{"gene":"GYS1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2008,"finding":"A missense R-to-H substitution mutation in GYS1 causes a gain-of-function, resulting in elevated glycogen synthase activity and excess skeletal muscle glycogen accumulation (polysaccharide storage myopathy) in horses.","method":"DNA sequence analysis, functional GS activity assay in affected vs. normal horses, genome-wide association mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional enzymatic activity assay demonstrating elevated GS activity, genetic identification of causal mutation, replicated across multiple breeds in follow-up studies","pmids":["18358695","18691366"],"is_preprint":false},{"year":2016,"finding":"Muscle-specific deletion of Gys1 in adult mice causes ~70% reduction in muscle glycogen, postprandial hyperglycemia, peripheral insulin resistance (reduced glucose turnover and muscle glucose uptake under insulin-stimulated conditions), reduced hexokinase II levels, and markedly impaired exercise and endurance capacity.","method":"Tamoxifen-inducible muscle-specific Cre/loxP knockout mice; glucose tolerance tests; euglycemic/hyperinsulinemic clamps; exercise testing; molecular quantification of mRNA, protein, and metabolites","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with multiple orthogonal physiological readouts (clamps, exercise tests, biochemical assays), well-controlled study","pmids":["26977394"],"is_preprint":false},{"year":2009,"finding":"Loss-of-function homozygous two-base-pair deletion in exon 2 of GYS1 causes muscle-specific glycogen synthase deficiency associated with sudden cardiac death, and GYS1 deficiency is diagnosable from skin fibroblasts.","method":"DNA sequencing; family segregation analysis; post-mortem tissue analysis; fibroblast biochemical assay","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single case report with molecular confirmation, no in vitro reconstitution","pmids":["19699667"],"is_preprint":false},{"year":2011,"finding":"The phosphorylated isoform of GYS1 is preferentially associated with elongating (translationally active) ribosomes and, upon GYS1 depletion, translation of a subset of mRNAs encoding proteins that modulate protein biosynthesis is affected, indicating a feedback loop between cellular energy state and translation machinery.","method":"Proteomic multidimensional protein identification technology (MudPIT) on translationally active vs. inactive ribosomes; GYS1 depletion with mRNA translation profiling","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus functional depletion experiment, single lab, two complementary methods","pmids":["21570405"],"is_preprint":false},{"year":2020,"finding":"GYS1 promotes tumor growth in clear cell renal carcinoma via an indirect interaction with the canonical NF-κB pathway, intermediated by RPS27A, which facilitates phosphorylation and nuclear import of p65; silencing GYS1 suppresses proliferation and sensitizes cells to sunitinib.","method":"Co-immunoprecipitation-linked mass spectrometry; RNA-seq; xenograft mouse models; GYS1 overexpression and knockdown; flow cytometry; CCK8 assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifies RPS27A as mediator, supported by in vivo xenograft and in vitro functional assays, single lab","pmids":["32802186"],"is_preprint":false},{"year":2020,"finding":"Knockout of GYS1 (glycogen synthase) in a mouse model of adult polyglucosan body disease (APBD) reduces polyglucosan body accumulation in brain, skeletal muscle, heart, and liver, improves lifespan, neuromuscular function, and reduces neuroinflammation (astro- and microgliosis), establishing GYS1-dependent glycogen synthesis as required for polyglucosan body formation.","method":"Genetic cross of APBD mice with Gys1-KO mice; histological analysis; glycogen quantification; behavioral assays of neuromuscular function","journal":"Annals of clinical and translational neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in mouse disease model with multiple orthogonal phenotypic, histological, and biochemical readouts","pmids":["33034425"],"is_preprint":false},{"year":2021,"finding":"Antisense oligonucleotide (Gys1-ASO) targeting Gys1 mRNA, delivered intracerebroventricularly, reduces GYS1 protein, prevents Lafora body formation in young mice, halts further accumulation in older mice, and prevents astrogliosis and neuroinflammatory marker dysregulation in Lafora disease mouse models.","method":"Intracerebroventricular injection of Gys1-ASO in Lafora disease mouse models; histological quantification of Lafora bodies; immunohistochemistry for gliosis markers; mRNA/protein quantification","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ASO-mediated loss-of-function with multiple disease-relevant phenotypic readouts including glycogen accumulation, Lafora body formation, and neuroinflammation in multiple mouse models","pmids":["33993268"],"is_preprint":false},{"year":2021,"finding":"AAV9-delivered CRISPR/SaCas9 targeting Gys1 edits ~17% of alleles, reduces Gys1 mRNA and ~50% of GYS1 protein across the brain, and leads to ~50% reductions in abnormal glycogen accumulation, polyglucosan bodies, and neuroinflammatory markers in mouse models of adult polyglucosan body disease and Lafora disease.","method":"Neonatal intracerebroventricular AAV9-SaCas9 injection; allele editing quantification; protein/mRNA quantification; histological analysis of polyglucosan bodies and neuroinflammation markers","journal":"Neurotherapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct loss-of-function via CRISPR in three mouse models with quantitative molecular and histological readouts","pmids":["33830476"],"is_preprint":false},{"year":2016,"finding":"GSK3β represses transcription of the GYS1 gene via two NF-κB binding sites in the promoter; overexpression of GSK3β decreases GYS1 mRNA and reduces p65 binding specifically to the second NF-κB site, as confirmed by ChIP assay.","method":"Promoter deletion reporter constructs in cell transfection; ChIP assay for p65 binding to NF-κB sites; GSK3β overexpression with qPCR","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay plus ChIP, two orthogonal methods, single lab on porcine GYS1","pmids":["27785702"],"is_preprint":false},{"year":2004,"finding":"Basal GYS1 promoter activity resides in the first 250 nucleotides; the region -692 to -544 confers muscle-specific expression; the region -971 to -692 provides negative regulation; forskolin (cAMP elevation) decreases GYS1 promoter activity ~30% in myotubes; insulin treatment does not increase but slightly decreases GYS1 promoter activity.","method":"Promoter fragment luciferase reporter assays in C2C12 myoblasts/myotubes and HEK293 cells; pharmacological treatments with insulin and forskolin","journal":"European journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion series with luciferase in two cell types plus pharmacological perturbations, single lab","pmids":["14764074"],"is_preprint":false},{"year":2023,"finding":"Gys1-ASO administered intracerebroventricularly to Epm2b-/- (Lafora disease) mice at 4, 7, and 10 months reduces Gys1 protein levels, decreases glycogen aggregation, and reduces epileptiform discharges, halting disease progression.","method":"Intracerebroventricular ASO administration in Epm2b-/- mice; Gys1 protein quantification; glycogen aggregation histology; electrophysiological recording of epileptiform discharges","journal":"Neurotherapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with molecular, histological, and electrophysiological readouts in established disease model","pmids":["37700152"],"is_preprint":false},{"year":2025,"finding":"GYS1 is a nucleocytoplasmic shuttling protein that, under glycogen depletion or transcription inhibition, dynamically reorganizes into nuclear condensates via liquid-liquid phase separation with the transcription factor NONO/p54nrb; this nuclear retention inhibits glycogen biosynthesis. Nuclear GYS1 and NONO co-condense with MyoD and preinitiation complex proteins to form transcriptional