{"gene":"TNR","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2020,"finding":"Loss-of-function (biallelic) variants in TNR (Tenascin-R) cause a nonprogressive autosomal recessive neurodevelopmental disorder with spasticity and transient opisthotonus in humans, establishing TNR as essential for normal CNS development, consistent with its known role in perineuronal net formation around interneurons.","method":"Exome sequencing and matchmaking in 13 individuals from 8 unrelated families with biallelic TNR variants (homozygous loss-of-function and missense); clinical phenotyping","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics with multiple independent families and orthogonal variant types, but no direct in vitro/in vivo functional reconstitution of the molecular mechanism","pmids":["32099069"],"is_preprint":false},{"year":2012,"finding":"Tenascin-R (TN-R) inhibits axonal regeneration after spinal cord injury; antagonist polyclonal antibody against TN-R promoted neurite outgrowth on TN-R substrate in vitro and, when administered in vivo, decreased RhoA activation and improved functional recovery after corticospinal tract transection in rats.","method":"In vitro neurite outgrowth assay on TN-R substrate with antibody antagonist; in vivo rat spinal cord dorsal hemisection model with local antibody administration; RhoA activation assay","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo methods in a single study, direct molecular readout (RhoA activation), single lab","pmids":["22902990"],"is_preprint":false},{"year":2023,"finding":"A TNR frameshift variant (c.831dupC, predicted to truncate >75% of the open reading frame) in Weimaraner dogs is associated with an exercise-induced paroxysmal dystonia-ataxia syndrome, demonstrating that loss of Tenascin-R function causes movement disorders in a canine model.","method":"Whole genome sequencing; identification of private homozygous frameshift variant in TNR; genotype-phenotype association in 4 affected and 70 unaffected dogs","journal":"Movement disorders : official journal of the Movement Disorder Society","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic association with perfect segregation in a cohort, but no direct functional/molecular mechanism study","pmids":["37023257"],"is_preprint":false},{"year":2025,"finding":"Biallelic TNR missense variants cause neurodevelopmental disorders with variable expressivity and reduced penetrance; TNR knockdown in vitro enhanced expression of dopamine receptor D2 (DRD2), indicating a negative regulatory relationship between TNR and DRD2 in the dopaminergic synaptic pathway.","method":"Exome and Sanger sequencing; Western blot and immunofluorescence; in vitro TNR knockdown with DRD2 expression measurement; systems genetics (BXD strains, co-expression analysis)","journal":"Journal of human genetics / Neurotoxicity research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro knockdown with single molecular readout (DRD2 expression), single lab, no mechanistic reconstitution","pmids":["41233622","41091226"],"is_preprint":false},{"year":2024,"finding":"Tenascin-R (Tnr) forms a complex with receptor protein tyrosine phosphatase zeta (RPTPζ) within perineuronal nets (PNNs), and this complex is bound to the neuronal cell surface by the GPI-linked protein contactin-1 (Cntn1); disruption of Cntn1 binding impairs PNN structure.","method":"Biochemical fractionation, structural analysis, and functional cell-surface binding assays in a perineuronal net context; PNN structural assessment upon Cntn1 manipulation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical and structural approach with functional validation of PNN structure, preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Piccolo, via an astrocyte-specific isoform localizing at the Golgi, regulates secretion of Tenascin-R (TNR) from astrocytes; loss of Piccolo (Pclo gt/gt) leads to altered extracellular TNR levels from astrocytes, which correlates with impaired synaptogenesis and altered neuronal network activity.","method":"RNA-sequencing, immunohistochemistry/immunocytochemistry, astrocyte-conditioned media experiments, Pclo gt/gt rat model, co-culture synapse density assays, electrophysiology (mEPSCs, mIPSCs)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in a single study with functional rescue by conditioned media, but preprint and single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Tenascin-R expression in cortical neurons is suppressed by hydrocortisone at 7 days in vitro (DIV) but not at 14 DIV; glucocorticoid receptor antagonism elevated TnR protein levels at 14 DIV, demonstrating developmental stage-dependent