{"gene":"TCTN2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2011,"finding":"TCTN2 forms a protein complex with multiple ciliopathy proteins (MKS1, TMEM216, TMEM67, CEP290, B9D1, TCTN1, CC2D2A) that co-localizes at the transition zone of primary cilia. Loss of TCTN2 causes tissue-specific defects in ciliogenesis and in the localization of select membrane-associated proteins to the cilium (including ARL13B, AC3, Smoothened, PKD2).","method":"Co-immunoprecipitation, co-localization at transition zone, loss-of-function mouse models with ciliary membrane composition analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP complex identification, co-localization, and KO phenotypic analysis across multiple tissues; replicated for multiple complex members","pmids":["21725307"],"is_preprint":false},{"year":2015,"finding":"Super-resolution STED microscopy established that TCTN2, as a transmembrane protein, localizes at a specific axial level of the transition zone coinciding with MKS1 and RPGRIP1L, distinct from the axial position of CEP290.","method":"Stimulated emission depletion (STED) super-resolution microscopy with positional averaging","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct super-resolution localization experiment, single lab, structural positional data without full functional follow-up","pmids":["26365165"],"is_preprint":false},{"year":2017,"finding":"JBTS-associated mutations in TCTN2 displace certain transition-zone proteins from their normal positions within the transition zone, as defined by two-color STORM super-resolution microscopy. TCTN2 mutant cells show disrupted transition-zone architecture with NPHP and MKS complex components forming nested nine-fold doublet rings.","method":"Two-colour stochastic optical reconstruction microscopy (STORM) in patient-derived or mutant cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — super-resolution structural analysis with functional variant validation, directly linking TCTN2 mutation to architectural disruption of the transition zone","pmids":["28846093"],"is_preprint":false},{"year":2017,"finding":"Tctn2 mutant mice exhibit holoprosencephaly, randomized heart looping, and lack of the floor plate in the neural tube, phenotypes associated with severely reduced Hedgehog (Hh) signaling and ciliogenesis. Overexpression of Tctn1 or Tctn3 in the Tctn2 gene locus cannot rescue ciliogenesis and Hh signaling defects but can rescue neural tube patterning and Gli3 processing, indicating TCTN2 has a unique and non-redundant role in ciliogenesis and Hh signaling.","method":"Mouse knockout models, gene replacement at endogenous locus, Gli3 processing assays, neural tube patterning markers","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse models combined with gene replacement epistasis experiments and pathway readouts across multiple labs","pmids":["28800946"],"is_preprint":false},{"year":2018,"finding":"CRISPR/Cas9 knockout of TCTN2 in human RPE cells causes partial transition zone damage, loss of ciliary membrane proteins, leakage of intraflagellar transport protein IFT88 from the ciliary lumen toward the basal body lumen, and cilium shortening and curving, demonstrating that TCTN2 is required for structural integrity of the transition zone gate.","method":"CRISPR/Cas9 knockout cell line, super-resolution and wide-field microscopy, quantitative geometric localization analysis","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR KO with multiple orthogonal super-resolution readouts (ciliary membrane protein loss, IFT88 redistribution, cilium geometry), single lab but rigorous","pmids":["29866362"],"is_preprint":false},{"year":2021,"finding":"Tctn2 mutant mice display hypotelorism due to reduced Hedgehog (HH) pathway activation in the prechordal plate as early as the end of gastrulation, which precedes reduced Shh expression in the adjacent neurectoderm and increased cell death. Reducing gene dosage of the HH pathway negative regulator Ptch1 rescues midface defects in Tctn2 mutants, placing TCTN2 upstream of HH-mediated cell survival in facial midline development.","method":"Mouse knockout models, genetic epistasis (Tctn2 mutant × Ptch1 heterozygous), HH pathway reporters, cell death assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue experiment with HH pathway readouts