{"gene":"DTNA","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2023,"finding":"α-dystrobrevin (DTNA) is a component of the dystrophin-glycoprotein complex (DGC) that interacts with dystrophin/utrophin and α-syntrophin; a deletion variant in the coiled-coil domain of α-dystrobrevin (p.Gln523_Glu529del) disrupts the interaction between α-dystrobrevin and syntrophin, and is associated with reduced immunoreactivity of DGC proteins (dystrophin, sarcoglycans, dystroglycans) in patient muscle biopsies.","method":"Immunofluorescence of patient muscle biopsies, co-immunoprecipitation/interaction assay demonstrating disrupted α-dystrobrevin–syntrophin binding","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction disruption shown in patient tissue with immunofluorescence and interaction assay, single study","pmids":["36799992"],"is_preprint":false},{"year":2020,"finding":"DTNA (α-dystrobrevin) directly binds STAT3 protein and promotes STAT3 phosphorylation, which in turn induces TGFβ1 expression and represses P53 expression in HBV-infected hepatocellular carcinoma cells; DTNA knockdown suppressed proliferation and promoted apoptosis in these cells.","method":"Co-immunoprecipitation (predicted and confirmed), shRNA knockdown, western blotting, MTT assay, flow cytometry, in vivo mouse model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed DTNA–STAT3 interaction, functional rescue with shRNA, single lab","pmids":["32619495"],"is_preprint":false},{"year":2022,"finding":"In mouse embryonic stem cell-derived cardiomyocytes, Dtna (dystrobrevin-α) promotes binding of the dystrophin-glycoprotein complex (DGC) to YAP (yes-associated protein), reducing nuclear YAP proportion and expression of YAP target genes, thereby promoting cardiomyocyte maturation; Dtna expression is post-transcriptionally repressed by miR-540-3p and is protected by lncRNA Cmarr acting as a competitive endogenous RNA.","method":"lncRNA/miRNA overexpression, Dtna expression modulation, DGC–YAP interaction assay, nuclear/cytoplasmic fractionation, ESC-CM maturation assays","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mechanistic link between Dtna, DGC–YAP interaction, and cardiomyocyte maturation established in single study with multiple methods","pmids":["36035750"],"is_preprint":false},{"year":2017,"finding":"Overexpression of a missense mutation (p.N49S) in DTNA (α-dystrobrevin) under a cardiac-specific promoter in transgenic mice causes left ventricular noncompaction phenotype, including deep trabeculation, LV dilation, and cardiac systolic dysfunction, establishing a causal role for DTNA in cardiac development.","method":"Transgenic mouse model (Myh6:DtnaN49S), echocardiography, histological observation, immunoblotting","journal":"International heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with phenotypic characterization, single lab, multiple phenotypic readouts","pmids":["29118297"],"is_preprint":false},{"year":2014,"finding":"A missense mutation in the DTNA gene produces a novel splice site that skips exon 21, leading to a shorter alternative transcript, and DTNA protein is expressed in the neurosensorial epithelium of the crista ampullaris, consistent with a role in inner ear function.","method":"Whole-exome sequencing, mRNA sequencing/splice analysis, immunohistochemistry in rat crista ampullaris","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — splice mechanism identified by sequencing and confirmed at mRNA level, protein localization by IHC only, no functional experiment on mechanism","pmids":["25305078"],"is_preprint":false}],"current_model":"α-dystrobrevin (DTNA) is a cytoskeleton-interacting membrane protein and component of the dystrophin-glycoprotein complex (DGC) that directly binds dystrophin/utrophin, syntrophin, and STAT3; its coiled-coil domain interaction with syntrophin is required for DGC integrity in skeletal muscle, and in cardiomyocytes it facilitates DGC–YAP interaction to regulate maturation signaling, while also activating STAT3 phosphorylation and downstream TGFβ1/P53 pathways in HBV-infected liver cells."