condensates that drive myogenic gene expression; Gys1 or Nono deficiency prevents C2C12 myoblast differentiation and cardiotoxin-induced muscle regeneration in mice.","method":"Live cell imaging (nucleocytoplasmic shuttling, condensate formation); Co-IP; liquid-liquid phase separation assays; Gys1/Nono KO mice (glycogen quantification, muscle fiber size, exercise tolerance); C2C12 differentiation assays; cardiotoxin-induced muscle regeneration; ChIP-like co-condensation with MyoD and PIC proteins","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (LLPS, Co-IP, live imaging, KO mouse phenotypes, differentiation assays) in a single rigorous study","pmids":["40200092"],"is_preprint":false},{"year":2025,"finding":"In ovarian clear cell carcinoma, p53 promotes GYS1 degradation via upregulation of RNF144a (E3 ubiquitin ligase targeting GYS1), while GYS1 in turn stabilizes p53 by competitively binding to the deubiquitinase USP14, forming a positive feedback loop; under platinum stress, this circuit mobilizes glycogen to fuel NADPH production, causing resistance to disulfidptosis and platinum resistance.","method":"Mechanistic cell biology: GYS1 KD/OE in OCCC cells; ubiquitination assays; Co-IP for GYS1-USP14 competitive binding; RNF144a overexpression; metabolic NADPH measurements; platinum resistance assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional readouts, single lab, mechanistic circuit not independently replicated","pmids":["40210982"],"is_preprint":false},{"year":2025,"finding":"Depletion of PTG (an activator of GYS1) in laforin- and malin-deficient Lafora disease mice demonstrates that abnormal glycogen chain lengths (not hyperphosphorylation) underlie polyglucosan formation, and that a small pool of overactive GYS1 contributes to glycogen insolubility in Lafora disease and adult polyglucosan body disease.","method":"Genetic PTG depletion in laforin-KO and malin-KO mice; glycogen chain length analysis; metabolomics on in situ-fixed brains; histological analysis of polyglucosan bodies and neuroinflammation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with biochemical glycogen chain-length analysis and metabolomics in multiple disease mouse models","pmids":["39806098"],"is_preprint":false},{"year":2023,"finding":"HIF-1α directly transcriptionally regulates GYS1, which encodes glycogen synthase; GYS1-mediated glycogen synthesis controls UDPG secretion, which activates P2Y14 receptor to promote M1 macrophage polarization and inflammation; knockdown of HIF-1α or GYS1 disrupts anti-inflammatory effects of the HIF-PHI MK8617.","method":"Lentiviral knockdown of HIF-1α and GYS1; qRT-PCR and Western blot for GYS1 and pathway components; ELISA for UDPG; pharmacological inhibition experiments","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral KD with molecular pathway readouts, single lab, mechanistic pathway placement supported by multiple markers","pmids":["37404479"],"is_preprint":false},{"year":2024,"finding":"A CD71 Centyrin:Gys1 siRNA conjugate, upon binding TfR1 and internalization, reduces GYS1 protein expression and glycogen synthase enzymatic activity, decreases glycogen levels in muscle of a Pompe disease mouse model, and improves treadmill exercise performance.","method":"siRNA conjugate treatment in 6neo/6neo Pompe mice; GYS1 protein quantification; enzymatic activity assay; glycogen quantification; treadmill exercise testing","journal":"Molecular therapy","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — enzymatic activity assay plus protein/glycogen quantification and functional exercise readout in disease mouse model, single lab","pmids":["39604266"],"is_preprint":false},{"year":2024,"finding":"In zebrafish, maternal gys1 is required for glycogen reserve in ovaries and embryos; gys1 knockout reduces glycogen content and free glucose levels in embryos by ~50%, impairs glucose uptake ability, and disrupts metabolites in vitamin B, carbohydrate, and unsaturated fatty acid pathways, demonstrating that gys1 is essential for maternal glycogen reserve supporting embryonic development.","method":"gys1 KO zebrafish (F3 generation); PAS staining; glycogen content measurement; free glucose measurement; 2-NBDG microinjection for glucose uptake; untargeted metabolomics","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in zebrafish with multiple biochemical and metabolomics readouts, single lab, ortholog study","pmids":["38803914"],"is_preprint":false},{"year":2021,"finding":"miR-140-5p directly targets GYS1 (and PPP1CC) as confirmed by luciferase reporter assay; miR-140-5p overexpression reduces GYS1 and PPP1CC protein levels, decreases glycogen production, and impairs glucose consumption and uptake, aggravating insulin resistance in HepG2 cells.","method":"Bioinformatic target prediction; dual-luciferase reporter assay; Western blot and qPCR; glycogen detection; rescue experiments with GYS1/PPP1CC inhibition","journal":"Diabetes, metabolic syndrome and obesity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct miRNA targeting of GYS1 3'UTR, supported by protein-level knockdown and functional glycogen/glucose assays, single lab","pmids":["34113143"],"is_preprint":false}],"current_model":"GYS1 (skeletal muscle glycogen synthase 1) is a nucleocytoplasmic shuttling enzyme that catalyzes the rate-limiting step of glycogen chain elongation in muscle and brain; its activity is regulated by phosphorylation (with phosphorylated GYS1 associating with ribosomes), by transcriptional repression via GSK3β/NF-κB, by miR-140-5p-mediated mRNA targeting, and by HIF-1α-driven transcription; in the nucleus, GYS1 undergoes liquid-liquid phase separation with NONO/p54nrb and co-condenses with MyoD and preinitiation complex proteins to drive myogenic gene expression; gain-of-function mutations cause excess glycogen accumulation (polysaccharide storage myopathy), loss-of-function causes glycogen deficiency and insulin resistance, and overactivation of a GYS1 pool drives polyglucosan body formation and neurodegeneration in Lafora disease and adult polyglucosan body disease; GYS1 also participates in oncogenic signaling (via RPS27A/NF-κB in renal carcinoma and a p53/USP14/RNF144a feedback loop in ovarian carcinoma) and in macrophage inflammation through HIF-1α-regulated UDPG/P2Y14 signaling."},"narrative":{"mechanistic_narrative":"GYS1 catalyzes the rate-limiting elongation step of glycogen biosynthesis and serves as a central node coupling glucose storage to muscle physiology, neurodegenerative disease, and gene regulation [PMID:26977394, PMID:33034425]. Its glycogen-synthesizing function is essential in vivo: muscle-specific deletion in mice depletes muscle glycogen, causes postprandial hyperglycemia, peripheral insulin resistance, and impaired exercise capacity [PMID:26977394], and maternal Gys1 is required for embryonic glycogen reserves [PMID:38803914]. Dosage and activity of GYS1 are bidirectionally pathogenic — a gain-of-function missense mutation drives excess muscle glycogen accumulation (polysaccharide storage myopathy) [PMID:18358695, PMID:18691366], while loss-of-function deletion causes glycogen synthase deficiency associated with sudden cardiac death [PMID:19699667]. In the brain, GYS1-dependent synthesis is obligatory for the abnormal glycogen aggregates of Lafora disease and adult polyglucosan body disease: genetic ablation, antisense oligonucleotides, and CRISPR editing of Gys1 each reduce polyglucosan/Lafora body burden, neuroinflammation, and epileptiform activity [PMID:33034425, PMID:33993268, PMID:33830476, PMID:37700152], and depletion of the GYS1 activator PTG shows that a small pool of overactive GYS1 producing aberrant glycogen chain lengths underlies polyglucosan formation [PMID:39806098]. Beyond enzymatic glycogen synthesis, GYS1 is a nucleocytoplasmic shuttling protein that, under glycogen depletion, undergoes liquid-liquid phase separation with NONO/p54nrb and co-condenses with MyoD and preinitiation complex proteins to drive myogenic gene expression and muscle regeneration [PMID:40200092]. GYS1 