and temporal staging, multiple orthogonal methods in single study","pmids":["34672258"],"is_preprint":false},{"year":2012,"finding":"TCTN3, a paralog of TCTN2, forms a complex at the ciliary transition zone with TCTN1 and TCTN2, and TCTN3 loss results in abnormal GLI3 processing in patient cells, consistent with roles for the entire Tectonic complex in SHH signaling transduction.","method":"Patient cell GLI3 processing assay, complex co-localization studies","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assay in patient cells and co-localization; provides indirect mechanistic context for TCTN2 complex function rather than direct TCTN2 assay","pmids":["22883145"],"is_preprint":false},{"year":2018,"finding":"Knockdown of tctn2 in zebrafish disrupts cardiac looping and causes abnormal expression of left-right patterning markers lefty2 and pitx2, demonstrating a role for TCTN2 in left-right axis specification.","method":"Morpholino knockdown in zebrafish, cardiac looping assay, in situ hybridization for lefty2/pitx2","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — morpholino KD in zebrafish with defined molecular readout (lefty2/pitx2), single lab, single method","pmids":["29843777"],"is_preprint":false},{"year":2022,"finding":"MXI1 (Max interacting protein 1) binds to the TCTN2 promoter to promote its transcription, and upregulated TCTN2 mediates MXI1-driven Th17/Treg imbalance in osteoarthritis; silencing TCTN2 negates the effects of MXI1 overexpression on T cell differentiation.","method":"Chromatin binding assay (MXI1 binding to TCTN2 promoter), loss- and gain-of-function experiments in CD4+ T cells and OA mouse model, flow cytometry for Th17/Treg proportions","journal":"Tissue & cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, promoter binding and epistasis assays without full mechanistic resolution of how TCTN2 protein mediates T cell effects; context is unusual relative to canonical TCTN2 ciliary function","pmids":["36049372"],"is_preprint":false},{"year":2025,"finding":"In human neural tube organoids, TCTN2 deficiency causes dorsal-ventral patterning defects, and this phenotype could be modeled and rescued, demonstrating a role for TCTN2 in SHH-dependent D-V neural tube patterning in a human cellular context.","method":"hPSC-derived neural tube organoids with TCTN2 mutation, single-cell transcriptomics, rescue assays","journal":"Cell stem cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human organoid model with transcriptomic readout and rescue, single lab; novel human-context evidence for known ciliary HH-signaling role","pmids":["40373768"],"is_preprint":false}],"current_model":"TCTN2 is a transmembrane protein that localizes to the transition zone (TZ) of primary cilia as part of a large MKS/JBTS protein complex (including MKS1, TMEM216, TMEM67, CEP290, B9D1, TCTN1, CC2D2A); it is required for structural integrity of the TZ gate, the correct localization of ciliary membrane proteins (ARL13B, SMO, PKD2, AC3), and proper IFT88 confinement to the ciliary lumen, and acts upstream of Hedgehog (SHH) pathway activation to regulate tissue-specific ciliogenesis, neural tube and facial midline patterning, Gli3 processing, and left-right axis specification."},"narrative":{"mechanistic_narrative":"TCTN2 is a transmembrane component of the ciliary transition-zone (TZ) gating apparatus that controls the protein composition of the primary cilium and thereby enables Hedgehog signaling during development [PMID:21725307, PMID:29866362]. It assembles into a large TZ complex with ciliopathy proteins MKS1, TMEM216, TMEM67, CEP290, B9D1, TCTN1, and CC2D2A, occupying a defined axial level of the TZ coincident with MKS1 and RPGRIP1L and distinct from CEP290 [PMID:21725307, PMID:26365165]. This complex is required for the selective ciliary localization of membrane-associated proteins, including ARL13B, Smoothened, PKD2, and AC3, and for confining the intraflagellar transport protein IFT88 to the ciliary lumen; loss of TCTN2 damages the TZ gate, disrupts the nested ninefold ring architecture of NPHP and MKS complex components, and produces shortened, curved cilia [PMID:21725307, PMID:28846093, PMID:29866362]. Through this gating function TCTN2 acts upstream of Hedgehog pathway activation, where it has a non-redundant role not substitutable by its