{"gene":"EPM2AIP1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2003,"finding":"EPM2AIP1 protein was identified as a direct binding partner of laforin (EPM2A gene product) through a yeast two-hybrid screen of a human brain cDNA library, confirmed by coimmunoprecipitation of in vivo-transfected protein. Interaction specificity was validated using EPM2A deletion constructs. EPM2AIP1 and laforin also show subcellular colocalization.","method":"Yeast two-hybrid screen, coimmunoprecipitation of transfected proteins, EPM2A deletion construct analysis, subcellular colocalization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and yeast two-hybrid with deletion constructs, single lab, two orthogonal methods","pmids":["12782127"],"is_preprint":false},{"year":2004,"finding":"EPM2AIP1 protein localizes on polyglucosan masses (Lafora bodies) in vivo, as demonstrated by immunogold electron microscopy and colocalization studies in a laforin-trap transgenic mouse model.","method":"Immunogold electron microscopy, transgenic mouse model with laforin trap, colocalization on Lafora bodies","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunogold EM in a mouse model, single lab, single method but with rigorous controls","pmids":["15102711"],"is_preprint":false},{"year":2013,"finding":"Epm2aip1 is a glycogen synthase (GS)-associated protein. Absence of Epm2aip1 in mice impairs allosteric activation of GS by glucose 6-phosphate, decreases hepatic glycogen synthesis, increases liver fat, causes hepatic insulin resistance, and protects against age-related obesity.","method":"Epm2aip1 knockout mouse model, GS activity assays (allosteric activation by glucose 6-phosphate), hepatic glycogen measurement, metabolic phenotyping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined biochemical readout (GS allosteric activation), multiple phenotypic endpoints measured, mechanistic pathway placement established","pmids":["24142699"],"is_preprint":false},{"year":2010,"finding":"The MLH1-93G>A promoter polymorphism bidirectionally affects transcription from the shared MLH1/EPM2AIP1 promoter: the -93G allele drives higher MLH1 promoter activity, while the -93A allele drives higher EPM2AIP1 promoter activity. EMSAs indicate the polymorphism alters the affinity of nuclear protein factors binding to this region.","method":"Luciferase reporter assays with MLH1/EPM2AIP1 promoter constructs in forward and reverse orientation, electrophoretic mobility shift assay (EMSA)","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional promoter assay in multiple cell lines with EMSA, single lab, two orthogonal methods","pmids":["21206982"],"is_preprint":false},{"year":2022,"finding":"MLH1 promoter methylation silences EPM2AIP1 protein expression (nuclear EPM2AIP1 loss detected by IHC in 81.8% of methylated endometrial tumors with 94.5% sensitivity), establishing that the shared MLH1/EPM2AIP1 bidirectional promoter methylation coordinately suppresses both genes' expression.","method":"Immunohistochemistry for EPM2AIP1 protein, correlated with MLH1 promoter methylation testing by quantitative PCR in 119 endometrial carcinoma cases","journal":"The American journal of surgical pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — IHC-based protein expression correlated with methylation across large case series (n=119), replicated in a second study (PMID:40468018), no in vitro mechanistic dissection","pmids":["34772843","40468018"],"is_preprint":false}],"current_model":"EPM2AIP1 encodes a protein that physically interacts with laforin (EPM2A) and co-localizes with polyglucosan (Lafora body) masses, and functions as a glycogen synthase-associated protein that modulates allosteric activation of glycogen synthase by glucose 6-phosphate — its absence impairs hepatic glycogen synthesis and causes insulin resistance; additionally, EPM2AIP1 expression is co-regulated with MLH1 through a shared bidirectional promoter whose methylation or polymorphic variation coordinately silences both genes."},"narrative":{"mechanistic_narrative":"EPM2AIP1 is a glycogen synthase-associated protein that links the laforin-dependent regulation of glycogen metabolism to whole-body energy homeostasis [PMID:12782127, PMID:24142699]. It was first identified as a direct binding partner of laforin (the EPM2A gene product) and colocalizes with laforin in cells and on polyglucosan masses (Lafora bodies) in vivo [PMID:12782127, PMID:15102711]. Functionally, EPM2AIP1 modulates the allosteric activation of glycogen synthase by glucose 6-phosphate; in its absence, hepatic glycogen synthesis is reduced, liver fat increases, and animals develop hepatic insulin resistance while being protected from age-related obesity [PMID:24142699]. Independently of its metabolic role, EPM2AIP1 is transcribed from a bidirectional promoter shared with MLH1, such that a -93G>A promoter polymorphism reciprocally apportions transcriptional activity