glucocorticoid regulation of TNR expression.","method":"Cultured mouse cortical neurons; mRNA and protein level measurements after hydrocortisone treatment; glucocorticoid receptor antagonism experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method per time point, expression-level readout without direct mechanistic dissection of the TNR protein function","pmids":[],"is_preprint":true}],"current_model":"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein that is required for the formation and structural integrity of perineuronal nets (via a complex with RPTPζ anchored to the neuronal surface by contactin-1), inhibits axonal regeneration after injury through a RhoA-dependent mechanism, is secreted from astrocytes in a Piccolo-dependent manner to support synaptogenesis, and negatively regulates dopamine receptor D2 (DRD2) expression; loss-of-function variants in humans and dogs cause nonprogressive neurodevelopmental and movement disorders."},"narrative":{"mechanistic_narrative":"Tenascin-R (TNR) is a CNS extracellular matrix glycoprotein required for normal neurodevelopment, as biallelic loss-of-function and missense variants cause a nonprogressive autosomal recessive disorder with spasticity in humans [PMID:32099069] and an analogous exercise-induced paroxysmal dystonia-ataxia syndrome in a canine model carrying a truncating frameshift variant [PMID:37023257]. Within perineuronal nets, TNR forms a complex with receptor protein tyrosine phosphatase zeta (RPTPζ) that is anchored to the neuronal surface by the GPI-linked protein contactin-1 (Cntn1), and disrupting Cntn1 binding impairs net structure. TNR also constrains axonal plasticity: it inhibits neurite outgrowth and axonal regeneration after spinal cord injury through a RhoA-dependent mechanism, and antibody antagonism reduces RhoA activation and improves functional recovery [PMID:22902990]. TNR is delivered to the matrix through Piccolo-dependent secretion from astrocytes, which supports synaptogenesis and shapes neuronal network activity, and it negatively regulates dopamine receptor D2 (DRD2) expression [PMID:41233622, PMID:41091226].","teleology":[{"year":2012,"claim":"Established that TNR is not merely a structural matrix component but an active inhibitor of axonal regeneration, defining a signaling mechanism through which it limits CNS plasticity.","evidence":"In vitro neurite outgrowth on TN-R substrate with antagonist antibody plus in vivo rat spinal cord hemisection and RhoA activation assay","pmids":["22902990"],"confidence":"Medium","gaps":["Receptor mediating the RhoA-dependent inhibitory signal not identified","Single lab, single injury model"]},{"year":2020,"claim":"Connected TNR loss directly to human disease, establishing that the gene is essential for normal CNS development.","evidence":"Exome sequencing and matchmaking across 13 individuals from 8 families with biallelic variants; clinical phenotyping","pmids":["32099069"],"confidence":"Medium","gaps":["No functional reconstitution linking specific variants to molecular defect","Mechanism connecting perineuronal net loss to spasticity unresolved"]},{"year":2023,"claim":"Demonstrated that TNR loss-of-function causes movement disorders across species, supporting a conserved requirement for TNR in motor circuit function.","evidence":"Whole genome sequencing and genotype-phenotype segregation in 4 affected and 70 unaffected Weimaraner dogs","pmids":["37023257"],"confidence":"Medium","gaps":["No molecular mechanism study","Cellular basis of paroxysmal phenotype unknown"]},{"year":2024,"claim":"Resolved how TNR is physically organized and retained within perineuronal nets, identifying its binding partners and surface anchor.","evidence":"Biochemical fractionation, structural analysis, and cell-surface binding assays with Cntn1 manipulation in a PNN context (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Stoichiometry and structural detail of the TNR–RPTPζ–Cntn1 assembly not fully defined"]},{"year":2025,"claim":"Identified the cellular source and secretory route of matrix TNR, linking astrocytic Piccolo-dependent secretion to synaptogenesis and circuit activity.","evidence":"RNA-seq, immunostaining, astrocyte-conditioned media rescue, Pclo gt/gt rat, co-culture synapse density, and electrophysiology (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Direct mechanism by which secreted TNR promotes synapse formation not defined"]},{"year":2025,"claim":"Extended the disease spectrum to missense variants and proposed a regulatory link between TNR and dopaminergic signaling via DRD2.","evidence":"Exome/Sanger sequencing, Western blot and immunofluorescence, in vitro