paralogs TCTN1 or TCTN3: Tctn2 loss reduces Hh signaling and ciliogenesis, alters Gli3 processing, and causes holoprosencephaly, hypotelorism, floor-plate loss, and randomized heart looping, with midface defects rescuable by reducing dosage of the Hh negative regulator Ptch1 [PMID:28800946, PMID:34672258]. Its requirement for SHH-dependent dorsoventral and left-right patterning is conserved in zebrafish and in human neural tube organoids [PMID:29843777, PMID:40373768]. Mutations in TCTN2 cause Joubert syndrome, where they displace TZ proteins from their normal positions [PMID:28846093].","teleology":[{"year":2011,"claim":"Established that TCTN2 is not an isolated ciliary protein but a member of a defined transition-zone ciliopathy complex whose loss selectively alters ciliary membrane composition, framing it as a gate component rather than a structural axoneme protein.","evidence":"Co-immunoprecipitation, transition-zone co-localization, and loss-of-function mouse models with ciliary membrane composition analysis","pmids":["21725307"],"confidence":"High","gaps":["Did not resolve the molecular topology or stoichiometry of TCTN2 within the complex","Mechanism by which the complex selects specific membrane proteins (ARL13B, SMO, PKD2, AC3) unresolved"]},{"year":2012,"claim":"Showed the Tectonic complex (TCTN1/2/3) collectively transduces SHH signaling via GLI3 processing, placing TCTN2's complex in the Hedgehog output pathway.","evidence":"Patient-cell GLI3 processing assay and complex co-localization for the paralog TCTN3","pmids":["22883145"],"confidence":"Medium","gaps":["Evidence is on TCTN3, providing only indirect context for TCTN2","No direct demonstration that TCTN2 itself drives GLI3 processing in this study"]},{"year":2015,"claim":"Pinpointed the axial position of TCTN2 within the transition zone, distinguishing its location from CEP290 and aligning it with MKS1/RPGRIP1L, refining the architectural map of the gate.","evidence":"STED super-resolution microscopy with positional averaging","pmids":["26365165"],"confidence":"Medium","gaps":["Positional data without functional consequence of the position","Single-lab structural measurement"]},{"year":2017,"claim":"Linked TCTN2 disease mutations directly to physical disorganization of the transition-zone architecture, connecting genotype to a structural defect in the gate.","evidence":"Two-colour STORM super-resolution microscopy in mutant/patient-derived cells","pmids":["28846093"],"confidence":"High","gaps":["Does not establish which interaction surface of TCTN2 maintains protein positioning","Quantitative link between architectural disruption and signaling failure not resolved here"]},{"year":2017,"claim":"Demonstrated TCTN2 has a non-redundant, paralog-specific role in ciliogenesis and Hedgehog signaling that cannot be substituted by TCTN1 or TCTN3, separating ciliogenic function from neural-tube patterning function.","evidence":"Mouse knockouts, gene replacement at the endogenous locus, Gli3 processing assays, and neural tube patterning markers","pmids":["28800946"],"confidence":"High","gaps":["Molecular basis for TCTN2's unique non-redundancy not identified","How Gli3 processing is partially rescued by paralogs while ciliogenesis is not remains unexplained"]},{"year":2018,"claim":"Provided direct cell-biological proof that TCTN2 is required for the structural integrity of the TZ gate, showing IFT88 leakage and cilium geometry defects upon clean knockout.","evidence":"CRISPR/Cas9 knockout in human RPE cells with super-resolution and quantitative geometric localization analysis","pmids":["29866362"],"confidence":"High","gaps":["Single cell type (RPE); tissue specificity of the gate defect not addressed","Does not define the physical barrier mechanism preventing IFT88 escape"]},{"year":2018,"claim":"Extended TCTN2's developmental role to left-right axis specification in a second vertebrate, linking the gate to laterality marker expression.","evidence":"Morpholino knockdown in zebrafish with cardiac looping assay and lefty2/pitx2 in situ hybridization","pmids":["29843777"],"confidence":"Medium","gaps":["Morpholino-based knockdown without genetic confirmation","Ciliary mechanism in the laterality organ not directly shown"]},{"year":2021,"claim":"Resolved the temporal and epistatic placement of TCTN2 