between the two genes by altering nuclear-factor binding [PMID:21206982], and methylation of this shared promoter coordinately silences both MLH1 and EPM2AIP1 protein expression in endometrial carcinoma [PMID:34772843, PMID:40468018].","teleology":[{"year":2003,"claim":"Established the first molecular partner of EPM2AIP1, placing it within the laforin signaling/glycogen-disease axis rather than as an orphan protein.","evidence":"Yeast two-hybrid screen of human brain cDNA, coimmunoprecipitation of transfected proteins, and EPM2A deletion-construct mapping with subcellular colocalization","pmids":["12782127"],"confidence":"Medium","gaps":["Interaction shown for transfected/overexpressed proteins, not at endogenous levels","Functional consequence of the laforin-EPM2AIP1 interaction not defined","Binding interface on EPM2AIP1 not mapped"]},{"year":2004,"claim":"Demonstrated where EPM2AIP1 acts in disease tissue by localizing it directly on polyglucosan inclusions, connecting it physically to the pathological substrate of Lafora disease.","evidence":"Immunogold electron microscopy and colocalization in a laforin-trap transgenic mouse model","pmids":["15102711"],"confidence":"Medium","gaps":["Does not establish whether EPM2AIP1 contributes to Lafora body formation or is recruited passively","Single localization method in a transgenic trap model","No human tissue confirmation in this finding"]},{"year":2013,"claim":"Resolved the biochemical function of EPM2AIP1 by showing it tunes allosteric activation of glycogen synthase, defining a concrete role in hepatic glycogen synthesis and insulin sensitivity.","evidence":"Epm2aip1 knockout mouse with glycogen synthase activity assays, hepatic glycogen measurement, and metabolic phenotyping","pmids":["24142699"],"confidence":"High","gaps":["Whether EPM2AIP1 binds glycogen synthase directly or acts through laforin is unresolved","Structural basis for modulating glucose 6-phosphate allostery unknown","Tissue specificity beyond liver not fully characterized"]},{"year":2010,"claim":"Showed that EPM2AIP1 expression is genetically coupled to MLH1 via a shared bidirectional promoter, explaining co-regulation of two functionally unrelated genes.","evidence":"Bidirectional luciferase reporter assays of the MLH1/EPM2AIP1 promoter and EMSA across cell lines","pmids":["21206982"],"confidence":"Medium","gaps":["Identity of the polymorphism-sensitive nuclear factors not determined","In vivo relevance of allele-specific apportioning not established","No link between this regulation and EPM2AIP1's metabolic function"]},{"year":2022,"claim":"Demonstrated that promoter methylation coordinately silences EPM2AIP1 with MLH1, making EPM2AIP1 protein loss a correlate of MLH1 epigenetic inactivation in tumors.","evidence":"Immunohistochemistry for EPM2AIP1 correlated with MLH1 promoter methylation by qPCR across 119 endometrial carcinomas, replicated in a second series","pmids":["34772843","40468018"],"confidence":"Medium","gaps":["Correlative IHC/methylation data without in vitro mechanistic dissection","Functional consequence of EPM2AIP1 loss in tumor cells not tested","Whether EPM2AIP1 silencing contributes to tumorigenesis or is a bystander is unknown"]},{"year":null,"claim":"How EPM2AIP1's two distinct contexts — glycogen synthase regulation/laforin binding versus MLH1-coupled transcriptional regulation — relate mechanistically, and whether EPM2AIP1 has an independent function in either, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure or domain-level mechanism for any EPM2AIP1 activity","No demonstration of direct glycogen synthase binding","No causal role established for EPM2AIP1 loss in cancer phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]}],"complexes":[],"partners":["EPM2A","MLH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L775","full_name":"EPM2A-interacting protein 1","aliases":["Laforin-interacting protein"],"length_aa":607,"mass_kda":70.4,"function":"","subcellular_location":"Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q7L775/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPM2AIP1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EPM2AIP1","total_profiled":1310},"omim":[{"mim_id":"607911","title":"EPM2A-INTERACTING PROTEIN 1; EPM2AIP1","url":"https://www.omim.org/entry/607911"},{"mim_id":"607566","title":"EPM2A GLUCAN PHOSPHATASE, LAFORIN; EPM2A","url":"https://www.omim.org/entry/607566"}],"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/EPM2AIP1"},"hgnc":{"alias_symbol":["KIAA0766","FLJ11207"],"prev_symbol":[]},"alphafold":{"accession":"Q7L775","domains":[{"cath_id":"-","chopping":"21-84","consensus_level":"high","plddt":82.052,"start":21,"end":84},{"cath_id":"-","chopping":"93-280_500-607","consensus_level":"medium","plddt":88.9941,"start":93,"end":607},{"cath_id":"-","chopping":"287-478","consensus_level":"high","plddt":85.3433,"start":287,"end":478}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L775","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L775-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L775-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPM2AIP1","jax_strain_url":"https://www.jax.org/strain/search?query=EPM2AIP1"},"sequence":{"accession":"Q7L775","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L775.