcification: a systematic review.","date":"2016","source":"Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia","url":"https://pubmed.ncbi.nlm.nih.gov/28134400","citation_count":25,"is_preprint":false},{"pmid":"27547048","id":"PMC_27547048","title":"Matrix Gla protein in tumoral pathology.","date":"2016","source":"Clujul medical (1957)","url":"https://pubmed.ncbi.nlm.nih.gov/27547048","citation_count":24,"is_preprint":false},{"pmid":"20359742","id":"PMC_20359742","title":"The incorporation of GALA peptide into a protein cage for an acid-inducible molecular switch.","date":"2010","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/20359742","citation_count":24,"is_preprint":false},{"pmid":"19819238","id":"PMC_19819238","title":"Identification of four alternatively spliced transcripts of the Ucma/GRP gene, encoding a new Gla-containing protein.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19819238","citation_count":24,"is_preprint":false},{"pmid":"10474688","id":"PMC_10474688","title":"Expression of the gene encoding the matrix gla protein by mature osteoblasts in human fracture non-unions.","date":"1999","source":"Molecular pathology : MP","url":"https://pubmed.ncbi.nlm.nih.gov/10474688","citation_count":24,"is_preprint":false},{"pmid":"36284362","id":"PMC_36284362","title":"Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin.","date":"2022","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/36284362","citation_count":22,"is_preprint":false},{"pmid":"31538831","id":"PMC_31538831","title":"Relationship of matrix Gla protein and vitamin K with vascular calcification in hemodialysis patients.","date":"2019","source":"Renal failure","url":"https://pubmed.ncbi.nlm.nih.gov/31538831","citation_count":22,"is_preprint":false},{"pmid":"8214087","id":"PMC_8214087","title":"Matrix Gla protein mRNA expression in cultured type II pneumocytes.","date":"1993","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8214087","citation_count":21,"is_preprint":false},{"pmid":"25990696","id":"PMC_25990696","title":"Matrix Gla protein regulates calcification of the aortic valve.","date":"2015","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/25990696","citation_count":20,"is_preprint":false},{"pmid":"30889231","id":"PMC_30889231","title":"The GalNAc-T Activation (GALA) Pathway: Drivers and markers.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30889231","citation_count":19,"is_preprint":false},{"pmid":"30663245","id":"PMC_30663245","title":"Natural alleles of GLA for grain length and awn development were differently domesticated in rice subspecies japonica and indica.","date":"2019","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/30663245","citation_count":19,"is_preprint":false},{"pmid":"15210134","id":"PMC_15210134","title":"Expression of matrix Gla protein and osteonectin mRNA by human aortic smooth muscle cells.","date":"2004","source":"Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15210134","citation_count":19,"is_preprint":false},{"pmid":"22551898","id":"PMC_22551898","title":"New mutations in the GLA gene in Brazilian families with Fabry disease.","date":"2012","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22551898","citation_count":19,"is_preprint":false},{"pmid":"11562192","id":"PMC_11562192","title":"Synthesis and characterization of membrane-active GALA-OKT9 conjugates.","date":"2001","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11562192","citation_count":18,"is_preprint":false},{"pmid":"11550673","id":"PMC_11550673","title":"Matrix Gla protein in Xenopus laevis: molecular cloning, tissue distribution, and evolutionary considerations.","date":"2001","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/11550673","citation_count":18,"is_preprint":false},{"pmid":"25210519","id":"PMC_25210519","title":"Matrix gla protein binds to fibronectin and enhances cell attachment and spreading on fibronectin.","date":"2014","source":"International journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25210519","citation_count":17,"is_preprint":false},{"pmid":"35740923","id":"PMC_35740923","title":"Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35740923","citation_count":16,"is_preprint":false},{"pmid":"28707070","id":"PMC_28707070","title":"Functional Role of Matrix gla Protein in Glioma Cell Migration.","date":"2017","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/28707070","citation_count":15,"is_preprint":false},{"pmid":"30033123","id":"PMC_30033123","title":"Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension.","date":"2018","source":"Journal of the American Society of Hypertension : JASH","url":"https://pubmed.ncbi.nlm.nih.gov/30033123","citation_count":15,"is_preprint":false},{"pmid":"26691501","id":"PMC_26691501","title":"Molecular and clinical studies in five index cases with novel mutations in the GLA gene.