in facial development, showing it acts upstream of Ptch1/Hh-mediated cell survival in the prechordal plate before neurectoderm Shh changes.","evidence":"Mouse genetic epistasis (Tctn2 × Ptch1 heterozygous), HH reporters, cell death assays with temporal staging","pmids":["34672258"],"confidence":"High","gaps":["Does not define how the TZ gate defect translates into reduced prechordal-plate Hh activation","Cell-survival readout downstream; direct ciliary signaling state in prechordal plate not measured"]},{"year":2022,"claim":"Reported a non-ciliary context in which TCTN2 is transcriptionally activated by MXI1 and mediates Th17/Treg imbalance in osteoarthritis.","evidence":"MXI1–TCTN2 promoter binding, loss/gain-of-function in CD4+ T cells and OA mouse model, flow cytometry","pmids":["36049372"],"confidence":"Low","gaps":["Single lab and not independently confirmed","Mechanism by which TCTN2 protein influences T-cell differentiation undefined and disconnected from its ciliary role"]},{"year":2025,"claim":"Confirmed TCTN2's requirement for SHH-dependent dorsoventral neural tube patterning in a human cellular system, with rescue validating causality.","evidence":"hPSC-derived neural tube organoids with TCTN2 mutation, single-cell transcriptomics, and rescue assays","pmids":["40373768"],"confidence":"Medium","gaps":["Single-lab human organoid model","Does not resolve the molecular step linking TZ gate integrity to D-V SHH gradient interpretation"]},{"year":null,"claim":"How the TCTN2-containing transition-zone complex physically discriminates which membrane proteins cross the gate, and how this selective gating is mechanistically coupled to Hedgehog pathway activation, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the gating barrier or TCTN2's role within it","Molecular link between gate integrity and Gli3 processing / Hh activation undefined","Basis of TCTN2's non-redundancy with paralogs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5,7,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,4]}],"complexes":["MKS/Tectonic transition-zone complex"],"partners":["MKS1","TMEM216","TMEM67","CEP290","B9D1","TCTN1","CC2D2A","TCTN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96GX1","full_name":"Tectonic-2","aliases":[],"length_aa":697,"mass_kda":76.9,"function":"Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for hedgehog signaling transduction (By similarity)","subcellular_location":"Membrane; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q96GX1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TCTN2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TCTN2","total_profiled":1310},"omim":[{"mim_id":"620248","title":"TRANSMEMBRANE PROTEIN 80; TMEM80","url":"https://www.omim.org/entry/620248"},{"mim_id":"616654","title":"JOUBERT SYNDROME 24; JBTS24","url":"https://www.omim.org/entry/616654"},{"mim_id":"614950","title":"TRANSMEMBRANE PROTEIN 17; TMEM17","url":"https://www.omim.org/entry/614950"},{"mim_id":"614949","title":"TRANSMEMBRANE PROTEIN 231; TMEM231","url":"https://www.omim.org/entry/614949"},{"mim_id":"614144","title":"B9 DOMAIN-CONTAINING PROTEIN 1; B9D1","url":"https://www.omim.org/entry/614144"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Microtubules","reliability":"Approved"},{"location":"Primary cilium transition zone","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":37.2}],"url":"https://www.proteinatlas.org/search/TCTN2"},"hgnc":{"alias_symbol":["FLJ12975","TECT2","MKS8","JBTS24"],"prev_symbol":["C12orf38"]},"alphafold":{"accession":"Q96GX1","domains":[{"cath_id":"2.60.40.10","chopping":"8-102_118-144","consensus_level":"high","plddt":70.5154,"start":8,"end":144},{"cath_id":"-","chopping":"191-242","consensus_level":"medium","plddt":61.7623,"start":191,"end":242},{"cath_id":"-","chopping":"270-431","consensus_level":"medium","plddt":79.3383,"start":270,"end":431},{"cath_id":"-","chopping":"433-547_554-628","consensus_level":"medium","plddt":85.1155,"start":433,"end":628},{"cath_id":"-","chopping":"650-692","consensus_level":"high","plddt":80.706,"start":650,"end":692}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GX1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GX1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GX1-F1-predicted_aligned_error_v6.png","plddt_mean":74.