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L775/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L775"}},"corpus_meta":[{"pmid":"16285940","id":"PMC_16285940","title":"MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer.","date":"2005","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16285940","citation_count":138,"is_preprint":false},{"pmid":"15102711","id":"PMC_15102711","title":"Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15102711","citation_count":80,"is_preprint":false},{"pmid":"24105770","id":"PMC_24105770","title":"Multiplex mapping of chromatin accessibility and DNA methylation within targeted single molecules identifies epigenetic heterogeneity in neural stem cells and glioblastoma.","date":"2013","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/24105770","citation_count":43,"is_preprint":false},{"pmid":"22763379","id":"PMC_22763379","title":"MLH1 methylation screening is effective in identifying epimutation carriers.","date":"2012","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/22763379","citation_count":34,"is_preprint":false},{"pmid":"12782127","id":"PMC_12782127","title":"Identification of a novel protein interacting with laforin, the EPM2a progressive myoclonus epilepsy gene product.","date":"2003","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/12782127","citation_count":33,"is_preprint":false},{"pmid":"21206982","id":"PMC_21206982","title":"Functional effects of the MLH1-93G>A polymorphism on MLH1/EPM2AIP1 promoter activity.","date":"2010","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21206982","citation_count":28,"is_preprint":false},{"pmid":"31200767","id":"PMC_31200767","title":"DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas.","date":"2019","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/31200767","citation_count":21,"is_preprint":false},{"pmid":"24142699","id":"PMC_24142699","title":"Deficiency of a glycogen synthase-associated protein, Epm2aip1, causes decreased glycogen synthesis and hepatic insulin resistance.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24142699","citation_count":19,"is_preprint":false},{"pmid":"17573221","id":"PMC_17573221","title":"Altered DNA copy number in patients with different seizure disorder type: by array-CGH.","date":"2007","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/17573221","citation_count":18,"is_preprint":false},{"pmid":"34772843","id":"PMC_34772843","title":"EPM2AIP1 Immunohistochemistry Can Be Used as Surrogate Testing for MLH1 Promoter Methylation in Endometrial Cancer.","date":"2022","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34772843","citation_count":10,"is_preprint":false},{"pmid":"37833839","id":"PMC_37833839","title":"MSI-XGNN: an explainable GNN computational framework integrating transcription- and methylation-level biomarkers for microsatellite instability detection.","date":"2023","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/37833839","citation_count":10,"is_preprint":false},{"pmid":"37848431","id":"PMC_37848431","title":"The admixed brushtail possum genome reveals invasion history in New Zealand and novel imprinted genes.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37848431","citation_count":8,"is_preprint":false},{"pmid":"35455641","id":"PMC_35455641","title":"WGCNA-Based DNA Methylation Profiling Analysis on Allopurinol-Induced Severe Cutaneous Adverse Reactions: A DNA Methylation Signature for Predisposing Drug Hypersensitivity.","date":"2022","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35455641","citation_count":6,"is_preprint":false},{"pmid":"35976509","id":"PMC_35976509","title":"Transcriptome analysis of peripheral blood mononuclear cells in patients with type 1 diabetes mellitus.","date":"2022","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/35976509","citation_count":5,"is_preprint":false},{"pmid":"21480884","id":"PMC_21480884","title":"A new locus for autosomal dominant generalized epilepsy associated with mild mental retardation on chromosome 3p.","date":"2011","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/21480884","citation_count":5,"is_preprint":false},{"pmid":"40468018","id":"PMC_40468018","title":"EPM2 AIP1 immunohistochemistry as a surrogate of promoter methylation analysis in endometrial carcinoma.","date":"2025","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40468018","citation_count":4,"is_preprint":false},{"pmid":"38945374","id":"PMC_38945374","title":"EPM2AIP1 immunohistochemistry is inadequate as a surrogate marker for MLH1 promoter hypermethylation testing