},"narrative":{"mechanistic_narrative":"α-dystrobrevin (DTNA) is a component of the dystrophin-glycoprotein complex (DGC) that links the complex to the cytoskeleton and to downstream signaling, with roles spanning skeletal muscle integrity, cardiac development, and tissue-specific signaling [PMID:36799992, PMID:36035750]. Within the DGC, DTNA interacts with dystrophin/utrophin and α-syntrophin, and its coiled-coil domain mediates the syntrophin interaction; an in-frame coiled-coil deletion (p.Gln523_Glu529del) disrupts α-dystrobrevin–syntrophin binding and reduces immunoreactivity of dystrophin, sarcoglycans, and dystroglycans in patient muscle, demonstrating that this interaction is required for DGC stability [PMID:36799992]. In cardiomyocytes, DTNA promotes binding of the DGC to YAP, lowering nuclear YAP and YAP target-gene expression to drive cardiomyocyte maturation [PMID:36035750], and a cardiac-specific missense mutation (p.N49S) causes a left ventricular noncompaction phenotype in transgenic mice, establishing a causal role in cardiac development [PMID:29118297]. Beyond its structural role, DTNA directly binds STAT3 and promotes its phosphorylation, inducing TGFβ1 and repressing P53 to support proliferation and survival in HBV-infected hepatocellular carcinoma cells [PMID:32619495].","teleology":[{"year":2014,"claim":"Established that DTNA is expressed in inner ear sensory epithelium and that a missense mutation can generate an aberrant splice product, linking the gene to inner ear function.","evidence":"Whole-exome and mRNA sequencing with splice analysis, immunohistochemistry in rat crista ampullaris","pmids":["25305078"],"confidence":"Low","gaps":["No functional experiment testing the consequence of the splice variant on protein activity","Localization shown by IHC only, no mechanistic role established","No connection drawn between the truncated transcript and a physiological phenotype"]},{"year":2017,"claim":"Demonstrated a causal role for DTNA in cardiac development by showing a point mutant produces left ventricular noncompaction in vivo.","evidence":"Cardiac-specific transgenic mouse (Myh6:DtnaN49S) with echocardiography, histology, and immunoblotting","pmids":["29118297"],"confidence":"Medium","gaps":["Molecular mechanism connecting the N49S mutation to trabeculation defects not defined","Overexpression model leaves dominant-negative versus gain-of-function ambiguity","Single lab, no patient-genotype correlation"]},{"year":2020,"claim":"Identified a signaling function for DTNA beyond the cytoskeleton, showing direct STAT3 binding drives a TGFβ1/P53 axis controlling proliferation and survival.","evidence":"Co-IP, shRNA knockdown, western blotting, MTT and flow cytometry assays, in vivo mouse model in HBV-infected HCC cells","pmids":["32619495"],"confidence":"Medium","gaps":["Mechanism by which DTNA promotes STAT3 phosphorylation not resolved","Whether this signaling role operates outside HBV-infected liver context unknown","Single lab, reciprocal validation of interaction limited"]},{"year":2022,"claim":"Connected DTNA to a maturation-signaling pathway in cardiomyocytes by showing it bridges the DGC to YAP and is itself regulated by a ceRNA/miRNA network.","evidence":"lncRNA/miRNA overexpression, DGC–YAP interaction assay, nuclear/cytoplasmic fractionation, ESC-CM maturation assays","pmids":["36035750"],"confidence":"Medium","gaps":["Direct versus indirect nature of the DGC–YAP interaction not fully resolved","Whether this YAP regulation occurs in adult cardiomyocytes in vivo unknown","Single study"]},{"year":2023,"claim":"Established that the DTNA coiled-coil–syntrophin interaction is required for DGC integrity, using a patient-derived deletion that disrupts binding and destabilizes the complex.","evidence":"Immunofluorescence of patient muscle biopsies and interaction assay showing disrupted α-dystrobrevin–syntrophin binding","pmids":["36799992"],"confidence":"Medium","gaps":["Single study; structural basis of the coiled-coil interaction not solved","Quantitative contribution of DTNA loss to disease severity unclear","Functional reconstitution of restored binding not performed"]},{"year":null,"claim":"How DTNA's structural role in DGC assembly is mechanistically coupled to its signaling outputs (STAT3, YAP) across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of DTNA within the DGC","Tissue-specific switching between cytoskeletal and signaling functions undefined","No unified accounting of muscle, cardiac, hepatic, and inner-ear phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"complexes":["dystrophin-glycoprotein complex"],"partners":["DMD","UTRN","SNTA1","STAT3","YAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4J8","full_name":"Dystrobrevin alpha","aliases":["Alpha-dystrobrevin","Dystrophin-related protein 3"],"length_aa":743,"mass_kda":83.9,"function":"May be involved in the formation and stability of synapses as well as being involved in the clustering of nicotinic acetylcholine receptors","subcellular_location":"Cytoplasm; Synapse; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y4J8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DTNA","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"UTRN","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/DTNA","total_profiled":1310},"omim":[{"mim_id":"620971","title":"MYOPATHY WITH MYALGIA, INCREASED SERUM CREATINE KINASE, AND WITH OR WITHOUT EPISODIC RHABDOMYOLYSIS 