{"gene":"UTRN","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1991,"finding":"UTRN (DMDL) protein is localized near acetylcholine receptors at neuromuscular junctions in normal and mdx mouse intercostal muscle, and is present in nonjunctional sarcolemma of Duchenne muscular dystrophy patients (where dystrophin is absent), as well as in vascular smooth muscle and proliferating brain cell lines, as determined by a panel of 19 monoclonal antibodies against different epitopes.","method":"Immunolocalization with monoclonal antibodies (panel of 19 antibodies against different epitopes), Western blotting, immunocytochemistry","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by multiple antibodies against defined epitopes, replicated across multiple tissue types in a single rigorous study","pmids":["1757469"],"is_preprint":false},{"year":2006,"finding":"MyoD suppresses UTRN expression during skeletal muscle differentiation by directly activating transcription of miR-206, which targets sequences in the Utrn 3' UTR that are sufficient to suppress UTRN expression in the presence of miR-206.","method":"Reporter assays with Utrn 3' UTR sequences, miR-206 gain-of-function in MyoD-converted fibroblasts, direct transcriptional activation of miR-206 by MyoD shown by ChIP/promoter assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, gain-of-function, promoter analysis) in a single rigorous study establishing the MyoD→miR-206→UTRN pathway","pmids":["17030984"],"is_preprint":false},{"year":2007,"finding":"UTRN functions as a tumor suppressor: antisense expression of UTRN induced cellular transformation, wild-type UTRN overexpression in breast cancer cells inhibited tumor cell growth in vitro and reduced tumor potential in nude mice, and inactivating mutations (exon deletions, splicing errors, nonsense mutations) were found in breast cancer, neuroblastoma, and malignant melanoma.","method":"Functional screening (antisense-induced transformation), overexpression in breast cancer cell lines (in vitro growth assay, nude mouse xenograft), RT-PCR and in vitro transcription/translation assay for mutations","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression and loss-of-function assays with in vivo xenograft, single lab, multiple orthogonal methods","pmids":["17384672"],"is_preprint":false},{"year":2021,"finding":"UTRN overexpression in A375 melanoma cells inhibits cell proliferation and suppresses the p38 and JNK1/c-Jun signaling pathways; activation of these pathways with the Epac activator 8-pCPT-2'-O-Me-cAMP partially rescues proliferation, placing UTRN upstream of MAPK signaling in melanoma growth control.","method":"Stable UTRN overexpression in melanoma cells, CCK-8 and EdU proliferation assays, Western blot for p38/JNK1/c-Jun, pharmacological rescue with Epac activator","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain-of-function with pathway rescue experiment, single lab, multiple orthogonal methods","pmids":["33632212"],"is_preprint":false},{"year":2022,"finding":"CCN5 gene transfer upregulates utrophin expression in mdx/utrn(±) mice; a utrophin promoter assay and RNA-seq analysis confirmed that CCN5 directly associates with utrophin transcriptional regulation, identifying utrophin as a novel transcriptional target of CCN5.","method":"CCN5 gene transfer via AAV9 in mdx/utrn(±) mice, utrophin promoter assay, RNA-seq analysis","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay and RNA-seq supporting direct transcriptional regulation, single lab, two orthogonal methods","pmids":["35557546"],"is_preprint":false},{"year":2025,"finding":"Biallelic loss-of-function variants in UTRN (compound heterozygosity: splicing variant c.8434+1G>A introducing a premature stop codon and a large deletion spanning exons 3-51) cause a novel autosomal recessive multiple congenital arthrogryposis syndrome, demonstrating that utrophin is required for normal musculoskeletal and multi-organ development.","method":"Trio whole-genome sequencing, RNA-seq analysis confirming aberrant splicing and truncated protein isoform","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human genetics with RNA-seq validation of molecular consequence, single case, novel finding","pmids":["41244983"],"is_preprint":false}],"current_model":"Utrophin (UTRN) is an autosomal homologue of dystrophin that localizes to neuromuscular junctions and vascular smooth muscle under normal conditions, and compensatorily distributes to the non-junctional sarcolemma when dystrophin is absent; its expression is post-transcriptionally suppressed during skeletal muscle differentiation via MyoD-driven miR-206 targeting the UTRN 3' UTR, it acts as a tumor suppressor (with inactivating mutations in several cancers and growth-inhibitory function mediated at least partly through suppression of p38/JNK/c-Jun MAPK signaling), and biallelic loss-of-function variants cause a novel recessive multiple congenital arthrogryposis syndrome."