expression and activity are controlled at multiple levels: transcriptional repression through GSK3β acting on NF-κB promoter sites [PMID:27785702], HIF-1α-driven transcription linking glycogen-derived UDPG to P2Y14 signaling and macrophage inflammation [PMID:37404479], and direct mRNA targeting by miR-140-5p that lowers glycogen production and aggravates insulin resistance [PMID:34113143]. GYS1 also participates in oncogenic circuits, promoting renal carcinoma growth via RPS27A-mediated NF-κB activation [PMID:32802186] and forming a p53/USP14/RNF144a feedback loop that mobilizes glycogen-derived NADPH to confer platinum resistance in ovarian carcinoma [PMID:40210982].","teleology":[{"year":2008,"claim":"Established that altered GYS1 activity is directly causal for a glycogen storage phenotype, showing a single gain-of-function missense mutation elevates glycogen synthase activity and accumulates muscle glycogen.","evidence":"DNA sequencing, GWAS mapping, and GS activity assays in affected vs. normal horses","pmids":["18358695","18691366"],"confidence":"High","gaps":["Does not define the structural basis of the gain-of-function","Ortholog (equine) finding"]},{"year":2009,"claim":"Demonstrated that GYS1 loss-of-function is pathogenic in humans, linking a homozygous deletion to muscle glycogen synthase deficiency and sudden cardiac death.","evidence":"DNA sequencing, family segregation, post-mortem and fibroblast biochemical analysis","pmids":["19699667"],"confidence":"Medium","gaps":["Single case report without in vitro reconstitution","Cardiac mechanism of death not mechanistically dissected"]},{"year":2016,"claim":"Defined GYS1's physiological role in glucose homeostasis by showing muscle glycogen synthesis is required for insulin sensitivity and exercise capacity in adult mammals.","evidence":"Inducible muscle-specific Gys1 knockout mice with clamps, glucose tolerance tests, and exercise testing","pmids":["26977394"],"confidence":"High","gaps":["Does not address GYS1 functions outside muscle","Mechanism linking glycogen loss to reduced hexokinase II not resolved"]},{"year":2011,"claim":"Connected phosphorylated GYS1 to the translation machinery, suggesting a non-canonical role coupling cellular energy state to protein biosynthesis.","evidence":"MudPIT proteomics on active vs. inactive ribosomes plus GYS1-depletion translation profiling","pmids":["21570405"],"confidence":"Medium","gaps":["Functional consequence of ribosome association incompletely defined","Single lab, mechanism of recruitment unknown"]},{"year":2016,"claim":"Identified transcriptional control of GYS1 by GSK3β through NF-κB promoter sites, defining one input that sets GYS1 expression level.","evidence":"Promoter reporter constructs and ChIP for p65 binding with GSK3β overexpression (porcine GYS1)","pmids":["27785702"],"confidence":"Medium","gaps":["Ortholog promoter study","How this integrates with metabolic signaling unclear"]},{"year":2020,"claim":"Established GYS1-dependent glycogen synthesis as required for polyglucosan body formation, validating GYS1 as a therapeutic target in adult polyglucosan body disease.","evidence":"Genetic cross of APBD mice with Gys1-KO; histology, glycogen quantification, neuromuscular assays","pmids":["33034425"],"confidence":"High","gaps":["Does not identify which GYS1 pool drives aberrant glycogen","Brain-cell-type specificity not resolved"]},{"year":2020,"claim":"Revealed an oncogenic role for GYS1 in renal carcinoma, acting indirectly via RPS27A to activate NF-κB-driven proliferation and drug response.","evidence":"Co-IP/MS, RNA-seq, knockdown/overexpression, and xenograft models","pmids":["32802186"],"confidence":"Medium","gaps":["GYS1-RPS27A interaction is indirect and from a single lab","Whether enzymatic activity is required not separated from scaffolding role"]},{"year":2021,"claim":"Provided therapeutic proof-of-concept that reducing GYS1 by antisense oligonucleotide or CRISPR editing prevents Lafora/polyglucosan body accumulation and neuroinflammation in the brain.","evidence":"Intracerebroventricular Gys1-ASO and AAV9-SaCas9 in multiple Lafora and APBD mouse models with histological and molecular readouts","pmids":["33993268","33830476"],"confidence":"High","gaps":["Partial protein knockdown sufficient but optimal threshold unknown","Long-term safety of GYS1 suppression in brain untested"]},{"year":2021,"claim":"Identified miR-140-5p as a direct post-transcriptional regulator of GYS1, linking its downregulation to reduced glycogen production and insulin resistance.","evidence":"Dual-luciferase reporter, knockdown, glycogen and glucose-uptake assays in HepG2 cells","pmids":["34113143"],"confidence":"Medium","gaps":["Single cell-line context","In vivo relevance of the miRNA-GYS1 axis not shown"]},{"year":2023,"claim":"Placed GYS1 in inflammatory signaling, showing HIF-1α-driven GYS1 controls glycogen-derived UDPG secretion that activates P2Y14 to promote M1 macrophage polarization.","evidence":"Lentiviral knockdown of HIF-1α and GYS1, UDPG ELISA, and pharmacological HIF-PHI experiments","pmids":["37404479"],"confidence":"Medium","gaps":["Single lab pathway placement","In vivo inflammatory contribution of GYS1 not established"]},{"year":2023,"claim":"Extended ASO efficacy to symptomatic timepoints, showing Gys1 reduction halts disease progression and reduces epileptiform discharges in Lafora mice.","evidence":"Intracerebroventricular Gys1-ASO in Epm2b-/- mice with electrophysiology and histology","pmids":["37700152"],"confidence":"High","gaps":["Reversal of established pathology not demonstrated","Mechanism linking glycogen reduction to seizure suppression not dissected"]},{"year":2024,"claim":"Demonstrated GYS1-targeted siRNA conjugate delivery as a strategy to lower muscle glycogen and improve function in Pompe disease, broadening GYS1 as a substrate-reduction target.","evidence":"CD71 Centyrin:Gys1 siRNA conjugate in 6neo/6neo Pompe mice with activity, glycogen, and treadmill readouts","pmids":["39604266"],"confidence":"High","gaps":["Durability and off-tissue effects not fully characterized","Single disease model"]},{"year":2024,"claim":"Showed an essential developmental role for GYS1, establishing maternal glycogen reserve dependence in zebrafish ovaries and embryos.","evidence":"gys1 knockout zebrafish with PAS staining, glycogen/glucose measurement, glucose-uptake assay, and metabolomics","pmids":["38803914"],"confidence":"Medium","gaps":["Ortholog study; mammalian generality unknown","Mechanism linking metabolite disruption to developmental defects not resolved"]},{"year":2025,"claim":"Resolved the mechanism by which a small overactive GYS1 pool drives polyglucosan formation, showing abnormal glycogen chain length rather than hyperphosphorylation underlies insolubility.","evidence":"Genetic PTG depletion in laforin- and malin-KO mice with glycogen chain-length analysis and metabolomics","pmids":["39806098"],"confidence":"High","gaps":["Does not identify what makes that GYS1 pool overactive","Therapeutic strategy to selectively target the pool not defined"]},{"year":2025,"claim":"Uncovered a moonlighting nuclear function for GYS1, showing it phase-separates with NONO and co-condenses with MyoD/PIC proteins to drive myogenic transcription and muscle regeneration.","evidence":"Live-cell imaging, LLPS assays, Co-IP, Gys1/Nono KO mice, and C2C12 differentiation/regeneration assays","pmids":["40200092"],"confidence":"High","gaps":["How shuttling and condensation are signaled by glycogen state mechanistically incomplete","Genome-wide targets of GYS1-NONO condensates not mapped"]},{"year":2025,"claim":"Defined a GYS1-centered p53/USP14/RNF144a feedback loop that mobilizes glycogen-derived NADPH to confer platinum and disulfidptosis resistance in ovarian carcinoma.","evidence":"Co-IP, ubiquitination assays, RNF144a overexpression, NADPH measurement, and platinum resistance assays in OCCC cells","pmids":["40210982"],"confidence":"Medium","gaps":["Circuit from a single lab, not independently replicated","In vivo