2; MMCKR2","url":"https://www.omim.org/entry/620971"},{"mim_id":"620539","title":"ZINC FINGER SWIM DOMAIN-CONTAINING PROTEIN 4; ZSWIM4","url":"https://www.omim.org/entry/620539"},{"mim_id":"620138","title":"MYOPATHY WITH MYALGIA, INCREASED SERUM CREATINE KINASE, AND WITH OR WITHOUT EPISODIC RHABDOMYOLYSIS 1; MMCKR1","url":"https://www.omim.org/entry/620138"},{"mim_id":"618510","title":"DYSTROTELIN; DYTN","url":"https://www.omim.org/entry/618510"},{"mim_id":"617128","title":"INHIBITORY SYNAPTIC FACTOR 1; INSYN1","url":"https://www.omim.org/entry/617128"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Intermediate filaments","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":204.2},{"tissue":"choroid plexus","ntpm":72.0},{"tissue":"heart muscle","ntpm":140.1},{"tissue":"skeletal muscle","ntpm":152.8},{"tissue":"tongue","ntpm":197.5}],"url":"https://www.proteinatlas.org/search/DTNA"},"hgnc":{"alias_symbol":["D18S892E","DTN","DTN-1","DTN-2","DTN-3","DRP3"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y4J8","domains":[{"cath_id":"1.10.238.10","chopping":"2-236","consensus_level":"high","plddt":91.5688,"start":2,"end":236},{"cath_id":"3.30.60.90","chopping":"239-294","consensus_level":"high","plddt":93.5643,"start":239,"end":294}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4J8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4J8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4J8-F1-predicted_aligned_error_v6.png","plddt_mean":69.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DTNA","jax_strain_url":"https://www.jax.org/strain/search?query=DTNA"},"sequence":{"accession":"Q9Y4J8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4J8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4J8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4J8"}},"corpus_meta":[{"pmid":"25305078","id":"PMC_25305078","title":"Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25305078","citation_count":91,"is_preprint":false},{"pmid":"1924370","id":"PMC_1924370","title":"Site-specific effect of thymine dimer formation on dAn.dTn tract bending and its biological implications.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1924370","citation_count":88,"is_preprint":false},{"pmid":"8422354","id":"PMC_8422354","title":"Symmetry and molecular structure of a DNA triple helix: d(T)n.d(A)n.d(T)n.","date":"1993","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8422354","citation_count":67,"is_preprint":false},{"pmid":"1420182","id":"PMC_1420182","title":"Structure of d(T)n.d(A)n.d(T)n: the DNA triple helix has B-form geometry with C2'-endo sugar pucker.","date":"1992","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1420182","citation_count":66,"is_preprint":false},{"pmid":"2747797","id":"PMC_2747797","title":"Measurement of anomalously high hydration of (dA)n.(dT)n double helices in dilute solution.","date":"1989","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2747797","citation_count":63,"is_preprint":false},{"pmid":"11929929","id":"PMC_11929929","title":"Directional asymmetry of neurons in cortical areas MT and MST projecting to the NOT-DTN in macaques.","date":"2002","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/11929929","citation_count":46,"is_preprint":false},{"pmid":"11375918","id":"PMC_11375918","title":"Cortical input to the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN) in macaques: a retrograde tracing study.","date":"2001","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/11375918","citation_count":34,"is_preprint":false},{"pmid":"2216711","id":"PMC_2216711","title":"Long (dA)n.(dT)n tracts can form intramolecular triplexes under superhelical stress.","date":"1990","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2216711","citation_count":31,"is_preprint":false},{"pmid":"6280155","id":"PMC_6280155","title":"Differential stabilization by netropsin of inducible B-like conformations in deoxyribo-, ribo- and 2'-deoxy-2'-fluororibo-adenosine containing duplexes of (dA)n . (dT)n and (dA)n . (dU)na.","date":"1982","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6280155","citation_count":25,"is_preprint":false},{"pmid":"29118297","id":"PMC_29118297","title":"Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a DTNA Mutation.","date":"2017","source":"International heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/29118297","citation_count":19,"is_preprint":false},{"pmid":"1706717","id":"PMC_1706717","title":"The effects of actinomycin on the structure of dAn.dTn and (dA-dT)n regions surrounding its GC binding site. A footprinting study.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1706717","citation_count":19,"is_preprint":false},{"pmid":"32619495","id":"PMC_32619495","title":"DTNA promotes HBV-induced hepatocellular carcinoma progression by activating STAT3 and regulating TGFβ1 and P53 signaling.