},"narrative":{"mechanistic_narrative":"Utrophin (UTRN) is an autosomal dystrophin-related protein concentrated near acetylcholine receptors at the neuromuscular junction in normal muscle and present in vascular smooth muscle and proliferating cell lines, that redistributes to the non-junctional sarcolemma in Duchenne muscular dystrophy muscle where dystrophin is absent [PMID:1757469]. Its expression is post-transcriptionally restrained during skeletal muscle differentiation through a MyoD-driven program in which MyoD directly transactivates miR-206, and miR-206 targets the UTRN 3' UTR to suppress utrophin levels [PMID:17030984]; utrophin transcription is positively controlled by CCN5, which acts on the utrophin promoter and can upregulate its expression in mdx/utrn(±) muscle [PMID:35557546]. Beyond muscle, UTRN behaves as a tumor suppressor: its loss promotes cellular transformation while restoring wild-type UTRN inhibits cancer cell growth and tumor formation, and inactivating mutations occur in breast cancer, neuroblastoma, and melanoma [PMID:17384672], with growth suppression mediated in part by dampening p38 and JNK1/c-Jun MAPK signaling [PMID:33632212]. Biallelic loss-of-function variants in UTRN cause an autosomal recessive multiple congenital arthrogryposis syndrome, establishing a requirement for utrophin in normal musculoskeletal and multi-organ development [PMID:41244983].","teleology":[{"year":1991,"claim":"Established where the dystrophin homologue utrophin resides in tissue, defining its normal junctional localization and its capacity to occupy the sarcolemma when dystrophin is missing.","evidence":"Immunolocalization with a panel of 19 epitope-specific monoclonal antibodies plus Western blotting across normal, mdx, and Duchenne muscular dystrophy muscle and other tissues","pmids":["1757469"],"confidence":"High","gaps":["Did not define the molecular basis of redistribution to non-junctional sarcolemma","No binding partners or membrane-anchoring complex identified","Functional consequence of the localization not tested"]},{"year":2006,"claim":"Resolved how utrophin is downregulated during myogenesis, identifying a MyoD→miR-206→UTRN 3' UTR axis as the post-transcriptional brake on its expression.","evidence":"Reporter assays of the Utrn 3' UTR, miR-206 gain-of-function in MyoD-converted fibroblasts, and promoter/ChIP analysis of MyoD activation of miR-206","pmids":["17030984"],"confidence":"High","gaps":["Did not address whether this axis can be exploited to elevate utrophin therapeutically","Other regulators of UTRN expression not surveyed"]},{"year":2007,"claim":"Recast utrophin as a tumor suppressor, showing its loss drives transformation and its restoration inhibits tumor growth, with recurrent inactivating mutations in multiple cancers.","evidence":"Antisense-induced transformation screen, wild-type UTRN overexpression in breast cancer cells with in vitro growth assay and nude mouse xenograft, and RT-PCR/in vitro transcription-translation mutation analysis","pmids":["17384672"],"confidence":"Medium","gaps":["Single lab; tumor-suppressor mechanism not defined in this study","Mutation frequencies across tumor cohorts not quantified","Domain(s) required for growth suppression unmapped"]},{"year":2021,"claim":"Provided a signaling mechanism for utrophin's growth suppression, placing it upstream of p38 and JNK1/c-Jun MAPK activity in melanoma.","evidence":"Stable UTRN overexpression in A375 melanoma cells with CCK-8/EdU proliferation assays, Western blot for p38/JNK1/c-Jun, and pharmacological rescue using an Epac activator","pmids":["33632212"],"confidence":"Medium","gaps":["Single cell line and single lab","Direct molecular link between utrophin and MAPK components not established","Whether the same pathway operates in other tumor types untested"]},{"year":2022,"claim":"Identified a positive transcriptional regulator of utrophin, showing CCN5 acts on the utrophin promoter to upregulate its expression in a dystrophic muscle