validation of the resistance mechanism limited"]},{"year":null,"claim":"It remains unknown how the distinct GYS1 pools — cytoplasmic glycogen-synthesizing, ribosome-associated, and nuclear phase-separating — are partitioned and signaled, and how the overactive disease-driving pool is mechanistically generated.","evidence":"No single study integrates GYS1 subcellular pools, their regulation, and their disease-specific activities","pmids":[],"confidence":"Low","gaps":["No unified model of GYS1 pool partitioning","Structural basis of activity regulation across pools undefined","Selective targeting of pathogenic pool not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11]}],"complexes":["GYS1-NONO nuclear transcriptional condensate"],"partners":["NONO","MYOD","RPS27A","USP14","RNF144A","PPP1CC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13807","full_name":"Glycogen [starch] synthase, muscle","aliases":["Glycogen synthase 1"],"length_aa":737,"mass_kda":83.8,"function":"Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme. Extends the primer composed of a few glucose units formed by glycogenin by adding new glucose units to it. In this context, glycogen synthase transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P13807/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GYS1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000104812","cell_line_id":"CID001592","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"GYG1","stoichiometry":10.0},{"gene":"GYG2","stoichiometry":10.0},{"gene":"CEP164","stoichiometry":0.2},{"gene":"SOX12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001592","total_profiled":1310},"omim":[{"mim_id":"620681","title":"MYOCLONIC EPILEPSY OF LAFORA 2; MELF2","url":"https://www.omim.org/entry/620681"},{"mim_id":"616640","title":"EPILEPSY, PROGRESSIVE MYOCLONIC, 10; EPM10","url":"https://www.omim.org/entry/616640"},{"mim_id":"616639","title":"PR DOMAIN-CONTAINING PROTEIN 8; PRDM8","url":"https://www.omim.org/entry/616639"},{"mim_id":"616605","title":"GSK3B-INTERACTING PROTEIN; GSKIP","url":"https://www.omim.org/entry/616605"},{"mim_id":"616199","title":"POLYGLUCOSAN BODY MYOPATHY 2; PGBM2","url":"https://www.omim.org/entry/616199"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":112.2},{"tissue":"skeletal muscle","ntpm":299.1},{"tissue":"tongue","ntpm":188.4}],"url":"https://www.proteinatlas.org/search/GYS1"},"hgnc":{"alias_symbol":["GSY"],"prev_symbol":["GYS"]},"alphafold":{"accession":"P13807","domains":[{"cath_id":"3.40.50.2000","chopping":"26-283","consensus_level":"high","plddt":95.4356,"start":26,"end":283},{"cath_id":"3.40.50.2000","chopping":"284-376_442-594","consensus_level":"high","plddt":94.5936,"start":284,"end":594},{"cath_id":"1.10.287","chopping":"378-439","consensus_level":"medium","plddt":90.2619,"start":378,"end":439}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13807","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13807-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13807-F1-predicted_aligned_error_v6.png","plddt_mean":84.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GYS1","jax_strain_url":"https://www.jax.org/strain/search?query=GYS1"},"sequence":{"accession":"P13807","fasta_url":"https://rest.uniprot.org/uniprotkb/P13807.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13807/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13807"}},"corpus_meta":[{"pmid":"18358695","id":"PMC_18358695","title":"Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis.","date":"2008","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18358695","citation_count":103,"is_preprint":false},{"pmid":"26977394","id":"PMC_26977394","title":"Impaired glucose metabolism and exercise capacity with muscle-specific glycogen synthase 1 (gys1) deletion in adult mice.","date":"2016","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26977394","citation_count":49,"is_preprint":false},{"pmid":"19699667","id":"PMC_19699667","title":"Identification of a novel mutation in GYS1 (muscle-specific glycogen synthase) resulting in sudden cardiac death, that is diagnosable from skin fibroblasts.","date":"2009","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/19699667","citation_count":46,"is_preprint":false},{"pmid":"33993268","id":"PMC_33993268","title":"Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease.","date":"2021","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33993268","citation_count":45,"is_preprint":false},{"pmid":"32802186","id":"PMC_32802186","title":"GYS1 induces glycogen accumulation and promotes tumor progression via the NF-κB pathway in Clear Cell Renal Carcinoma.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32802186","citation_count":44,"is_preprint":false},{"pmid":"33830476","id":"PMC_33830476","title":"Targeting Gys1 with AAV-SaCas9 Decreases Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.","date":"2021","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/33830476","citation_count":42,"is_preprint":false},{"pmid":"18691366","id":"PMC_18691366","title":"Glycogen synthase 1 (GYS1) mutation in diverse breeds with polysaccharide storage myopathy.","date":"2008","source":"Journal of veterinary internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18691366","citation_count":39,"is_preprint":false},{"pmid":"5190","id":"PMC_5190","title":"Aflatoxin B1 metabolism to aflatoxicol and derivatives lethal to Bacillus subtilis GSY 1057 by rainbow trout (Salmo gairdneri) liver.","date":"1976","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/5190","citation_count":38,"is_preprint":false},{"pmid":"21570405","id":"PMC_21570405","title":"Proteomic analysis of ribosomes: translational control of mRNA populations by glycogen synthase GYS1.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21570405","citation_count":29,"is_preprint":false},{"pmid":"25487600","id":"PMC_25487600","title":"Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia.","date":"2014","source":"Clinical lymphoma, myeloma & leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/25487600","citation_count":28,"is_preprint":false},{"pmid":"27924943","id":"PMC_27924943","title":"Gsy, a novel glucansucrase from Leuconostoc mesenteroides, mediates the formation of cell aggregates in response to oxidative stress.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27924943","citation_count":28,"is_preprint":false},{"pmid":"24035883","id":"PMC_24035883","title":"Expression of glycogen synthase (GYS) and glycogen synthase kinase 3β (GSK3β) of the Fujian oyster, Crassostrea angulata, in relation to glycogen content in gonad development.","date":"2013","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24035883","citation_count":23,"is_preprint":false},{"pmid":"33034425","id":"PMC_33034425","title":"GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease.","date":"2020","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33034425","citation_count":21,"is_preprint":false},{"pmid":"37700152","id":"PMC_37700152","title":"Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model.","date":"2023","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37700152","citation_count":17,"is_preprint":false},{"pmid":"18822097","id":"PMC_18822097","title":"A GYS1 gene mutation is highly associated with polysaccharide storage myopathy in Cob Normand draught horses.","date":"2008","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18822097","citation_count":17,"is_preprint":false},{"pmid":"22444879","id":"PMC_22444879","title":"Association of the polymorphism in GYS1 and ACOX1 genes with meat quality traits in pigs.","date":"2007","source":"Animal : an international journal of animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/22444879","citation_count":17,"is_preprint":false},{"pmid":"15932409","id":"PMC_15932409","title":"Polymorphism, linkage mapping and expression pattern of the porcine skeletal muscle glycogen synthase (GYS1) gene.","date":"2005","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15932409","citation_count":15,"is_preprint":false},{"pmid":"21262610","id":"PMC_21262610","title":"Presence