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32619495","citation_count":17,"is_preprint":false},{"pmid":"33476260","id":"PMC_33476260","title":"Telomeric double-strand DNA-binding proteins DTN-1 and DTN-2 ensure germline immortality in Caenorhabditis elegans.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33476260","citation_count":12,"is_preprint":false},{"pmid":"35148685","id":"PMC_35148685","title":"Whole-exome sequencing reveals a rare missense variant in DTNA in an Iranian pedigree with early-onset atrial fibrillation.","date":"2022","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/35148685","citation_count":11,"is_preprint":false},{"pmid":"2559771","id":"PMC_2559771","title":"Antibody-nucleic acid complexes. Oligo(dG)n and -(dT)n specificities associated with anti-DNA antibodies from autoimmune MRL mice.","date":"1989","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2559771","citation_count":11,"is_preprint":false},{"pmid":"8828860","id":"PMC_8828860","title":"The nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) of opossums (Didelphis marsupialis aurita).","date":"1996","source":"Brain, behavior and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/8828860","citation_count":10,"is_preprint":false},{"pmid":"36799992","id":"PMC_36799992","title":"Variants in DTNA cause a mild, dominantly inherited muscular dystrophy.","date":"2023","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/36799992","citation_count":9,"is_preprint":false},{"pmid":"26893613","id":"PMC_26893613","title":"Ring chromosome 18 in combination with 18q12.1 (DTNA) interstitial microdeletion in a patient with multiple congenital defects.","date":"2016","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26893613","citation_count":8,"is_preprint":false},{"pmid":"9700923","id":"PMC_9700923","title":"Analysis of a curved DNA constructed from alternating dAn:dTn-tracts in linear and supercoiled form by high resolution chemical probing.","date":"1998","source":"Biophysical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9700923","citation_count":8,"is_preprint":false},{"pmid":"36035750","id":"PMC_36035750","title":"Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression.","date":"2022","source":"Molecular therapy. 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Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mechanistic link between Dtna, DGC–YAP interaction, and cardiomyocyte maturation established in single study with multiple methods\",\n      \"pmids\": [\"36035750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of a missense mutation (p.N49S) in DTNA (α-dystrobrevin) under a cardiac-specific promoter in transgenic mice causes left ventricular noncompaction phenotype, including deep trabeculation, LV dilation, and cardiac systolic dysfunction, establishing a causal role for DTNA in cardiac development.\",\n      \"method\": \"Transgenic mouse model (Myh6:DtnaN49S), echocardiography, histological observation, immunoblotting\",\n      \"journal\": \"International heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with phenotypic characterization, single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"29118297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A missense mutation in the DTNA gene produces a novel splice site that skips exon 21, leading to a shorter alternative transcript, and DTNA protein is expressed in the neurosensorial epithelium of the crista ampullaris, consistent with a role in inner ear function.\",\n      \"method\": \"Whole-exome sequencing, mRNA sequencing/splice analysis, immunohistochemistry in rat crista ampullaris\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — splice mechanism identified by sequencing and confirmed at mRNA level, protein localization by IHC only, no functional experiment on mechanism\",\n      \"pmids\": [\"25305078\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"α-dystrobrevin (DTNA) is a cytoskeleton-interacting membrane protein and component of the dystrophin-glycoprotein complex (DGC) that directly binds dystrophin/utrophin, syntrophin, and STAT3; its coiled-coil domain interaction with syntrophin is required for DGC integrity in skeletal muscle, and in cardiomyocytes it facilitates DGC–YAP interaction to regulate maturation signaling, while also activating STAT3 phosphorylation and downstream TGFβ1/P53 pathways in HBV-infected liver cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"α-dystrobrevin (DTNA) is a component of the dystrophin-glycoprotein complex (DGC) that links the complex to the cytoskeleton and to downstream signaling, with roles spanning skeletal muscle integrity, cardiac development, and tissue-specific signaling [#0, #2]. Within the DGC, DTNA interacts