context.","evidence":"AAV9-mediated CCN5 gene transfer in mdx/utrn(±) mice, utrophin promoter assay, and RNA-seq","pmids":["35557546"],"confidence":"Medium","gaps":["Direct CCN5 occupancy of the utrophin promoter not shown","Mechanism linking secreted CCN5 to utrophin transcription unresolved","Single lab"]},{"year":2025,"claim":"Connected UTRN loss to a human Mendelian phenotype, showing biallelic loss-of-function causes a recessive multiple congenital arthrogryposis syndrome.","evidence":"Trio whole-genome sequencing with RNA-seq confirmation of aberrant splicing and a truncated protein isoform","pmids":["41244983"],"confidence":"Medium","gaps":["Single case; genotype-phenotype spectrum unknown","Developmental mechanism linking utrophin loss to arthrogryposis not defined","No functional rescue demonstrated"]},{"year":null,"claim":"How utrophin's membrane-anchoring/cytoskeletal role mechanistically intersects with its tumor-suppressive and developmental functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct binding partners or complex composition characterized in the corpus","No structural model linking domains to its distinct functions","Mechanism by which utrophin restrains MAPK signaling not molecularly defined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46939","full_name":"Utrophin","aliases":["Dystrophin-related protein 1","DRP-1"],"length_aa":3433,"mass_kda":394.5,"function":"May play a role in anchoring the cytoskeleton to the plasma membrane","subcellular_location":"Postsynaptic cell membrane; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P46939/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UTRN","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000152818","cell_line_id":"CID000623","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":1},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"SNTB2","stoichiometry":10.0},{"gene":"DAG1","stoichiometry":4.0},{"gene":"CTNNAL1","stoichiometry":4.0},{"gene":"KIDINS220","stoichiometry":4.0},{"gene":"DTNA","stoichiometry":4.0},{"gene":"CCT2","stoichiometry":0.2},{"gene":"CCT4","stoichiometry":0.2},{"gene":"CCT6A","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"MARK2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000623","total_profiled":1310},"omim":[{"mim_id":"608931","title":"MYASTHENIC SYNDROME, CONGENITAL, 4C, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY; CMS4C","url":"https://www.omim.org/entry/608931"},{"mim_id":"603590","title":"ACETYLGLUCOSAMINYLTRANSFERASE-LIKE PROTEIN; LARGE1","url":"https://www.omim.org/entry/603590"},{"mim_id":"601411","title":"SARCOGLYCAN, DELTA; SGCD","url":"https://www.omim.org/entry/601411"},{"mim_id":"600409","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-DELTA; PPARD","url":"https://www.omim.org/entry/600409"},{"mim_id":"310200","title":"MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD","url":"https://www.omim.org/entry/310200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UTRN"},"hgnc":{"alias_symbol":["DRP","DRP1"],"prev_symbol":["DMDL"]},"alphafold":{"accession":"P46939","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46939","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46939-4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46939-4-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UTRN","jax_strain_url":"https://www.jax.org/strain/search?query=UTRN"},"sequence":{"accession":"P46939","fasta_url":"https://rest.uniprot.org/uniprotkb/P46939.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46939/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46939"}},"corpus_meta":[{"pmid":"17030984","id":"PMC_17030984","title":"MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17030984","citation_count":270,"is_preprint":false},{"pmid":"1757469","id":"PMC_1757469","title":"Localization of the DMDL gene-encoded dystrophin-related protein using a panel of nineteen monoclonal antibodies: presence at neuromuscular junctions, in the sarcolemma of dystrophic skeletal muscle, in vascular and other smooth muscles, and in proliferating brain cell lines.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1757469","citation_count":216,"is_preprint":false},{"pmid":"21254093","id":"PMC_21254093","title":"Impaired respiratory function in mdx and mdx/utrn(+/-) mice.","date":"2011","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/21254093","citation_count":66,"is_preprint":false},{"pmid":"17511564","id":"PMC_17511564","title":"Multipotential mesoangioblast stem cell therapy in the mdx/utrn-/- mouse model for Duchenne muscular dystrophy.","date":"2007","source":"Regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17511564","citation_count":48,"is_preprint":false},{"pmid":"17384672","id":"PMC_17384672","title":"UTRN on chromosome 6q24 is mutated in multiple tumors.