in colorectal cancer.","date":"2024","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38945374","citation_count":3,"is_preprint":false},{"pmid":"42136687","id":"PMC_42136687","title":"Exceptional Response to Lenvatinib plus Pembrolizumab after Pembrolizumab Failure in MLH1-Methylated Deficient Mismatch Repair/Microsatellite Instability-High Endometrial Cancer: A Case Report.","date":"2026","source":"Case reports in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42136687","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11760,"output_tokens":1335,"usd":0.027652,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8018,"output_tokens":2187,"usd":0.047383,"stage2_stop_reason":"end_turn"},"total_usd":0.075035,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"EPM2AIP1 protein was identified as a direct binding partner of laforin (EPM2A gene product) through a yeast two-hybrid screen of a human brain cDNA library, confirmed by coimmunoprecipitation of in vivo-transfected protein. Interaction specificity was validated using EPM2A deletion constructs. EPM2AIP1 and laforin also show subcellular colocalization.\",\n      \"method\": \"Yeast two-hybrid screen, coimmunoprecipitation of transfected proteins, EPM2A deletion construct analysis, subcellular colocalization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and yeast two-hybrid with deletion constructs, single lab, two orthogonal methods\",\n      \"pmids\": [\"12782127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EPM2AIP1 protein localizes on polyglucosan masses (Lafora bodies) in vivo, as demonstrated by immunogold electron microscopy and colocalization studies in a laforin-trap transgenic mouse model.\",\n      \"method\": \"Immunogold electron microscopy, transgenic mouse model with laforin trap, colocalization on Lafora bodies\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunogold EM in a mouse model, single lab, single method but with rigorous controls\",\n      \"pmids\": [\"15102711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Epm2aip1 is a glycogen synthase (GS)-associated protein. Absence of Epm2aip1 in mice impairs allosteric activation of GS by glucose 6-phosphate, decreases hepatic glycogen synthesis, increases liver fat, causes hepatic insulin resistance, and protects against age-related obesity.\",\n      \"method\": \"Epm2aip1 knockout mouse model, GS activity assays (allosteric activation by glucose 6-phosphate), hepatic glycogen measurement, metabolic phenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined biochemical readout (GS allosteric activation), multiple phenotypic endpoints measured, mechanistic pathway placement established\",\n      \"pmids\": [\"24142699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The MLH1-93G>A promoter polymorphism bidirectionally affects transcription from the shared MLH1/EPM2AIP1 promoter: the -93G allele drives higher MLH1 promoter activity, while the -93A allele drives higher EPM2AIP1 promoter activity. EMSAs indicate the polymorphism alters the affinity of nuclear protein factors binding to this region.\",\n      \"method\": \"Luciferase reporter assays with MLH1/EPM2AIP1 promoter constructs in forward and reverse orientation, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional promoter assay in multiple cell lines with EMSA, single lab, two orthogonal methods\",\n      \"pmids\": [\"21206982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MLH1 promoter methylation silences EPM2AIP1 protein expression (nuclear EPM2AIP1 loss detected by IHC in 81.8% of methylated endometrial tumors with 94.5% sensitivity), establishing that the shared MLH1/EPM2AIP1 bidirectional promoter methylation coordinately suppresses both genes' expression.\",\n      \"method\": \"Immunohistochemistry for EPM2AIP1 protein, correlated with MLH1 promoter methylation testing by quantitative PCR in 119 endometrial carcinoma cases\",\n      \"journal\": \"The American journal of surgical pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — IHC-based protein expression correlated with methylation across large case series (n=119), replicated in a second study (PMID:40468018), no in vitro mechanistic dissection\",\n      \"pmids\": [\"34772843\", \"40468018\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPM2AIP1 encodes a protein that physically interacts with laforin (EPM2A) and co-localizes with polyglucosan (Lafora body) masses, and functions as a glycogen synthase-associated protein that modulates allosteric activation of glycogen synthase by glucose 6-phosphate — its absence impairs hepatic glycogen synthesis and causes insulin resistance; additionally, EPM2AIP1 expression is co-regulated with MLH1 through a shared bidirectional promoter whose methylation or polymorphic variation coordinately silences both genes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPM2AIP1 is a glycogen synthase-associated protein that