TNR knockdown with DRD2 readout, BXD systems genetics","pmids":["41233622","41091226"],"confidence":"Low","gaps":["Single molecular readout (DRD2 expression) without mechanistic reconstitution","Directness of TNR–DRD2 relationship unestablished","Reduced penetrance not mechanistically explained"]},{"year":null,"claim":"The receptor and downstream signaling pathway by which TNR transduces its effects on axon growth, synaptogenesis, and DRD2 regulation remain only partially defined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified mechanism linking PNN assembly, RhoA-dependent growth inhibition, and dopaminergic regulation","No structural model of human disease variants"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]}],"complexes":["perineuronal net"],"partners":["PTPRZ1","CNTN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92752","full_name":"Tenascin-R","aliases":["Janusin","Restrictin"],"length_aa":1358,"mass_kda":149.6,"function":"Neural extracellular matrix (ECM) protein involved in interactions with different cells and matrix components. These interactions can influence cellular behavior by either evoking a stable adhesion and differentiation, or repulsion and inhibition of neurite growth. Binding to cell surface gangliosides inhibits RGD-dependent integrin-mediated cell adhesion and results in an inhibition of PTK2/FAK1 (FAK) phosphorylation and cell detachment. Binding to membrane surface sulfatides results in a oligodendrocyte adhesion and differentiation. Interaction with CNTN1 induces a repulsion of neurons and an inhibition of neurite outgrowth. Interacts with SCN2B may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier. TNR-linked chondroitin sulfate glycosaminoglycans are involved in the interaction with FN1 and mediate inhibition of cell adhesion and neurite outgrowth. The highly regulated addition of sulfated carbohydrate structure may modulate the adhesive properties of TNR over the course of development and during synapse maintenance (By similarity)","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q92752/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNR","total_profiled":1310},"omim":[{"mim_id":"619653","title":"NEURODEVELOPMENTAL DISORDER, NONPROGRESSIVE, WITH SPASTICITY AND TRANSIENT OPISTHOTONUS; NEDSTO","url":"https://www.omim.org/entry/619653"},{"mim_id":"608751","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8; CMH8","url":"https://www.omim.org/entry/608751"},{"mim_id":"602272","title":"TRANSCRIPTION FACTOR 4; TCF4","url":"https://www.omim.org/entry/602272"},{"mim_id":"601995","title":"TENASCIN R; TNR","url":"https://www.omim.org/entry/601995"},{"mim_id":"600985","title":"TENASCIN XB; TNXB","url":"https://www.omim.org/entry/600985"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":38.9},{"tissue":"retina","ntpm":15.1}],"url":"https://www.proteinatlas.org/search/TNR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q92752","domains":[{"cath_id":"-","chopping":"175-203","consensus_level":"medium","plddt":72.3883,"start":175,"end":203},{"cath_id":"2.60.40.10","chopping":"328-414","consensus_level":"high","plddt":87.8068,"start":328,"end":414},{"cath_id":"2.60.40.10","chopping":"420-485_496-502","consensus_level":"high","plddt":88.0926,"start":420,"end":502},{"cath_id":"2.60.40.10","chopping":"509-592","consensus_level":"high","plddt":84.8996,"start":509,"end":592},{"cath_id":"2.60.40.10","chopping":"599-684","consensus_level":"high","plddt":87.6744,"start":599,"end":684},{"cath_id":"2.60.40.10","chopping":"691-773","consensus_level":"medium","plddt":84.2257,"start":691,"end":773},{"cath_id":"2.60.40.10","chopping":"782-862","consensus_level":"high","plddt":82.8964,"start":782,"end":862},{"cath_id":"2.60.40.10","chopping":"958-1039","consensus_level":"medium","plddt":86.5957,"start":958,"end":1039},{"cath_id":"2.60.40.10","chopping":"1049-1128","consensus_level":"medium","plddt":83.8233,"start":1049,"end":1128},{"cath_id":"3.90.215.10","chopping":"1139-1355","consensus_level":"high","plddt":90.1522,"start":1139,"end":1355}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92752","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92752-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92752-F1-predicted_aligned_error_v6.png","plddt_mean":78.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNR","jax_strain_url":"https://www.jax.org/strain/search?query=TNR"},"sequence":{"accession":"Q92752","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92752.