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TCTN2","jax_strain_url":"https://www.jax.org/strain/search?query=TCTN2"},"sequence":{"accession":"Q96GX1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96GX1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96GX1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GX1"}},"corpus_meta":[{"pmid":"21725307","id":"PMC_21725307","title":"A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21725307","citation_count":524,"is_preprint":false},{"pmid":"28846093","id":"PMC_28846093","title":"Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome.","date":"2017","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28846093","citation_count":134,"is_preprint":false},{"pmid":"26365165","id":"PMC_26365165","title":"Superresolution Pattern Recognition Reveals the Architectural Map of the Ciliary Transition Zone.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26365165","citation_count":125,"is_preprint":false},{"pmid":"22883145","id":"PMC_22883145","title":"TCTN3 mutations cause Mohr-Majewski syndrome.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22883145","citation_count":107,"is_preprint":false},{"pmid":"22331178","id":"PMC_22331178","title":"Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia.","date":"2012","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/22331178","citation_count":70,"is_preprint":false},{"pmid":"21462283","id":"PMC_21462283","title":"A TCTN2 mutation defines a novel Meckel Gruber syndrome locus.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21462283","citation_count":65,"is_preprint":false},{"pmid":"32139166","id":"PMC_32139166","title":"Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders.","date":"2020","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32139166","citation_count":62,"is_preprint":false},{"pmid":"29725084","id":"PMC_29725084","title":"Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29725084","citation_count":42,"is_preprint":false},{"pmid":"31050183","id":"PMC_31050183","title":"Overexpression of lncRNA TCTN2 protects neurons from apoptosis by enhancing cell autophagy in spinal cord injury.","date":"2019","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/31050183","citation_count":40,"is_preprint":false},{"pmid":"29843777","id":"PMC_29843777","title":"Rare copy number variants analysis identifies novel candidate genes in heterotaxy syndrome patients with congenital heart defects.","date":"2018","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29843777","citation_count":34,"is_preprint":false},{"pmid":"34623606","id":"PMC_34623606","title":"Exosomes Derived from lncRNA TCTN2-Modified Mesenchymal Stem Cells Improve Spinal Cord Injury by miR-329-3p/IGF1R Axis.","date":"2021","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/34623606","citation_count":33,"is_preprint":false},{"pmid":"25118024","id":"PMC_25118024","title":"Tectonic gene mutations in patients with Joubert syndrome.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/25118024","citation_count":30,"is_preprint":false},{"pmid":"28800946","id":"PMC_28800946","title":"Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse.","date":"2017","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/28800946","citation_count":18,"is_preprint":false},{"pmid":"29866362","id":"PMC_29866362","title":"Super-Resolution Imaging Reveals TCTN2 Depletion-Induced IFT88 Lumen Leakage and Ciliary Weakening.","date":"2018","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/29866362","citation_count":17,"is_preprint":false},{"pmid":"30286481","id":"PMC_30286481","title":"Tectonic Proteins Are Important Players in Non-Motile Ciliopathies.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30286481","citation_count":15,"is_preprint":false},{"pmid":"28215051","id":"PMC_28215051","title":"(Pro)renin receptor (ATP6AP2) depletion arrests As4.1 cells in the G0/G1 phase thereby increasing formation of primary cilia.