links the laforin-dependent regulation of glycogen metabolism to whole-body energy homeostasis [#0, #2]. It was first identified as a direct binding partner of laforin (the EPM2A gene product) and colocalizes with laforin in cells and on polyglucosan masses (Lafora bodies) in vivo [#0, #1]. Functionally, EPM2AIP1 modulates the allosteric activation of glycogen synthase by glucose 6-phosphate; in its absence, hepatic glycogen synthesis is reduced, liver fat increases, and animals develop hepatic insulin resistance while being protected from age-related obesity [#2]. Independently of its metabolic role, EPM2AIP1 is transcribed from a bidirectional promoter shared with MLH1, such that a -93G>A promoter polymorphism reciprocally apportions transcriptional activity between the two genes by altering nuclear-factor binding [#3], and methylation of this shared promoter coordinately silences both MLH1 and EPM2AIP1 protein expression in endometrial carcinoma [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first molecular partner of EPM2AIP1, placing it within the laforin signaling/glycogen-disease axis rather than as an orphan protein.\",\n      \"evidence\": \"Yeast two-hybrid screen of human brain cDNA, coimmunoprecipitation of transfected proteins, and EPM2A deletion-construct mapping with subcellular colocalization\",\n      \"pmids\": [\"12782127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction shown for transfected/overexpressed proteins, not at endogenous levels\",\n        \"Functional consequence of the laforin-EPM2AIP1 interaction not defined\",\n        \"Binding interface on EPM2AIP1 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated where EPM2AIP1 acts in disease tissue by localizing it directly on polyglucosan inclusions, connecting it physically to the pathological substrate of Lafora disease.\",\n      \"evidence\": \"Immunogold electron microscopy and colocalization in a laforin-trap transgenic mouse model\",\n      \"pmids\": [\"15102711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not establish whether EPM2AIP1 contributes to Lafora body formation or is recruited passively\",\n        \"Single localization method in a transgenic trap model\",\n        \"No human tissue confirmation in this finding\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the biochemical function of EPM2AIP1 by showing it tunes allosteric activation of glycogen synthase, defining a concrete role in hepatic glycogen synthesis and insulin sensitivity.\",\n      \"evidence\": \"Epm2aip1 knockout mouse with glycogen synthase activity assays, hepatic glycogen measurement, and metabolic phenotyping\",\n      \"pmids\": [\"24142699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether EPM2AIP1 binds glycogen synthase directly or acts through laforin is unresolved\",\n        \"Structural basis for modulating glucose 6-phosphate allostery unknown\",\n        \"Tissue specificity beyond liver not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that EPM2AIP1 expression is genetically coupled to MLH1 via a shared bidirectional promoter, explaining co-regulation of two functionally unrelated genes.\",\n      \"evidence\": \"Bidirectional luciferase reporter assays of the MLH1/EPM2AIP1 promoter and EMSA across cell lines\",\n      \"pmids\": [\"21206982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the polymorphism-sensitive nuclear factors not determined\",\n        \"In vivo relevance of allele-specific apportioning not established\",\n        \"No link between this regulation and EPM2AIP1's metabolic function\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that promoter methylation coordinately silences EPM2AIP1 with MLH1, making EPM2AIP1 protein loss a correlate of MLH1 epigenetic inactivation in tumors.\",\n      \"evidence\": \"Immunohistochemistry for EPM2AIP1 correlated with MLH1 promoter methylation by qPCR across 119 endometrial carcinomas, replicated in a second series\",\n      \"pmids\": [\"34772843\", \"40468018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlative IHC/methylation data without in vitro mechanistic dissection\",\n        \"Functional consequence of EPM2AIP1 loss in tumor cells not tested\",\n        \"Whether EPM2AIP1 silencing contributes to tumorigenesis or is a bystander is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EPM2AIP1's two distinct contexts — glycogen synthase regulation/laforin binding versus MLH1-coupled transcriptional regulation — relate mechanistically, and whether EPM2AIP1 has an independent function in either, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure or domain-level mechanism for any EPM2AIP1 activity\",\n        \"No demonstration of direct glycogen synthase binding\",\n        \"No causal role established for EPM2AIP1 loss in cancer phenotypes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EPM2A\", \"MLH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}