{"gene":"RBM12","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2017,"finding":"Truncating mutations in RBM12 (nonsense mutation c.2377G>T producing a protein lacking a predicted RNA-recognition motif, and frameshift c.2532delT) segregate with psychosis in Icelandic and Finnish kindreds, establishing that loss of a functional RRM domain is genetically linked to schizophrenia/psychotic disorder with high penetrance.","method":"Whole-genome sequencing, long-range phasing, family-based genetic analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics with replication in two independent families, but no direct biochemical mechanistic assay performed in this paper","pmids":["28628109"],"is_preprint":false},{"year":2008,"finding":"RBM12 and CPNE1 share the same promoter and 5' exons in human, mouse, and zebrafish; co-expression of both genes from this shared promoter was confirmed by RT-PCR across multiple tissues, indicating coordinated transcriptional regulation.","method":"Genome-wide analysis of alternative splicing, RT-PCR in human and mouse tissues, comparative genomics","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct RT-PCR confirmation of co-expression from shared promoter across multiple tissues and species, single lab but multiple organisms","pmids":["18831769"],"is_preprint":false},{"year":2022,"finding":"RBM12 acts as a suppressor of fetal hemoglobin (HbF) expression in erythroid cells. CRISPR/Cas9-based screen identified RBM12; its depletion induced HbF and reduced cell sickling in SCD-derived erythroid cells. eCLIP-seq showed strong preferential binding of RBM12 to 5' UTRs of transcripts. The first of five RRM domains, together with a linker domain, is essential and sufficient for HbF regulation. RBM12 functions independently of known HbF regulators BCL11A and ZBTB7A/LRF.","method":"CRISPR/Cas9 screen, RBM12 knockdown/depletion, eCLIP-seq, transcriptome and proteome profiling, domain mutagenesis","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CRISPR screen, eCLIP, proteome, domain mutagenesis) in a single rigorous study with functional validation","pmids":["35622975"],"is_preprint":false},{"year":2023,"finding":"RBM12 is a repressor of the GPCR/cAMP/PKA signaling axis. Loss of RBM12 in HEK293 cells and iPSC-derived neurons leads to hyperactive cAMP production and increased PKA activity, as well as altered neuronal transcriptional responses to GPCR stimulation. RBM12 depletion alters expression of adenylyl cyclases, phosphodiesterase isoforms, and PKA regulatory and catalytic subunits. The two psychosis-linked truncating RBM12 variants fail to rescue GPCR/cAMP signaling hyperactivity, directly linking the loss-of-function mutations to this pathway.","method":"RBM12 knockdown in HEK293 cells and iPSC-derived neurons, cAMP assays, PKA activity assays, transcriptional reporter assays, rescue experiments with psychosis-linked truncating mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (cAMP, PKA, transcriptional), two cell models, disease-variant rescue experiments in a single rigorous study","pmids":["37543364"],"is_preprint":false},{"year":2023,"finding":"RBM12 (preprint version of the JBC paper) delineated as a repressor of GPCR/cAMP/PKA signaling; loss of RBM12 causes hyperactive cAMP and PKA activity, altered gene expression of pathway effectors, and the two familial psychosis truncating mutants fail to rescue hyperactivity.","method":"RBM12 knockdown, cAMP assay, PKA activity assay, transcriptional assays, mutant rescue in HEK293 and iPSC neurons","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint; same findings as peer-reviewed version (PMID 37543364), included for completeness but superseded by the published paper","pmids":["36711667"],"is_preprint":true},{"year":2024,"finding":"RBM12 drives PD-L1-mediated immune evasion in hepatocellular carcinoma by directly binding JAK1 mRNA via its 4th RRM domain and recruiting EIF4A2 through its 2nd RRM domain, thereby enhancing ribosome loading on JAK1 mRNA and promoting JAK1 translation; elevated JAK1 then activates JAK1/STAT1 signaling to transcriptionally upregulate PD-L1.","method":"Molecular binding assays (RBM12–JAK1 mRNA interaction), domain mapping (4th-RRM and 2nd-RRM), ribosome profiling/polysome analysis, EIF4A2 