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92752/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92752"}},"corpus_meta":[{"pmid":"21507193","id":"PMC_21507193","title":"Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C-reactive protein and standard pathological risk factors: the TNR-C score.","date":"2011","source":"BJU international","url":"https://pubmed.ncbi.nlm.nih.gov/21507193","citation_count":82,"is_preprint":false},{"pmid":"32099069","id":"PMC_32099069","title":"Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus.","date":"2020","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32099069","citation_count":25,"is_preprint":false},{"pmid":"9786439","id":"PMC_9786439","title":"Circadian rhythm of the soluble p75 tumor necrosis factor (sTNF-R75) receptor in humans--a possible explanation for the circadian kinetics of TNR-alpha effects.","date":"1998","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9786439","citation_count":18,"is_preprint":false},{"pmid":"28510183","id":"PMC_28510183","title":"CFTR and TNR-CFTR expression and function in the kidney.","date":"2014","source":"Biophysical reviews","url":"https://pubmed.ncbi.nlm.nih.gov/28510183","citation_count":16,"is_preprint":false},{"pmid":"30563984","id":"PMC_30563984","title":"A case-control genome-wide association study of ADHD discovers a novel association with the tenascin R (TNR) gene.","date":"2018","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30563984","citation_count":14,"is_preprint":false},{"pmid":"22902990","id":"PMC_22902990","title":"Passive immunization with tenascin-R (TN-R) polyclonal antibody promotes axonal regeneration and functional recovery after spinal cord injury in rats.","date":"2012","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/22902990","citation_count":10,"is_preprint":false},{"pmid":"27417533","id":"PMC_27417533","title":"A dynamic trinucleotide repeat (TNR) expansion in the DMD gene.","date":"2016","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/27417533","citation_count":9,"is_preprint":false},{"pmid":"18769035","id":"PMC_18769035","title":"Small nuclear RNAs U11 and U12 modulate expression of TNR-CFTR mRNA in mammalian kidneys.","date":"2008","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18769035","citation_count":5,"is_preprint":false},{"pmid":"37023257","id":"PMC_37023257","title":"A TNR Frameshift Variant in Weimaraner Dogs with an Exercise-Induced Paroxysmal Movement Disorder.","date":"2023","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/37023257","citation_count":4,"is_preprint":false},{"pmid":"21063095","id":"PMC_21063095","title":"The hypertonic environment differentially regulates wild-type CFTR and TNR-CFTR chloride channels.","date":"2010","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21063095","citation_count":3,"is_preprint":false},{"pmid":"15225161","id":"PMC_15225161","title":"TNR/11q#1 trinucleotide (GCC)n repeat alleles and predisposition to acute and chronic leukemia.","date":"2004","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15225161","citation_count":1,"is_preprint":false},{"pmid":"41091226","id":"PMC_41091226","title":"Identification of TNR as a Potential Hippocampal Biomarker of Novelty Seeking Behavior with Integrated Quantitative Proteomics and Systems Genetics Approaches.","date":"2025","source":"Neurotoxicity research","url":"https://pubmed.ncbi.nlm.nih.gov/41091226","citation_count":0,"is_preprint":false},{"pmid":"41233622","id":"PMC_41233622","title":"Biallelic variants in TNR cause neurodevelopmental disorders with variable expressivity.","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41233622","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.11.675234","title":"REV1 inhibition enhances trinucleotide repeat mutagenesis","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.11.675234","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.18.689032","title":"DNMT1 Coordinates PV Interneuron–Glia Coupling to Maintain Cortical Network Stability and Regulate 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\"method\": \"Exome sequencing and matchmaking in 13 individuals from 8 unrelated families with biallelic TNR variants (homozygous loss-of-function and missense); clinical phenotyping\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics with multiple independent families and orthogonal variant types, but no direct in vitro/in vivo functional reconstitution of the molecular mechanism\",\n      \"pmids\": [\"32099069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tenascin-R (TN-R) inhibits axonal regeneration after spinal cord injury; antagonist polyclonal antibody against TN-R promoted neurite outgrowth on TN-R substrate in vitro and, when administered in vivo, decreased RhoA activation and improved functional recovery after corticospinal tract transection in rats.