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26691501","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50843,"output_tokens":749,"usd":0.081882,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6705,"output_tokens":1055,"usd":0.02995,"stage2_stop_reason":"end_turn"},"total_usd":0.111832,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the canonical GLA gene (alpha-galactosidase A, the Fabry disease gene) versus MGP (matrix Gla protein), and other symbol collisions.\n\n**Key observation:** The gene symbol queried is \"GLA\" with alias \"GALA\". The corpus is overwhelmingly about MGP (matrix Gla protein, gene symbol MGP/MGLAP), not about GLA (alpha-galactosidase A). The papers about \"GLA gene\" in the context of Fabry disease (PMIDs: 30477121, 19941952, 28988177, 21517827, 22551898, 26691501) are about the GLA gene encoding α-galactosidase A — this IS the canonical GLA gene (HGNC:4296).\n\nThe GALA alias in HGNC context refers to alpha-galactosidase A (GLA). However, virtually all the mechanistic papers in this corpus are about MGP (a different gene). The GALA peptide papers (synthetic peptide) are not about this gene. Papers about \"GALA adjuvant,\" \"GLA-SE,\" rice GLA, apple 'Gala', etc. are symbol collisions.\n\nPapers about Fabry disease GLA mutations provide some mechanistic data. Let me extract those carefully.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Three missense GLA mutations (p.C52Y, p.G183A, p.Y216C) reduce α-galactosidase A (α-Gal A) enzymatic activity without directly involving the active site, causing conformational Fabry disease; the p.G183A and p.Y216C mutant proteins showed increased activity and stabilization upon treatment with the pharmacological chaperone 1-deoxygalactonojirimycin (DGJ), while p.C52Y was not DGJ-responsive, as demonstrated by in vitro expression in COS-1 cells and patient lymphocytes with Western blot and activity assays.\",\n      \"method\": \"In vitro expression in COS-1 cells, Western blot, enzyme activity assays, 3D structural analysis, pharmacological chaperone (DGJ) treatment in patient lymphocytes\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro expression with activity assay and structural analysis, two orthogonal methods (biochemical + structural), single lab\",\n      \"pmids\": [\"19941952\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"The GLA gene encodes lysosomal α-galactosidase A (α-Gal A); loss-of-function mutations cause Fabry disease through reduced enzyme activity, and select missense mutations cause conformational defects rescuable by the active-site chaperone DGJ, while the mechanistic basis of most GLA mutations remains characterized primarily at the clinical/genetic level in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GLA encodes lysosomal α-galactosidase A (α-Gal A), an enzyme whose loss of activity underlies Fabry disease [#0]. Select missense mutations distant from the active site (p.C52Y, p.G183A, p.Y216C) reduce α-Gal A activity by destabilizing protein conformation rather than disrupting catalysis directly, defining a conformational class of Fabry-causing variants [#0]. The active-site-directed pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) increases activity and stabilizes the p.G183A and p.Y216C mutant proteins, whereas p.C52Y is not DGJ-responsive, indicating that chaperone rescue is mutation-specific [#0]. Beyond this characterization of conformational mutants and their chaperone responsiveness, no further mechanistic detail of α-Gal A catalysis or substrate processing has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"It was unknown whether GLA missense mutations outside the active site cause Fabry disease through conformational defects rather than direct catalytic disruption; this work established that such mutations reduce α-Gal A activity by destabilizing protein conformation and that some are rescuable by a pharmacological chaperone.\",\n      \"evidence\": \"In vitro expression of mutant α-Gal A in COS-1 cells and patient lymphocytes, with Western blot, enzyme activity assays, 3D structural analysis, and DGJ chaperone treatment\",\n      \"pmids\": [\"19941952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not establish why p.C52Y is unresponsive to DGJ at the structural level\",\n        \"Limited to three mutations; the conformational basis of most GLA variants is not defined\",\n        \"No direct measurement of substrate (e.g. globotriaosylceramide) processing by the mutant enzymes\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic mechanism, native substrate handling, and structural determinants distinguishing chaperone-responsive from non-responsive GLA mutations remain uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mechanistic model linking specific mutation positions to chaperone responsiveness\",\n        \"No characterization of α-Gal A enzymatic mechanism or substrate kinetics in this corpus\",\n        \"No structural data on the wild-type or mutant enzyme beyond modeling\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}