co-immunoprecipitation, JAK1/STAT1 pathway reporter assays, loss-of-function experiments in HCC cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-binding domain mapping, ribosome distribution assay, Co-IP for EIF4A2 recruitment, pathway readout) in a single rigorous study","pmids":["39187545"],"is_preprint":false},{"year":2023,"finding":"RBM12 promotes HCC cell proliferation, migration, invasion, and inhibits apoptosis, and induces EMT by secreting TGF-β1. CPNE1 was identified as a downstream gene regulated by RBM12. miR-497-5p directly targets and suppresses RBM12 (validated by dual-luciferase reporter assay), placing RBM12 in a miR-497-5p/RBM12/CPNE1 regulatory axis in liver cancer cells.","method":"Cytological assays (CCK8, colony formation, Transwell), dual-luciferase reporter assay for miR-497-5p–RBM12 interaction, RBM12 knockdown/overexpression, CPNE1 downstream analysis","journal":"Environmental research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — dual-luciferase validation of miRNA–RBM12 interaction and downstream CPNE1 link, multiple functional assays, single lab","pmids":["37793588"],"is_preprint":false},{"year":2025,"finding":"Rare predicted loss-of-function variants in RBM12 are associated with increased risk of coronary, cerebrovascular, and peripheral vascular atherosclerotic diseases in a large exome-wide association study, independent of traditional cardiovascular risk factors.","method":"Exome-wide association study in 434,438 UK Biobank participants","journal":"Circulation. Genomic and precision medicine","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — large-scale genetic association; no direct mechanistic experiment performed on RBM12 protein in this study","pmids":["41190437"],"is_preprint":false}],"current_model":"RBM12 is an RNA-binding protein containing five RRM domains that functions as a multi-context regulator: it suppresses fetal hemoglobin expression in erythroid cells by binding 5' UTRs of target mRNAs (requiring RRM1 and a linker domain); it promotes JAK1 mRNA translation in hepatocellular carcinoma by binding JAK1 mRNA via its 4th RRM and recruiting EIF4A2 via its 2nd RRM, thereby activating JAK1/STAT1/PD-L1 immune evasion; and it represses GPCR/cAMP/PKA signaling in neurons by regulating the expression of adenylyl cyclases, phosphodiesterases, and PKA subunits—a function disrupted by the two familial psychosis-associated truncating mutations."},"narrative":{"mechanistic_narrative":"RBM12 is a five-RRM RNA-binding protein that acts as a context-dependent post-transcriptional regulator, controlling target gene expression through direct binding of mRNA features and recruitment of translation machinery [PMID:35622975, PMID:39187545]. In erythroid cells it binds preferentially to 5' UTRs of transcripts and suppresses fetal hemoglobin expression, a function that requires its first RRM together with an adjacent linker domain and operates independently of the canonical HbF regulators BCL11A and ZBTB7A/LRF [PMID:35622975]. In hepatocellular carcinoma it binds JAK1 mRNA via its fourth RRM and recruits the translation factor EIF4A2 through its second RRM, increasing ribosome loading and JAK1 translation; the resulting JAK1/STAT1 signaling transcriptionally upregulates PD-L1 to drive immune evasion, and RBM12 also promotes HCC proliferation, invasion, and EMT within a miR-497-5p/RBM12/CPNE1 axis [PMID:39187545, PMID:37793588]. In neurons and HEK293 cells RBM12 represses the GPCR/cAMP/PKA signaling axis by setting the expression of adenylyl cyclases, phosphodiesterases, and PKA subunits, such that its loss yields hyperactive cAMP production and PKA activity [PMID:37543364]. Truncating mutations that remove an RRM segregate with psychosis in familial kindreds and fail to rescue this cAMP/PKA hyperactivity, directly linking RBM12 loss-of-function to psychotic disorder [PMID:28628109, PMID:37543364].","teleology":[{"year":2008,"claim":"Established that RBM12 is transcriptionally coupled to a neighboring gene, raising the possibility of coordinated regulation before any molecular function was known.","evidence":"Comparative genomics and RT-PCR showing shared promoter and 5' exons with CPNE1 across human, mouse, and zebrafish tissues","pmids":["18831769"],"confidence":"Medium","gaps":["Does not