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17384672","citation_count":33,"is_preprint":false},{"pmid":"23283493","id":"PMC_23283493","title":"Injection of vessel-derived stem cells prevents dilated cardiomyopathy and promotes angiogenesis and endogenous cardiac stem cell proliferation in mdx/utrn-/- but not aged mdx mouse models for duchenne muscular dystrophy.","date":"2012","source":"Stem cells translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23283493","citation_count":28,"is_preprint":false},{"pmid":"25423449","id":"PMC_25423449","title":"Molecular characterization of Lactobacillus plantarum DMDL 9010, a strain with efficient nitrite degradation capacity.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25423449","citation_count":27,"is_preprint":false},{"pmid":"27836895","id":"PMC_27836895","title":"Lifelong quercetin enrichment and cardioprotection in Mdx/Utrn+/- mice.","date":"2016","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27836895","citation_count":25,"is_preprint":false},{"pmid":"24943487","id":"PMC_24943487","title":"Human adipose tissue derived pericytes increase life span in Utrn (tm1Ked) Dmd (mdx) /J mice.","date":"2014","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/24943487","citation_count":25,"is_preprint":false},{"pmid":"33632212","id":"PMC_33632212","title":"UTRN inhibits melanoma growth by suppressing p38 and JNK/c-Jun signaling pathways.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33632212","citation_count":19,"is_preprint":false},{"pmid":"36570157","id":"PMC_36570157","title":"Structural, antioxidant, and immunomodulatory activities of an acidic exopolysaccharide from Lactiplantibacillus plantarum DMDL 9010.","date":"2022","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/36570157","citation_count":17,"is_preprint":false},{"pmid":"34850057","id":"PMC_34850057","title":"Circ_UTRN ameliorates caerulein-induced acute pancreatitis in vitro via reducing inflammation and promoting apoptosis through miR-320-3p/PTK2 axis.","date":"2022","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34850057","citation_count":14,"is_preprint":false},{"pmid":"16487708","id":"PMC_16487708","title":"Improvement in survival and muscle function in an mdx/utrn(-/-) double mutant mouse using a human retinal dystrophin transgene.","date":"2006","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/16487708","citation_count":12,"is_preprint":false},{"pmid":"20583184","id":"PMC_20583184","title":"Molecular characterization of a de novo 6q24.2q25.3 duplication interrupting UTRN in a patient with arthrogryposis.","date":"2010","source":"American journal of medical genetics. 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by a panel of 19 monoclonal antibodies against different epitopes.\",\n      \"method\": \"Immunolocalization with monoclonal antibodies (panel of 19 antibodies against different epitopes), Western blotting, immunocytochemistry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by multiple antibodies against defined epitopes, replicated across multiple tissue types in a single rigorous study\",\n      \"pmids\": [\"1757469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MyoD suppresses UTRN expression during skeletal muscle differentiation by directly activating transcription of miR-206, which targets sequences in the Utrn 3' UTR that are sufficient to suppress UTRN expression in the presence of miR-206.\",\n      \"method\": \"Reporter assays with Utrn 3' UTR sequences, miR-206 gain-of-function in MyoD-converted fibroblasts, direct transcriptional activation of miR-206 by MyoD shown by ChIP/promoter assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, gain-of-function, promoter analysis) in a single rigorous study establishing the MyoD→miR-206→UTRN pathway\",\n      \"pmids\": [\"17030984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UTRN functions as a tumor suppressor: antisense expression of UTRN induced cellular transformation, wild-type UTRN overexpression in breast cancer cells inhibited tumor cell growth in vitro and reduced tumor potential in nude mice, and inactivating mutations (exon deletions, splicing errors, nonsense mutations) were found in breast cancer, neuroblastoma, and malignant melanoma.