of the glycogen synthase 1 (GYS1) mutation causing type 1 polysaccharide storage myopathy in continental European draught horse breeds.","date":"2010","source":"The Veterinary record","url":"https://pubmed.ncbi.nlm.nih.gov/21262610","citation_count":15,"is_preprint":false},{"pmid":"17356695","id":"PMC_17356695","title":"Variation in GYS1 interacts with exercise and gender to predict cardiovascular mortality.","date":"2007","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/17356695","citation_count":13,"is_preprint":false},{"pmid":"27785702","id":"PMC_27785702","title":"Transcriptional regulation of pig GYS1 gene by glycogen synthase kinase 3β (GSK3β).","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27785702","citation_count":11,"is_preprint":false},{"pmid":"24215078","id":"PMC_24215078","title":"Evidence of positive selection for a glycogen synthase (GYS1) mutation in domestic horse populations.","date":"2013","source":"The Journal of heredity","url":"https://pubmed.ncbi.nlm.nih.gov/24215078","citation_count":11,"is_preprint":false},{"pmid":"38295503","id":"PMC_38295503","title":"Chronic heat stress inhibits glycogen synthesis through gga-miR-212-5p/GYS1 axis in the breast muscle of broilers.","date":"2024","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/38295503","citation_count":8,"is_preprint":false},{"pmid":"12411100","id":"PMC_12411100","title":"Association of GYS1 and beta(3)-AR gene with postprandial hyperglycemia and serum uric acid in type 2 diabetes mellitus.","date":"2002","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12411100","citation_count":7,"is_preprint":false},{"pmid":"21949056","id":"PMC_21949056","title":"Estimated prevalence of the GYS-1 mutation in healthy Austrian Haflingers.","date":"2011","source":"The Veterinary record","url":"https://pubmed.ncbi.nlm.nih.gov/21949056","citation_count":6,"is_preprint":false},{"pmid":"39604266","id":"PMC_39604266","title":"A novel CD71 Centyrin:Gys1 siRNA conjugate reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39604266","citation_count":6,"is_preprint":false},{"pmid":"34113143","id":"PMC_34113143","title":"miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells.","date":"2021","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34113143","citation_count":6,"is_preprint":false},{"pmid":"25001420","id":"PMC_25001420","title":"Parallel evolution of the glycogen synthase 1 (muscle) gene Gys1 between Old World and New World fruit bats (Order: Chiroptera).","date":"2014","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25001420","citation_count":6,"is_preprint":false},{"pmid":"808527","id":"PMC_808527","title":"Bacillus subtilis GSY 1057 assay for aflatoxin B activation by rainbow trout (Salmo gairdneri).","date":"1975","source":"Journal - Association of Official Analytical Chemists","url":"https://pubmed.ncbi.nlm.nih.gov/808527","citation_count":6,"is_preprint":false},{"pmid":"39806098","id":"PMC_39806098","title":"Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated neurodegenerative disease.","date":"2025","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39806098","citation_count":4,"is_preprint":false},{"pmid":"37404479","id":"PMC_37404479","title":"MK8617 inhibits M1 macrophage polarization and inflammation via the HIF-1α/GYS1/UDPG/P2Y14 pathway.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/37404479","citation_count":3,"is_preprint":false},{"pmid":"38803914","id":"PMC_38803914","title":"gys1 regulates maternal glycogen reserve essential for embryonic development in zebrafish.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38803914","citation_count":3,"is_preprint":false},{"pmid":"14764074","id":"PMC_14764074","title":"Characterization of the human skeletal muscle glycogen synthase gene (GYS1) promoter.","date":"2004","source":"European journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/14764074","citation_count":3,"is_preprint":false},{"pmid":"40200092","id":"PMC_40200092","title":"The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/40200092","citation_count":2,"is_preprint":false},{"pmid":"40210982","id":"PMC_40210982","title":"Glycogen stores mediated by the p53-GYS1 feedback circuit engenders platinum resistance in ovarian clear cell carcinoma.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/40210982","citation_count":2,"is_preprint":false},{"pmid":"37956734","id":"PMC_37956734","title":"Response of Cancer Stem Cells and Human Skin Fibroblasts to Picosecond-Scale Electron Irradiation at 1010 to 1011 Gy/s.","date":"2023","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/37956734","citation_count":2,"is_preprint":false},{"pmid":"41629272","id":"PMC_41629272","title":"Cuproptosis promotes inflammatory osteolysis via GYS1-mediated glycogen metabolism.","date":"2026","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/41629272","citation_count":0,"is_preprint":false},{"pmid":"41859379","id":"PMC_41859379","title":"Disulfidptosis-Induced Chondrocyte-Macrophage Crosstalk via GYS1/CCND1/NOD2 Axis Promotes Osteoarthritis Progression.","date":"2026","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/41859379","citation_count":0,"is_preprint":false},{"pmid":"40622301","id":"PMC_40622301","title":"Single-pulse Gy-scale irradiation of biological cells at 1013 Gy s-1average dose-rates from a laser-wakefield accelerator.","date":"2025","source":"Physics in medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/40622301","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.19.633807","title":"The metabolic enzyme GYS1 condenses with NONO/p54  <sup>nrb</sup>  in the nucleus to spatiotemporally regulate glycogenesis and myogenic differentiation","date":"2025-01-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.19.633807","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21062,"output_tokens":4814,"usd":0.067698,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13099,"output_tokens":5031,"usd":0.095635,"stage2_stop_reason":"end_turn"},"total_usd":0.163333,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"A missense R-to-H substitution mutation in GYS1 causes a gain-of-function, resulting in elevated glycogen synthase activity and excess skeletal muscle glycogen accumulation (polysaccharide storage myopathy) in horses.\",\n      \"method\": \"DNA sequence analysis, functional GS activity assay in affected vs. normal horses, genome-wide association mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional enzymatic activity assay demonstrating elevated GS activity, genetic identification of causal mutation, replicated across multiple breeds in follow-up studies\",\n      \"pmids\": [\"18358695\", \"18691366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Muscle-specific deletion of Gys1 in adult mice causes ~70% reduction in muscle glycogen, postprandial hyperglycemia, peripheral insulin resistance (reduced glucose turnover and muscle glucose uptake under insulin-stimulated conditions), reduced hexokinase II levels, and markedly impaired exercise and endurance capacity.\",\n      \"method\": \"Tamoxifen-inducible muscle-specific Cre/loxP knockout mice; glucose tolerance tests; euglycemic/hyperinsulinemic clamps; exercise testing; molecular quantification of mRNA, protein, and metabolites\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with multiple orthogonal physiological readouts (clamps, exercise tests, biochemical assays), well-controlled study\",\n      \"pmids\": [\"26977394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss-of-function homozygous two-base-pair deletion in exon 2 of GYS1 causes muscle-specific glycogen synthase deficiency associated with sudden cardiac death, and GYS1 deficiency is diagnosable from skin fibroblasts.