with dystrophin/utrophin and α-syntrophin, and its coiled-coil domain mediates the syntrophin interaction; an in-frame coiled-coil deletion (p.Gln523_Glu529del) disrupts α-dystrobrevin–syntrophin binding and reduces immunoreactivity of dystrophin, sarcoglycans, and dystroglycans in patient muscle, demonstrating that this interaction is required for DGC stability [#0]. In cardiomyocytes, DTNA promotes binding of the DGC to YAP, lowering nuclear YAP and YAP target-gene expression to drive cardiomyocyte maturation [#2], and a cardiac-specific missense mutation (p.N49S) causes a left ventricular noncompaction phenotype in transgenic mice, establishing a causal role in cardiac development [#3]. Beyond its structural role, DTNA directly binds STAT3 and promotes its phosphorylation, inducing TGFβ1 and repressing P53 to support proliferation and survival in HBV-infected hepatocellular carcinoma cells [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that DTNA is expressed in inner ear sensory epithelium and that a missense mutation can generate an aberrant splice product, linking the gene to inner ear function.\",\n      \"evidence\": \"Whole-exome and mRNA sequencing with splice analysis, immunohistochemistry in rat crista ampullaris\",\n      \"pmids\": [\"25305078\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional experiment testing the consequence of the splice variant on protein activity\",\n        \"Localization shown by IHC only, no mechanistic role established\",\n        \"No connection drawn between the truncated transcript and a physiological phenotype\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a causal role for DTNA in cardiac development by showing a point mutant produces left ventricular noncompaction in vivo.\",\n      \"evidence\": \"Cardiac-specific transgenic mouse (Myh6:DtnaN49S) with echocardiography, histology, and immunoblotting\",\n      \"pmids\": [\"29118297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism connecting the N49S mutation to trabeculation defects not defined\",\n        \"Overexpression model leaves dominant-negative versus gain-of-function ambiguity\",\n        \"Single lab, no patient-genotype correlation\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a signaling function for DTNA beyond the cytoskeleton, showing direct STAT3 binding drives a TGFβ1/P53 axis controlling proliferation and survival.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, western blotting, MTT and flow cytometry assays, in vivo mouse model in HBV-infected HCC cells\",\n      \"pmids\": [\"32619495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which DTNA promotes STAT3 phosphorylation not resolved\",\n        \"Whether this signaling role operates outside HBV-infected liver context unknown\",\n        \"Single lab, reciprocal validation of interaction limited\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected DTNA to a maturation-signaling pathway in cardiomyocytes by showing it bridges the DGC to YAP and is itself regulated by a ceRNA/miRNA network.\",\n      \"evidence\": \"lncRNA/miRNA overexpression, DGC–YAP interaction assay, nuclear/cytoplasmic fractionation, ESC-CM maturation assays\",\n      \"pmids\": [\"36035750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect nature of the DGC–YAP interaction not fully resolved\",\n        \"Whether this YAP regulation occurs in adult cardiomyocytes in vivo unknown\",\n        \"Single study\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that the DTNA coiled-coil–syntrophin interaction is required for DGC integrity, using a patient-derived deletion that disrupts binding and destabilizes the complex.\",\n      \"evidence\": \"Immunofluorescence of patient muscle biopsies and interaction assay showing disrupted α-dystrobrevin–syntrophin binding\",\n      \"pmids\": [\"36799992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; structural basis of the coiled-coil interaction not solved\",\n        \"Quantitative contribution of DTNA loss to disease severity unclear\",\n        \"Functional reconstitution of restored binding not performed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DTNA's structural role in DGC assembly is mechanistically coupled to its signaling outputs (STAT3, YAP) across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of DTNA within the DGC\",\n        \"Tissue-specific switching between cytoskeletal and signaling functions undefined\",\n        \"No unified accounting of muscle, cardiac, hepatic, and inner-ear phenotypes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"dystrophin-glycoprotein complex\"\n    ],\n    \"partners\": [\n      \"DMD\",\n      \"UTRN\",\n      \"SNTA1\",\n      \"STAT3\",\n      \"YAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}