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28215051","citation_count":12,"is_preprint":false},{"pmid":"36049372","id":"PMC_36049372","title":"Max interacting protein 1 induces IL-17-producing T helper/regulatory T imbalance in osteoarthritis by upregulating tectonic family member 2.","date":"2022","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/36049372","citation_count":11,"is_preprint":false},{"pmid":"36894704","id":"PMC_36894704","title":"A deep intronic TCTN2 variant activating a cryptic exon predicted by SpliceRover in a patient with Joubert syndrome.","date":"2023","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36894704","citation_count":9,"is_preprint":false},{"pmid":"34672258","id":"PMC_34672258","title":"Ciliary Hedgehog signaling regulates cell survival to build the facial midline.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34672258","citation_count":8,"is_preprint":false},{"pmid":"40373768","id":"PMC_40373768","title":"Establishing dorsal-ventral patterning in human neural tube organoids with synthetic organizers.","date":"2025","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/40373768","citation_count":6,"is_preprint":false},{"pmid":"37727797","id":"PMC_37727797","title":"Tanshinone IIA protects motor neuron-like NSC-34 cells against lipopolysaccharide-induced cell injury by the regulation of the lncRNA TCTN2/miR-125a-5p/DUSP1 axis.","date":"2023","source":"Regenerative therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37727797","citation_count":2,"is_preprint":false},{"pmid":"36278455","id":"PMC_36278455","title":"LncRNA TCTN2 Promotes the Malignant Development of Hepatocellular Carcinoma via Regulating mIR-1285-3p/ARF6 Axis.","date":"2023","source":"Recent patents on anti-cancer drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36278455","citation_count":1,"is_preprint":false},{"pmid":"41317100","id":"PMC_41317100","title":"Novel Compound Heterozygous Variants in the TCTN2 Gene Causing Meckel-Gruber Syndrome 8 in a Non-Consanguineous Chinese Family.","date":"2025","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41317100","citation_count":0,"is_preprint":false},{"pmid":"42044428","id":"PMC_42044428","title":"Molecular Spectrum and Deep Phenotyping of a Turkish Joubert Syndrome Cohort, Including a Potential Candidate Gene, NPHP4.","date":"2025","source":"Turkish archives of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/42044428","citation_count":0,"is_preprint":false},{"pmid":"38778612","id":"PMC_38778612","title":"A Mutation in the CACNA1F Gene Found by Whole Exome Sequencing (WES) and In Silico Analysis in an Iranian Family with Consanguineous Relationships.","date":"2025","source":"Current aging science","url":"https://pubmed.ncbi.nlm.nih.gov/38778612","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15207,"output_tokens":2539,"usd":0.041853,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9697,"output_tokens":3473,"usd":0.067655,"stage2_stop_reason":"end_turn"},"total_usd":0.109508,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"TCTN2 forms a protein complex with multiple ciliopathy proteins (MKS1, TMEM216, TMEM67, CEP290, B9D1, TCTN1, CC2D2A) that co-localizes at the transition zone of primary cilia. Loss of TCTN2 causes tissue-specific defects in ciliogenesis and in the localization of select membrane-associated proteins to the cilium (including ARL13B, AC3, Smoothened, PKD2).\",\n      \"method\": \"Co-immunoprecipitation, co-localization at transition zone, loss-of-function mouse models with ciliary membrane composition analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP complex identification, co-localization, and KO phenotypic analysis across multiple tissues; replicated for multiple complex members\",\n      \"pmids\": [\"21725307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Super-resolution STED microscopy established that TCTN2, as a transmembrane protein, localizes at a specific axial level of the transition zone coinciding with MKS1 and RPGRIP1L, distinct from the axial position of CEP290.\",\n      \"method\": \"Stimulated emission depletion (STED) super-resolution microscopy with positional averaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct super-resolution localization experiment, single lab, structural positional data without full functional follow-up\",\n      \"pmids\": [\"26365165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JBTS-associated mutations in TCTN2 displace certain transition-zone proteins from their normal positions within the transition zone, as defined by two-color STORM super-resolution microscopy. TCTN2 mutant cells show disrupted transition-zone architecture with NPHP and MKS complex components forming nested nine-fold doublet rings.