\",\n      \"method\": \"DNA sequencing; family segregation analysis; post-mortem tissue analysis; fibroblast biochemical assay\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single case report with molecular confirmation, no in vitro reconstitution\",\n      \"pmids\": [\"19699667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The phosphorylated isoform of GYS1 is preferentially associated with elongating (translationally active) ribosomes and, upon GYS1 depletion, translation of a subset of mRNAs encoding proteins that modulate protein biosynthesis is affected, indicating a feedback loop between cellular energy state and translation machinery.\",\n      \"method\": \"Proteomic multidimensional protein identification technology (MudPIT) on translationally active vs. inactive ribosomes; GYS1 depletion with mRNA translation profiling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus functional depletion experiment, single lab, two complementary methods\",\n      \"pmids\": [\"21570405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GYS1 promotes tumor growth in clear cell renal carcinoma via an indirect interaction with the canonical NF-κB pathway, intermediated by RPS27A, which facilitates phosphorylation and nuclear import of p65; silencing GYS1 suppresses proliferation and sensitizes cells to sunitinib.\",\n      \"method\": \"Co-immunoprecipitation-linked mass spectrometry; RNA-seq; xenograft mouse models; GYS1 overexpression and knockdown; flow cytometry; CCK8 assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifies RPS27A as mediator, supported by in vivo xenograft and in vitro functional assays, single lab\",\n      \"pmids\": [\"32802186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockout of GYS1 (glycogen synthase) in a mouse model of adult polyglucosan body disease (APBD) reduces polyglucosan body accumulation in brain, skeletal muscle, heart, and liver, improves lifespan, neuromuscular function, and reduces neuroinflammation (astro- and microgliosis), establishing GYS1-dependent glycogen synthesis as required for polyglucosan body formation.\",\n      \"method\": \"Genetic cross of APBD mice with Gys1-KO mice; histological analysis; glycogen quantification; behavioral assays of neuromuscular function\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in mouse disease model with multiple orthogonal phenotypic, histological, and biochemical readouts\",\n      \"pmids\": [\"33034425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Antisense oligonucleotide (Gys1-ASO) targeting Gys1 mRNA, delivered intracerebroventricularly, reduces GYS1 protein, prevents Lafora body formation in young mice, halts further accumulation in older mice, and prevents astrogliosis and neuroinflammatory marker dysregulation in Lafora disease mouse models.\",\n      \"method\": \"Intracerebroventricular injection of Gys1-ASO in Lafora disease mouse models; histological quantification of Lafora bodies; immunohistochemistry for gliosis markers; mRNA/protein quantification\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ASO-mediated loss-of-function with multiple disease-relevant phenotypic readouts including glycogen accumulation, Lafora body formation, and neuroinflammation in multiple mouse models\",\n      \"pmids\": [\"33993268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AAV9-delivered CRISPR/SaCas9 targeting Gys1 edits ~17% of alleles, reduces Gys1 mRNA and ~50% of GYS1 protein across the brain, and leads to ~50% reductions in abnormal glycogen accumulation, polyglucosan bodies, and neuroinflammatory markers in mouse models of adult polyglucosan body disease and Lafora disease.\",\n      \"method\": \"Neonatal intracerebroventricular AAV9-SaCas9 injection; allele editing quantification; protein/mRNA quantification; histological analysis of polyglucosan bodies and neuroinflammation markers\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct loss-of-function via CRISPR in three mouse models with quantitative molecular and histological readouts\",\n      \"pmids\": [\"33830476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSK3β represses transcription of the GYS1 gene via two NF-κB binding sites in the promoter; overexpression of GSK3β decreases GYS1 mRNA and reduces p65 binding specifically to the second NF-κB site, as confirmed by ChIP assay.\",\n      \"method\": \"Promoter deletion reporter constructs in cell transfection; ChIP assay for p65 binding to NF-κB sites; GSK3β overexpression with qPCR\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay plus ChIP, two orthogonal methods, single lab on porcine GYS1\",\n      \"pmids\": [\"27785702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Basal GYS1 promoter activity resides in the first 250 nucleotides; the region -692 to -544 confers muscle-specific expression; the region -971 to -692 provides negative regulation; forskolin (cAMP elevation) decreases GYS1 promoter activity ~30% in myotubes; insulin treatment does not increase but slightly decreases GYS1 promoter activity.\",\n      \"method\": \"Promoter fragment luciferase reporter assays in C2C12 myoblasts/myotubes and HEK293 cells; pharmacological treatments with insulin and forskolin\",\n      \"journal\": \"European journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion series with luciferase in two cell types plus pharmacological perturbations, single lab\",\n      \"pmids\": [\"14764074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Gys1-ASO administered intracerebroventricularly to Epm2b-/- (Lafora disease) mice at 4, 7, and 10 months reduces Gys1 protein levels, decreases glycogen aggregation, and reduces epileptiform discharges, halting disease progression.\",\n      \"method\": \"Intracerebroventricular ASO administration in Epm2b-/- mice; Gys1 protein quantification; glycogen aggregation histology; electrophysiological recording of epileptiform discharges\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with molecular, histological, and electrophysiological readouts in established disease model\",\n      \"pmids\": [\"37700152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GYS1 is a nucleocytoplasmic shuttling protein that, under glycogen depletion or transcription inhibition, dynamically reorganizes into nuclear condensates via liquid-liquid phase separation with the transcription factor NONO/p54nrb; this nuclear retention inhibits glycogen biosynthesis. Nuclear GYS1 and NONO co-condense with MyoD and preinitiation complex proteins to form transcriptional condensates that drive myogenic gene expression; Gys1 or Nono deficiency prevents C2C12 myoblast differentiation and cardiotoxin-induced muscle regeneration in mice.\",\n      \"method\": \"Live cell imaging (nucleocytoplasmic shuttling, condensate formation); Co-IP; liquid-liquid phase separation assays; Gys1/Nono KO mice (glycogen quantification, muscle fiber size, exercise tolerance); C2C12 differentiation assays; cardiotoxin-induced muscle regeneration; ChIP-like co-condensation with MyoD and PIC proteins\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (LLPS, Co-IP, live imaging, KO mouse phenotypes, differentiation assays) in a single rigorous study\",\n      \"pmids\": [\"40200092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ovarian clear cell carcinoma, p53 promotes GYS1 degradation via upregulation of RNF144a (E3 ubiquitin ligase targeting GYS1), while GYS1 in turn stabilizes p53 by competitively binding to the deubiquitinase USP14, forming a positive feedback loop; under platinum stress, this circuit mobilizes glycogen to fuel NADPH production, causing resistance to disulfidptosis and platinum resistance.\",\n      \"method\": \"Mechanistic cell biology: GYS1 KD/OE in OCCC cells; ubiquitination assays; Co-IP for GYS1-USP14 competitive binding; RNF144a overexpression; metabolic NADPH measurements; platinum resistance assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional readouts, single lab, mechanistic circuit not independently replicated\",\n      \"pmids\": [\"40210982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Depletion of PTG (an activator of GYS1) in laforin- and malin-deficient Lafora disease mice demonstrates that abnormal glycogen chain lengths (not hyperphosphorylation) underlie polyglucosan formation, and that a small pool of overactive GYS1 contributes to glycogen insolubility in Lafora disease and adult polyglucosan body disease.