establish any biochemical or RNA-binding function of the RBM12 protein","Functional consequence of shared CPNE1 promoter unresolved"]},{"year":2017,"claim":"Answered whether RBM12 has a defined disease role by linking RRM-truncating loss-of-function to a heritable phenotype, motivating mechanistic work.","evidence":"Whole-genome sequencing and family-based genetic analysis of psychosis kindreds identifying nonsense and frameshift mutations","pmids":["28628109"],"confidence":"Medium","gaps":["No biochemical assay of the protein in this study","Molecular pathway through which truncation causes psychosis unidentified"]},{"year":2022,"claim":"Defined the first molecular activity of RBM12 — sequence-specific mRNA binding to 5' UTRs — and a functional output, suppression of fetal hemoglobin, localizing activity to RRM1 plus a linker.","evidence":"CRISPR screen, depletion, eCLIP-seq, proteome profiling and domain mutagenesis in SCD-derived erythroid cells","pmids":["35622975"],"confidence":"High","gaps":["Mechanism by which 5' UTR binding suppresses HbF (translation vs. stability) not resolved","Direct target transcripts driving the phenotype not fully enumerated"]},{"year":2023,"claim":"Connected RBM12 loss-of-function to a signaling pathway and to the disease variants by showing it represses GPCR/cAMP/PKA signaling and that psychosis-linked truncations cannot rescue.","evidence":"Knockdown in HEK293 and iPSC-derived neurons, cAMP and PKA activity assays, transcriptional reporters, and disease-variant rescue experiments","pmids":["37543364","36711667"],"confidence":"High","gaps":["Direct mRNA targets among adenylyl cyclase/PDE/PKA effectors not mapped by binding data","Whether regulation is via the same 5' UTR-binding mode as in erythroid cells unknown"]},{"year":2023,"claim":"Extended RBM12 to cancer biology, showing pro-tumorigenic activity and placing it in a miRNA-controlled regulatory axis.","evidence":"Proliferation/migration/invasion assays, dual-luciferase validation of miR-497-5p targeting, and CPNE1 downstream analysis in HCC cells","pmids":["37793588"],"confidence":"Medium","gaps":["Mechanism linking RBM12 to CPNE1 and TGF-β1 secretion not biochemically defined","Single-lab functional study"]},{"year":2024,"claim":"Resolved a direct molecular mechanism by mapping distinct RRMs to mRNA binding and translation-factor recruitment, explaining how RBM12 drives JAK1/STAT1/PD-L1 immune evasion.","evidence":"RNA-binding domain mapping (RRM4 to JAK1 mRNA, RRM2 to EIF4A2), polysome/ribosome profiling, EIF4A2 Co-IP, and JAK1/STAT1 pathway readouts in HCC cells","pmids":["39187545"],"confidence":"High","gaps":["Whether the EIF4A2-recruitment mechanism operates at the 5' UTR targets seen in erythroid and neuronal contexts is untested","Structural basis of RRM-specific mRNA and EIF4A2 contacts not determined"]},{"year":2025,"claim":"Broadened the disease landscape by associating RBM12 loss-of-function with atherosclerotic vascular disease, though without a mechanism.","evidence":"Exome-wide association study in 434,438 UK Biobank participants","pmids":["41190437"],"confidence":"Low","gaps":["No mechanistic experiment performed on RBM12 in vascular tissue","Causal pathway linking RBM12 loss to atherosclerosis unknown"]},{"year":null,"claim":"It remains unknown whether RBM12's distinct context-specific outputs (HbF suppression, GPCR/cAMP/PKA repression, JAK1 translational activation) reflect a single unifying biochemical mechanism operating on different targets.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified target map across cell types","No structural model relating the five RRMs to their respective functions","Mechanistic basis of atherosclerosis association uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,5]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]}],"complexes":[],"partners":["EIF4A2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NTZ6","full_name":"RNA-binding protein 12","aliases":["RNA-binding motif protein 12","SH3/WW domain anchor protein in the nucleus","SWAN"],"length_aa":932,"mass_kda":97.4,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NTZ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM12","classification":"Not 