\",\n      \"method\": \"Functional screening (antisense-induced transformation), overexpression in breast cancer cell lines (in vitro growth assay, nude mouse xenograft), RT-PCR and in vitro transcription/translation assay for mutations\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression and loss-of-function assays with in vivo xenograft, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17384672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTRN overexpression in A375 melanoma cells inhibits cell proliferation and suppresses the p38 and JNK1/c-Jun signaling pathways; activation of these pathways with the Epac activator 8-pCPT-2'-O-Me-cAMP partially rescues proliferation, placing UTRN upstream of MAPK signaling in melanoma growth control.\",\n      \"method\": \"Stable UTRN overexpression in melanoma cells, CCK-8 and EdU proliferation assays, Western blot for p38/JNK1/c-Jun, pharmacological rescue with Epac activator\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain-of-function with pathway rescue experiment, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33632212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCN5 gene transfer upregulates utrophin expression in mdx/utrn(±) mice; a utrophin promoter assay and RNA-seq analysis confirmed that CCN5 directly associates with utrophin transcriptional regulation, identifying utrophin as a novel transcriptional target of CCN5.\",\n      \"method\": \"CCN5 gene transfer via AAV9 in mdx/utrn(±) mice, utrophin promoter assay, RNA-seq analysis\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay and RNA-seq supporting direct transcriptional regulation, single lab, two orthogonal methods\",\n      \"pmids\": [\"35557546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic loss-of-function variants in UTRN (compound heterozygosity: splicing variant c.8434+1G>A introducing a premature stop codon and a large deletion spanning exons 3-51) cause a novel autosomal recessive multiple congenital arthrogryposis syndrome, demonstrating that utrophin is required for normal musculoskeletal and multi-organ development.\",\n      \"method\": \"Trio whole-genome sequencing, RNA-seq analysis confirming aberrant splicing and truncated protein isoform\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human genetics with RNA-seq validation of molecular consequence, single case, novel finding\",\n      \"pmids\": [\"41244983\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Utrophin (UTRN) is an autosomal homologue of dystrophin that localizes to neuromuscular junctions and vascular smooth muscle under normal conditions, and compensatorily distributes to the non-junctional sarcolemma when dystrophin is absent; its expression is post-transcriptionally suppressed during skeletal muscle differentiation via MyoD-driven miR-206 targeting the UTRN 3' UTR, it acts as a tumor suppressor (with inactivating mutations in several cancers and growth-inhibitory function mediated at least partly through suppression of p38/JNK/c-Jun MAPK signaling), and biallelic loss-of-function variants cause a novel recessive multiple congenital arthrogryposis syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Utrophin (UTRN) is an autosomal dystrophin-related protein concentrated near acetylcholine receptors at the neuromuscular junction in normal muscle and present in vascular smooth muscle and proliferating cell lines, that redistributes to the non-junctional sarcolemma in Duchenne muscular dystrophy muscle where dystrophin is absent [#0]. Its expression is post-transcriptionally restrained during skeletal muscle differentiation through a MyoD-driven program in which MyoD directly transactivates miR-206, and miR-206 targets the UTRN 3' UTR to suppress utrophin levels [#1]; utrophin transcription is positively controlled by CCN5, which acts on the utrophin promoter and can upregulate its expression in mdx/utrn(\\u00b1) muscle [#4]. Beyond muscle, UTRN behaves as a tumor suppressor: its loss promotes cellular transformation while restoring wild-type UTRN inhibits cancer cell growth and tumor formation, and inactivating mutations occur in breast cancer, neuroblastoma, and melanoma [#2], with growth suppression mediated in part by dampening p38 and JNK1/c-Jun MAPK signaling [#3]. Biallelic loss-of-function variants in UTRN cause an autosomal recessive multiple congenital arthrogryposis syndrome, establishing a requirement for utrophin in normal musculoskeletal and multi-organ development [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established where the dystrophin homologue utrophin resides in tissue, defining its normal junctional localization and its capacity to occupy the sarcolemma when dystrophin is missing.