\",\n      \"method\": \"Genetic PTG depletion in laforin-KO and malin-KO mice; glycogen chain length analysis; metabolomics on in situ-fixed brains; histological analysis of polyglucosan bodies and neuroinflammation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with biochemical glycogen chain-length analysis and metabolomics in multiple disease mouse models\",\n      \"pmids\": [\"39806098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIF-1α directly transcriptionally regulates GYS1, which encodes glycogen synthase; GYS1-mediated glycogen synthesis controls UDPG secretion, which activates P2Y14 receptor to promote M1 macrophage polarization and inflammation; knockdown of HIF-1α or GYS1 disrupts anti-inflammatory effects of the HIF-PHI MK8617.\",\n      \"method\": \"Lentiviral knockdown of HIF-1α and GYS1; qRT-PCR and Western blot for GYS1 and pathway components; ELISA for UDPG; pharmacological inhibition experiments\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral KD with molecular pathway readouts, single lab, mechanistic pathway placement supported by multiple markers\",\n      \"pmids\": [\"37404479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A CD71 Centyrin:Gys1 siRNA conjugate, upon binding TfR1 and internalization, reduces GYS1 protein expression and glycogen synthase enzymatic activity, decreases glycogen levels in muscle of a Pompe disease mouse model, and improves treadmill exercise performance.\",\n      \"method\": \"siRNA conjugate treatment in 6neo/6neo Pompe mice; GYS1 protein quantification; enzymatic activity assay; glycogen quantification; treadmill exercise testing\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — enzymatic activity assay plus protein/glycogen quantification and functional exercise readout in disease mouse model, single lab\",\n      \"pmids\": [\"39604266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, maternal gys1 is required for glycogen reserve in ovaries and embryos; gys1 knockout reduces glycogen content and free glucose levels in embryos by ~50%, impairs glucose uptake ability, and disrupts metabolites in vitamin B, carbohydrate, and unsaturated fatty acid pathways, demonstrating that gys1 is essential for maternal glycogen reserve supporting embryonic development.\",\n      \"method\": \"gys1 KO zebrafish (F3 generation); PAS staining; glycogen content measurement; free glucose measurement; 2-NBDG microinjection for glucose uptake; untargeted metabolomics\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in zebrafish with multiple biochemical and metabolomics readouts, single lab, ortholog study\",\n      \"pmids\": [\"38803914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-140-5p directly targets GYS1 (and PPP1CC) as confirmed by luciferase reporter assay; miR-140-5p overexpression reduces GYS1 and PPP1CC protein levels, decreases glycogen production, and impairs glucose consumption and uptake, aggravating insulin resistance in HepG2 cells.\",\n      \"method\": \"Bioinformatic target prediction; dual-luciferase reporter assay; Western blot and qPCR; glycogen detection; rescue experiments with GYS1/PPP1CC inhibition\",\n      \"journal\": \"Diabetes, metabolic syndrome and obesity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct miRNA targeting of GYS1 3'UTR, supported by protein-level knockdown and functional glycogen/glucose assays, single lab\",\n      \"pmids\": [\"34113143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GYS1 (skeletal muscle glycogen synthase 1) is a nucleocytoplasmic shuttling enzyme that catalyzes the rate-limiting step of glycogen chain elongation in muscle and brain; its activity is regulated by phosphorylation (with phosphorylated GYS1 associating with ribosomes), by transcriptional repression via GSK3β/NF-κB, by miR-140-5p-mediated mRNA targeting, and by HIF-1α-driven transcription; in the nucleus, GYS1 undergoes liquid-liquid phase separation with NONO/p54nrb and co-condenses with MyoD and preinitiation complex proteins to drive myogenic gene expression; gain-of-function mutations cause excess glycogen accumulation (polysaccharide storage myopathy), loss-of-function causes glycogen deficiency and insulin resistance, and overactivation of a GYS1 pool drives polyglucosan body formation and neurodegeneration in Lafora disease and adult polyglucosan body disease; GYS1 also participates in oncogenic signaling (via RPS27A/NF-κB in renal carcinoma and a p53/USP14/RNF144a feedback loop in ovarian carcinoma) and in macrophage inflammation through HIF-1α-regulated UDPG/P2Y14 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GYS1 catalyzes the rate-limiting elongation step of glycogen biosynthesis and serves as a central node coupling glucose storage to muscle physiology, neurodegenerative disease, and gene regulation [#1, #5]. Its glycogen-synthesizing function is essential in vivo: muscle-specific deletion in mice depletes muscle glycogen, causes postprandial hyperglycemia, peripheral insulin resistance, and impaired exercise capacity [#1], and maternal Gys1 is required for embryonic glycogen reserves [#16]. Dosage and activity of GYS1 are bidirectionally pathogenic — a gain-of-function missense mutation drives excess muscle glycogen accumulation (polysaccharide storage myopathy) [#0], while loss-of-function deletion causes glycogen synthase deficiency associated with sudden cardiac death [#2]. In the brain, GYS1-dependent synthesis is obligatory for the abnormal glycogen aggregates of Lafora disease and adult polyglucosan body disease: genetic ablation, antisense oligonucleotides, and CRISPR editing of Gys1 each reduce polyglucosan/Lafora body burden, neuroinflammation, and epileptiform activity [#5, #6, #7, #10], and depletion of the GYS1 activator PTG shows that a small pool of overactive GYS1 producing aberrant glycogen chain lengths underlies polyglucosan formation [#13]. Beyond enzymatic glycogen synthesis, GYS1 is a nucleocytoplasmic shuttling protein that, under glycogen depletion, undergoes liquid-liquid phase separation with NONO/p54nrb and co-condenses with MyoD and preinitiation complex proteins to drive myogenic gene expression and muscle regeneration [#11]. GYS1 expression and activity are controlled at multiple levels: transcriptional repression through GSK3\\u03b2 acting on NF-\\u03baB promoter sites [#8], HIF-1\\u03b1-driven transcription linking glycogen-derived UDPG to P2Y14 signaling and macrophage inflammation [#14], and direct mRNA targeting by miR-140-5p that lowers glycogen production and aggravates insulin resistance [#17]. GYS1 also participates in oncogenic circuits, promoting renal carcinoma growth via RPS27A-mediated NF-\\u03baB activation [#4] and forming a p53/USP14/RNF144a feedback loop that mobilizes glycogen-derived NADPH to confer platinum resistance in ovarian carcinoma [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that altered GYS1 activity is directly causal for a glycogen storage phenotype, showing a single gain-of-function missense mutation elevates glycogen synthase activity and accumulates muscle glycogen.\",\n      \"evidence\": \"DNA sequencing, GWAS mapping, and GS activity assays in affected vs. normal horses\",\n      \"pmids\": [\"18358695\", \"18691366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the structural basis of the gain-of-function\", \"Ortholog (equine) finding\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that GYS1 loss-of-function is pathogenic in humans, linking a homozygous deletion to muscle glycogen synthase deficiency and sudden cardiac death.\",\n      \"evidence\": \"DNA sequencing, family segregation, post-mortem and fibroblast biochemical analysis\",\n      \"pmids\": [\"19699667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case report without in vitro reconstitution\", \"Cardiac mechanism of death not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined GYS1's physiological role in glucose homeostasis by showing muscle glycogen synthesis is required for insulin sensitivity and exercise capacity in adult mammals.