\",\n      \"method\": \"In vitro neurite outgrowth assay on TN-R substrate with antibody antagonist; in vivo rat spinal cord dorsal hemisection model with local antibody administration; RhoA activation assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo methods in a single study, direct molecular readout (RhoA activation), single lab\",\n      \"pmids\": [\"22902990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A TNR frameshift variant (c.831dupC, predicted to truncate >75% of the open reading frame) in Weimaraner dogs is associated with an exercise-induced paroxysmal dystonia-ataxia syndrome, demonstrating that loss of Tenascin-R function causes movement disorders in a canine model.\",\n      \"method\": \"Whole genome sequencing; identification of private homozygous frameshift variant in TNR; genotype-phenotype association in 4 affected and 70 unaffected dogs\",\n      \"journal\": \"Movement disorders : official journal of the Movement Disorder Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic association with perfect segregation in a cohort, but no direct functional/molecular mechanism study\",\n      \"pmids\": [\"37023257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic TNR missense variants cause neurodevelopmental disorders with variable expressivity and reduced penetrance; TNR knockdown in vitro enhanced expression of dopamine receptor D2 (DRD2), indicating a negative regulatory relationship between TNR and DRD2 in the dopaminergic synaptic pathway.\",\n      \"method\": \"Exome and Sanger sequencing; Western blot and immunofluorescence; in vitro TNR knockdown with DRD2 expression measurement; systems genetics (BXD strains, co-expression analysis)\",\n      \"journal\": \"Journal of human genetics / Neurotoxicity research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro knockdown with single molecular readout (DRD2 expression), single lab, no mechanistic reconstitution\",\n      \"pmids\": [\"41233622\", \"41091226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tenascin-R (Tnr) forms a complex with receptor protein tyrosine phosphatase zeta (RPTPζ) within perineuronal nets (PNNs), and this complex is bound to the neuronal cell surface by the GPI-linked protein contactin-1 (Cntn1); disruption of Cntn1 binding impairs PNN structure.\",\n      \"method\": \"Biochemical fractionation, structural analysis, and functional cell-surface binding assays in a perineuronal net context; PNN structural assessment upon Cntn1 manipulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical and structural approach with functional validation of PNN structure, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Piccolo, via an astrocyte-specific isoform localizing at the Golgi, regulates secretion of Tenascin-R (TNR) from astrocytes; loss of Piccolo (Pclo gt/gt) leads to altered extracellular TNR levels from astrocytes, which correlates with impaired synaptogenesis and altered neuronal network activity.\",\n      \"method\": \"RNA-sequencing, immunohistochemistry/immunocytochemistry, astrocyte-conditioned media experiments, Pclo gt/gt rat model, co-culture synapse density assays, electrophysiology (mEPSCs, mIPSCs)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in a single study with functional rescue by conditioned media, but preprint and single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tenascin-R expression in cortical neurons is suppressed by hydrocortisone at 7 days in vitro (DIV) but not at 14 DIV; glucocorticoid receptor antagonism elevated TnR protein levels at 14 DIV, demonstrating developmental stage-dependent glucocorticoid regulation of TNR expression.\",\n      \"method\": \"Cultured mouse cortical neurons; mRNA and protein level measurements after hydrocortisone treatment; glucocorticoid receptor antagonism experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per time point, expression-level readout without direct mechanistic dissection of the TNR protein function\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein that is required for the formation and structural integrity of perineuronal nets (via a complex with RPTPζ anchored to the neuronal surface by contactin-1), inhibits axonal regeneration after injury through a RhoA-dependent mechanism, is secreted from astrocytes in a Piccolo-dependent manner to support synaptogenesis, and negatively regulates dopamine receptor D2 (DRD2) expression; loss-of-function variants in humans and dogs cause nonprogressive neurodevelopmental and movement disorders.