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SCZD","url":"https://www.omim.org/entry/181500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM12"},"hgnc":{"alias_symbol":["HRIHFB2091","KIAA0765","SWAN"],"prev_symbol":[]},"alphafold":{"accession":"Q9NTZ6","domains":[{"cath_id":"3.30.70.330","chopping":"2-91","consensus_level":"high","plddt":90.4271,"start":2,"end":91},{"cath_id":"3.30.70.330","chopping":"301-384","consensus_level":"high","plddt":88.0512,"start":301,"end":384},{"cath_id":"3.30.70.330","chopping":"430-522","consensus_level":"high","plddt":88.2453,"start":430,"end":522},{"cath_id":"3.30.70.330","chopping":"544-628","consensus_level":"high","plddt":88.0966,"start":544,"end":628},{"cath_id":"3.30.70.330","chopping":"855-930","consensus_level":"high","plddt":88.2929,"start":855,"end":930}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTZ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTZ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTZ6-F1-predicted_aligned_error_v6.png","plddt_mean":64.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM12","jax_strain_url":"https://www.jax.org/strain/search?query=RBM12"},"sequence":{"accession":"Q9NTZ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NTZ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NTZ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTZ6"}},"corpus_meta":[{"pmid":"22703947","id":"PMC_22703947","title":"SWAN: 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CRISPR/Cas9-based screen identified RBM12; its depletion induced HbF and reduced cell sickling in SCD-derived erythroid cells. eCLIP-seq showed strong preferential binding of RBM12 to 5' UTRs of transcripts. The first of five RRM domains, together with a linker domain, is essential and sufficient for HbF regulation. RBM12 functions independently of known HbF regulators BCL11A and ZBTB7A/LRF.\",\n      \"method\": \"CRISPR/Cas9 screen, RBM12 knockdown/depletion, eCLIP-seq, transcriptome and proteome profiling, domain mutagenesis\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CRISPR screen, eCLIP, proteome, domain mutagenesis) in a single rigorous study with functional validation\",\n      \"pmids\": [\"35622975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM12 is a repressor of the GPCR/cAMP/PKA signaling axis. Loss of RBM12 in HEK293 cells and iPSC-derived neurons leads to hyperactive cAMP production and increased PKA activity, as well as altered neuronal transcriptional responses to GPCR stimulation. RBM12 depletion alters expression of adenylyl cyclases, phosphodiesterase isoforms, and PKA regulatory and catalytic subunits. The two psychosis-linked truncating RBM12 variants fail to rescue GPCR/cAMP signaling hyperactivity, directly linking the loss-of-function mutations to this pathway.\",\n      \"method\": \"RBM12 knockdown in HEK293 cells and iPSC-derived neurons, cAMP assays, PKA activity assays, transcriptional reporter assays, rescue experiments with psychosis-linked truncating mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (cAMP, PKA, transcriptional), two cell models, disease-variant rescue experiments in a single rigorous study\",\n      \"pmids\": [\"37543364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM12 (preprint version of the JBC paper) delineated as a repressor of GPCR/cAMP/PKA signaling; loss of RBM12 causes hyperactive cAMP and PKA activity, altered gene expression of pathway effectors, and the two familial psychosis truncating mutants fail to rescue hyperactivity.\",\n      \"method\": \"RBM12 knockdown, cAMP assay, PKA activity assay, transcriptional assays, mutant rescue in HEK293 and iPSC neurons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint; same findings as peer-reviewed version (PMID 37543364), included for completeness but superseded by the published paper\",\n      \"pmids\": [\"36711667\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM12 drives PD-L1-mediated immune evasion in hepatocellular carcinoma by directly binding JAK1 mRNA via its 4th RRM domain and recruiting EIF4A2 through its 2nd RRM domain, thereby enhancing ribosome loading on JAK1 mRNA and promoting JAK1 translation; elevated JAK1 then activates JAK1/STAT1 signaling to transcriptionally upregulate PD-L1.