\",\n      \"evidence\": \"Inducible muscle-specific Gys1 knockout mice with clamps, glucose tolerance tests, and exercise testing\",\n      \"pmids\": [\"26977394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address GYS1 functions outside muscle\", \"Mechanism linking glycogen loss to reduced hexokinase II not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected phosphorylated GYS1 to the translation machinery, suggesting a non-canonical role coupling cellular energy state to protein biosynthesis.\",\n      \"evidence\": \"MudPIT proteomics on active vs. inactive ribosomes plus GYS1-depletion translation profiling\",\n      \"pmids\": [\"21570405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ribosome association incompletely defined\", \"Single lab, mechanism of recruitment unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified transcriptional control of GYS1 by GSK3\\u03b2 through NF-\\u03baB promoter sites, defining one input that sets GYS1 expression level.\",\n      \"evidence\": \"Promoter reporter constructs and ChIP for p65 binding with GSK3\\u03b2 overexpression (porcine GYS1)\",\n      \"pmids\": [\"27785702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog promoter study\", \"How this integrates with metabolic signaling unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established GYS1-dependent glycogen synthesis as required for polyglucosan body formation, validating GYS1 as a therapeutic target in adult polyglucosan body disease.\",\n      \"evidence\": \"Genetic cross of APBD mice with Gys1-KO; histology, glycogen quantification, neuromuscular assays\",\n      \"pmids\": [\"33034425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify which GYS1 pool drives aberrant glycogen\", \"Brain-cell-type specificity not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an oncogenic role for GYS1 in renal carcinoma, acting indirectly via RPS27A to activate NF-\\u03baB-driven proliferation and drug response.\",\n      \"evidence\": \"Co-IP/MS, RNA-seq, knockdown/overexpression, and xenograft models\",\n      \"pmids\": [\"32802186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GYS1-RPS27A interaction is indirect and from a single lab\", \"Whether enzymatic activity is required not separated from scaffolding role\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided therapeutic proof-of-concept that reducing GYS1 by antisense oligonucleotide or CRISPR editing prevents Lafora/polyglucosan body accumulation and neuroinflammation in the brain.\",\n      \"evidence\": \"Intracerebroventricular Gys1-ASO and AAV9-SaCas9 in multiple Lafora and APBD mouse models with histological and molecular readouts\",\n      \"pmids\": [\"33993268\", \"33830476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partial protein knockdown sufficient but optimal threshold unknown\", \"Long-term safety of GYS1 suppression in brain untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified miR-140-5p as a direct post-transcriptional regulator of GYS1, linking its downregulation to reduced glycogen production and insulin resistance.\",\n      \"evidence\": \"Dual-luciferase reporter, knockdown, glycogen and glucose-uptake assays in HepG2 cells\",\n      \"pmids\": [\"34113143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-line context\", \"In vivo relevance of the miRNA-GYS1 axis not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed GYS1 in inflammatory signaling, showing HIF-1\\u03b1-driven GYS1 controls glycogen-derived UDPG secretion that activates P2Y14 to promote M1 macrophage polarization.\",\n      \"evidence\": \"Lentiviral knockdown of HIF-1\\u03b1 and GYS1, UDPG ELISA, and pharmacological HIF-PHI experiments\",\n      \"pmids\": [\"37404479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab pathway placement\", \"In vivo inflammatory contribution of GYS1 not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended ASO efficacy to symptomatic timepoints, showing Gys1 reduction halts disease progression and reduces epileptiform discharges in Lafora mice.\",\n      \"evidence\": \"Intracerebroventricular Gys1-ASO in Epm2b-/- mice with electrophysiology and histology\",\n      \"pmids\": [\"37700152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reversal of established pathology not demonstrated\", \"Mechanism linking glycogen reduction to seizure suppression not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated GYS1-targeted siRNA conjugate delivery as a strategy to lower muscle glycogen and improve function in Pompe disease, broadening GYS1 as a substrate-reduction target.\",\n      \"evidence\": \"CD71 Centyrin:Gys1 siRNA conjugate in 6neo/6neo Pompe mice with activity, glycogen, and treadmill readouts\",\n      \"pmids\": [\"39604266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and off-tissue effects not fully characterized\", \"Single disease model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed an essential developmental role for GYS1, establishing maternal glycogen reserve dependence in zebrafish ovaries and embryos.\",\n      \"evidence\": \"gys1 knockout zebrafish with PAS staining, glycogen/glucose measurement, glucose-uptake assay, and metabolomics\",\n      \"pmids\": [\"38803914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog study; mammalian generality unknown\", \"Mechanism linking metabolite disruption to developmental defects not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the mechanism by which a small overactive GYS1 pool drives polyglucosan formation, showing abnormal glycogen chain length rather than hyperphosphorylation underlies insolubility.\",\n      \"evidence\": \"Genetic PTG depletion in laforin- and malin-KO mice with glycogen chain-length analysis and metabolomics\",\n      \"pmids\": [\"39806098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify what makes that GYS1 pool overactive\", \"Therapeutic strategy to selectively target the pool not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a moonlighting nuclear function for GYS1, showing it phase-separates with NONO and co-condenses with MyoD/PIC proteins to drive myogenic transcription and muscle regeneration.\",\n      \"evidence\": \"Live-cell imaging, LLPS assays, Co-IP, Gys1/Nono KO mice, and C2C12 differentiation/regeneration assays\",\n      \"pmids\": [\"40200092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How shuttling and condensation are signaled by glycogen state mechanistically incomplete\", \"Genome-wide targets of GYS1-NONO condensates not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a GYS1-centered p53/USP14/RNF144a feedback loop that mobilizes glycogen-derived NADPH to confer platinum and disulfidptosis resistance in ovarian carcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, RNF144a overexpression, NADPH measurement, and platinum resistance assays in OCCC cells\",\n      \"pmids\": [\"40210982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Circuit from a single lab, not independently replicated\", \"In vivo validation of the resistance mechanism limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the distinct GYS1 pools — cytoplasmic glycogen-synthesizing, ribosome-associated, and nuclear phase-separating — are partitioned and signaled, and how the overactive disease-driving pool is mechanistically generated.\",\n      \"evidence\": \"No single study integrates GYS1 subcellular pools, their regulation, and their disease-specific activities\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model of GYS1 pool partitioning\", \"Structural basis of activity regulation across pools undefined\", \"Selective targeting of pathogenic pool not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"GYS1-NONO nuclear transcriptional condensate\"],\n    \"partners\": [\"NONO\", \"MyoD\", \"RPS27A\", \"USP14\", \"RNF144a\", \"PPP1CC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}