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Tenascin-R (TNR) is a CNS extracellular matrix glycoprotein required for normal neurodevelopment, as biallelic loss-of-function and missense variants cause a nonprogressive autosomal recessive disorder with spasticity in humans [#0] and an analogous exercise-induced paroxysmal dystonia-ataxia syndrome in a canine model carrying a truncating frameshift variant [#2]. Within perineuronal nets, TNR forms a complex with receptor protein tyrosine phosphatase zeta (RPTPζ) that is anchored to the neuronal surface by the GPI-linked protein contactin-1 (Cntn1), and disrupting Cntn1 binding impairs net structure [#4]. TNR also constrains axonal plasticity: it inhibits neurite outgrowth and axonal regeneration after spinal cord injury through a RhoA-dependent mechanism, and antibody antagonism reduces RhoA activation and improves functional recovery [#1]. TNR is delivered to the matrix through Piccolo-dependent secretion from astrocytes, which supports synaptogenesis and shapes neuronal network activity [#5], and it negatively regulates dopamine receptor D2 (DRD2) expression [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that TNR is not merely a structural matrix component but an active inhibitor of axonal regeneration, defining a signaling mechanism through which it limits CNS plasticity.\",\n      \"evidence\": \"In vitro neurite outgrowth on TN-R substrate with antagonist antibody plus in vivo rat spinal cord hemisection and RhoA activation assay\",\n      \"pmids\": [\"22902990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the RhoA-dependent inhibitory signal not identified\", \"Single lab, single injury model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected TNR loss directly to human disease, establishing that the gene is essential for normal CNS development.\",\n      \"evidence\": \"Exome sequencing and matchmaking across 13 individuals from 8 families with biallelic variants; clinical phenotyping\",\n      \"pmids\": [\"32099069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional reconstitution linking specific variants to molecular defect\", \"Mechanism connecting perineuronal net loss to spasticity unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that TNR loss-of-function causes movement disorders across species, supporting a conserved requirement for TNR in motor circuit function.\",\n      \"evidence\": \"Whole genome sequencing and genotype-phenotype segregation in 4 affected and 70 unaffected Weimaraner dogs\",\n      \"pmids\": [\"37023257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism study\", \"Cellular basis of paroxysmal phenotype unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved how TNR is physically organized and retained within perineuronal nets, identifying its binding partners and surface anchor.\",\n      \"evidence\": \"Biochemical fractionation, structural analysis, and cell-surface binding assays with Cntn1 manipulation in a PNN context (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Stoichiometry and structural detail of the TNR–RPTPζ–Cntn1 assembly not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the cellular source and secretory route of matrix TNR, linking astrocytic Piccolo-dependent secretion to synaptogenesis and circuit activity.\",\n      \"evidence\": \"RNA-seq, immunostaining, astrocyte-conditioned media rescue, Pclo gt/gt rat, co-culture synapse density, and electrophysiology (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Direct mechanism by which secreted TNR promotes synapse formation not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the disease spectrum to missense variants and proposed a regulatory link between TNR and dopaminergic signaling via DRD2.\",\n      \"evidence\": \"Exome/Sanger sequencing, Western blot and immunofluorescence, in vitro TNR knockdown with DRD2 readout, BXD systems genetics\",\n      \"pmids\": [\"41233622\", \"41091226\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single molecular readout (DRD2 expression) without mechanistic reconstitution\", \"Directness of TNR–DRD2 relationship unestablished\", \"Reduced penetrance not mechanistically explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor and downstream signaling pathway by which TNR transduces its effects on axon growth, synaptogenesis, and DRD2 regulation remain only partially defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified mechanism linking PNN assembly, RhoA-dependent growth inhibition, and dopaminergic regulation\", \"No structural model of human disease variants\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"perineuronal net\"],\n    \"partners\": [\"PTPRZ1\", \"CNTN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}