\",\n      \"method\": \"Molecular binding assays (RBM12–JAK1 mRNA interaction), domain mapping (4th-RRM and 2nd-RRM), ribosome profiling/polysome analysis, EIF4A2 co-immunoprecipitation, JAK1/STAT1 pathway reporter assays, loss-of-function experiments in HCC cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-binding domain mapping, ribosome distribution assay, Co-IP for EIF4A2 recruitment, pathway readout) in a single rigorous study\",\n      \"pmids\": [\"39187545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM12 promotes HCC cell proliferation, migration, invasion, and inhibits apoptosis, and induces EMT by secreting TGF-β1. CPNE1 was identified as a downstream gene regulated by RBM12. miR-497-5p directly targets and suppresses RBM12 (validated by dual-luciferase reporter assay), placing RBM12 in a miR-497-5p/RBM12/CPNE1 regulatory axis in liver cancer cells.\",\n      \"method\": \"Cytological assays (CCK8, colony formation, Transwell), dual-luciferase reporter assay for miR-497-5p–RBM12 interaction, RBM12 knockdown/overexpression, CPNE1 downstream analysis\",\n      \"journal\": \"Environmental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — dual-luciferase validation of miRNA–RBM12 interaction and downstream CPNE1 link, multiple functional assays, single lab\",\n      \"pmids\": [\"37793588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rare predicted loss-of-function variants in RBM12 are associated with increased risk of coronary, cerebrovascular, and peripheral vascular atherosclerotic diseases in a large exome-wide association study, independent of traditional cardiovascular risk factors.\",\n      \"method\": \"Exome-wide association study in 434,438 UK Biobank participants\",\n      \"journal\": \"Circulation. Genomic and precision medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — large-scale genetic association; no direct mechanistic experiment performed on RBM12 protein in this study\",\n      \"pmids\": [\"41190437\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM12 is an RNA-binding protein containing five RRM domains that functions as a multi-context regulator: it suppresses fetal hemoglobin expression in erythroid cells by binding 5' UTRs of target mRNAs (requiring RRM1 and a linker domain); it promotes JAK1 mRNA translation in hepatocellular carcinoma by binding JAK1 mRNA via its 4th RRM and recruiting EIF4A2 via its 2nd RRM, thereby activating JAK1/STAT1/PD-L1 immune evasion; and it represses GPCR/cAMP/PKA signaling in neurons by regulating the expression of adenylyl cyclases, phosphodiesterases, and PKA subunits—a function disrupted by the two familial psychosis-associated truncating mutations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM12 is a five-RRM RNA-binding protein that acts as a context-dependent post-transcriptional regulator, controlling target gene expression through direct binding of mRNA features and recruitment of translation machinery [#2, #5]. In erythroid cells it binds preferentially to 5' UTRs of transcripts and suppresses fetal hemoglobin expression, a function that requires its first RRM together with an adjacent linker domain and operates independently of the canonical HbF regulators BCL11A and ZBTB7A/LRF [#2]. In hepatocellular carcinoma it binds JAK1 mRNA via its fourth RRM and recruits the translation factor EIF4A2 through its second RRM, increasing ribosome loading and JAK1 translation; the resulting JAK1/STAT1 signaling transcriptionally upregulates PD-L1 to drive immune evasion, and RBM12 also promotes HCC proliferation, invasion, and EMT within a miR-497-5p/RBM12/CPNE1 axis [#5, #6]. In neurons and HEK293 cells RBM12 represses the GPCR/cAMP/PKA signaling axis by setting the expression of adenylyl cyclases, phosphodiesterases, and PKA subunits, such that its loss yields hyperactive cAMP production and PKA activity [#3]. Truncating mutations that remove an RRM segregate with psychosis in familial kindreds and fail to rescue this cAMP/PKA hyperactivity, directly linking RBM12 loss-of-function to psychotic disorder [#0, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that RBM12 is transcriptionally coupled to a neighboring gene, raising the possibility of coordinated regulation before any molecular function was known.