\",\n      \"evidence\": \"Immunolocalization with a panel of 19 epitope-specific monoclonal antibodies plus Western blotting across normal, mdx, and Duchenne muscular dystrophy muscle and other tissues\",\n      \"pmids\": [\"1757469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not define the molecular basis of redistribution to non-junctional sarcolemma\",\n        \"No binding partners or membrane-anchoring complex identified\",\n        \"Functional consequence of the localization not tested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how utrophin is downregulated during myogenesis, identifying a MyoD\\u2192miR-206\\u2192UTRN 3' UTR axis as the post-transcriptional brake on its expression.\",\n      \"evidence\": \"Reporter assays of the Utrn 3' UTR, miR-206 gain-of-function in MyoD-converted fibroblasts, and promoter/ChIP analysis of MyoD activation of miR-206\",\n      \"pmids\": [\"17030984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not address whether this axis can be exploited to elevate utrophin therapeutically\",\n        \"Other regulators of UTRN expression not surveyed\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Recast utrophin as a tumor suppressor, showing its loss drives transformation and its restoration inhibits tumor growth, with recurrent inactivating mutations in multiple cancers.\",\n      \"evidence\": \"Antisense-induced transformation screen, wild-type UTRN overexpression in breast cancer cells with in vitro growth assay and nude mouse xenograft, and RT-PCR/in vitro transcription-translation mutation analysis\",\n      \"pmids\": [\"17384672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; tumor-suppressor mechanism not defined in this study\",\n        \"Mutation frequencies across tumor cohorts not quantified\",\n        \"Domain(s) required for growth suppression unmapped\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided a signaling mechanism for utrophin's growth suppression, placing it upstream of p38 and JNK1/c-Jun MAPK activity in melanoma.\",\n      \"evidence\": \"Stable UTRN overexpression in A375 melanoma cells with CCK-8/EdU proliferation assays, Western blot for p38/JNK1/c-Jun, and pharmacological rescue using an Epac activator\",\n      \"pmids\": [\"33632212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cell line and single lab\",\n        \"Direct molecular link between utrophin and MAPK components not established\",\n        \"Whether the same pathway operates in other tumor types untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a positive transcriptional regulator of utrophin, showing CCN5 acts on the utrophin promoter to upregulate its expression in a dystrophic muscle context.\",\n      \"evidence\": \"AAV9-mediated CCN5 gene transfer in mdx/utrn(\\u00b1) mice, utrophin promoter assay, and RNA-seq\",\n      \"pmids\": [\"35557546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct CCN5 occupancy of the utrophin promoter not shown\",\n        \"Mechanism linking secreted CCN5 to utrophin transcription unresolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected UTRN loss to a human Mendelian phenotype, showing biallelic loss-of-function causes a recessive multiple congenital arthrogryposis syndrome.\",\n      \"evidence\": \"Trio whole-genome sequencing with RNA-seq confirmation of aberrant splicing and a truncated protein isoform\",\n      \"pmids\": [\"41244983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case; genotype-phenotype spectrum unknown\",\n        \"Developmental mechanism linking utrophin loss to arthrogryposis not defined\",\n        \"No functional rescue demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How utrophin's membrane-anchoring/cytoskeletal role mechanistically intersects with its tumor-suppressive and developmental functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct binding partners or complex composition characterized in the corpus\",\n        \"No structural model linking domains to its distinct functions\",\n        \"Mechanism by which utrophin restrains MAPK signaling not molecularly defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}