\",\n      \"evidence\": \"Comparative genomics and RT-PCR showing shared promoter and 5' exons with CPNE1 across human, mouse, and zebrafish tissues\",\n      \"pmids\": [\"18831769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish any biochemical or RNA-binding function of the RBM12 protein\", \"Functional consequence of shared CPNE1 promoter unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Answered whether RBM12 has a defined disease role by linking RRM-truncating loss-of-function to a heritable phenotype, motivating mechanistic work.\",\n      \"evidence\": \"Whole-genome sequencing and family-based genetic analysis of psychosis kindreds identifying nonsense and frameshift mutations\",\n      \"pmids\": [\"28628109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical assay of the protein in this study\", \"Molecular pathway through which truncation causes psychosis unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the first molecular activity of RBM12 — sequence-specific mRNA binding to 5' UTRs — and a functional output, suppression of fetal hemoglobin, localizing activity to RRM1 plus a linker.\",\n      \"evidence\": \"CRISPR screen, depletion, eCLIP-seq, proteome profiling and domain mutagenesis in SCD-derived erythroid cells\",\n      \"pmids\": [\"35622975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which 5' UTR binding suppresses HbF (translation vs. stability) not resolved\", \"Direct target transcripts driving the phenotype not fully enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected RBM12 loss-of-function to a signaling pathway and to the disease variants by showing it represses GPCR/cAMP/PKA signaling and that psychosis-linked truncations cannot rescue.\",\n      \"evidence\": \"Knockdown in HEK293 and iPSC-derived neurons, cAMP and PKA activity assays, transcriptional reporters, and disease-variant rescue experiments\",\n      \"pmids\": [\"37543364\", \"36711667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mRNA targets among adenylyl cyclase/PDE/PKA effectors not mapped by binding data\", \"Whether regulation is via the same 5' UTR-binding mode as in erythroid cells unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended RBM12 to cancer biology, showing pro-tumorigenic activity and placing it in a miRNA-controlled regulatory axis.\",\n      \"evidence\": \"Proliferation/migration/invasion assays, dual-luciferase validation of miR-497-5p targeting, and CPNE1 downstream analysis in HCC cells\",\n      \"pmids\": [\"37793588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking RBM12 to CPNE1 and TGF-β1 secretion not biochemically defined\", \"Single-lab functional study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved a direct molecular mechanism by mapping distinct RRMs to mRNA binding and translation-factor recruitment, explaining how RBM12 drives JAK1/STAT1/PD-L1 immune evasion.\",\n      \"evidence\": \"RNA-binding domain mapping (RRM4 to JAK1 mRNA, RRM2 to EIF4A2), polysome/ribosome profiling, EIF4A2 Co-IP, and JAK1/STAT1 pathway readouts in HCC cells\",\n      \"pmids\": [\"39187545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the EIF4A2-recruitment mechanism operates at the 5' UTR targets seen in erythroid and neuronal contexts is untested\", \"Structural basis of RRM-specific mRNA and EIF4A2 contacts not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the disease landscape by associating RBM12 loss-of-function with atherosclerotic vascular disease, though without a mechanism.\",\n      \"evidence\": \"Exome-wide association study in 434,438 UK Biobank participants\",\n      \"pmids\": [\"41190437\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic experiment performed on RBM12 in vascular tissue\", \"Causal pathway linking RBM12 loss to atherosclerosis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether RBM12's distinct context-specific outputs (HbF suppression, GPCR/cAMP/PKA repression, JAK1 translational activation) reflect a single unifying biochemical mechanism operating on different targets.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified target map across cell types\", \"No structural model relating the five RRMs to their respective functions\", \"Mechanistic basis of atherosclerosis association uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EIF4A2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}