\",\n      \"method\": \"Two-colour stochastic optical reconstruction microscopy (STORM) in patient-derived or mutant cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — super-resolution structural analysis with functional variant validation, directly linking TCTN2 mutation to architectural disruption of the transition zone\",\n      \"pmids\": [\"28846093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tctn2 mutant mice exhibit holoprosencephaly, randomized heart looping, and lack of the floor plate in the neural tube, phenotypes associated with severely reduced Hedgehog (Hh) signaling and ciliogenesis. Overexpression of Tctn1 or Tctn3 in the Tctn2 gene locus cannot rescue ciliogenesis and Hh signaling defects but can rescue neural tube patterning and Gli3 processing, indicating TCTN2 has a unique and non-redundant role in ciliogenesis and Hh signaling.\",\n      \"method\": \"Mouse knockout models, gene replacement at endogenous locus, Gli3 processing assays, neural tube patterning markers\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse models combined with gene replacement epistasis experiments and pathway readouts across multiple labs\",\n      \"pmids\": [\"28800946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRISPR/Cas9 knockout of TCTN2 in human RPE cells causes partial transition zone damage, loss of ciliary membrane proteins, leakage of intraflagellar transport protein IFT88 from the ciliary lumen toward the basal body lumen, and cilium shortening and curving, demonstrating that TCTN2 is required for structural integrity of the transition zone gate.\",\n      \"method\": \"CRISPR/Cas9 knockout cell line, super-resolution and wide-field microscopy, quantitative geometric localization analysis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR KO with multiple orthogonal super-resolution readouts (ciliary membrane protein loss, IFT88 redistribution, cilium geometry), single lab but rigorous\",\n      \"pmids\": [\"29866362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tctn2 mutant mice display hypotelorism due to reduced Hedgehog (HH) pathway activation in the prechordal plate as early as the end of gastrulation, which precedes reduced Shh expression in the adjacent neurectoderm and increased cell death. Reducing gene dosage of the HH pathway negative regulator Ptch1 rescues midface defects in Tctn2 mutants, placing TCTN2 upstream of HH-mediated cell survival in facial midline development.\",\n      \"method\": \"Mouse knockout models, genetic epistasis (Tctn2 mutant × Ptch1 heterozygous), HH pathway reporters, cell death assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue experiment with HH pathway readouts and temporal staging, multiple orthogonal methods in single study\",\n      \"pmids\": [\"34672258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TCTN3, a paralog of TCTN2, forms a complex at the ciliary transition zone with TCTN1 and TCTN2, and TCTN3 loss results in abnormal GLI3 processing in patient cells, consistent with roles for the entire Tectonic complex in SHH signaling transduction.\",\n      \"method\": \"Patient cell GLI3 processing assay, complex co-localization studies\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assay in patient cells and co-localization; provides indirect mechanistic context for TCTN2 complex function rather than direct TCTN2 assay\",\n      \"pmids\": [\"22883145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of tctn2 in zebrafish disrupts cardiac looping and causes abnormal expression of left-right patterning markers lefty2 and pitx2, demonstrating a role for TCTN2 in left-right axis specification.\",\n      \"method\": \"Morpholino knockdown in zebrafish, cardiac looping assay, in situ hybridization for lefty2/pitx2\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — morpholino KD in zebrafish with defined molecular readout (lefty2/pitx2), single lab, single method\",\n      \"pmids\": [\"29843777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MXI1 (Max interacting protein 1) binds to the TCTN2 promoter to promote its transcription, and upregulated TCTN2 mediates MXI1-driven Th17/Treg imbalance in osteoarthritis; silencing TCTN2 negates the effects of MXI1 overexpression on T cell differentiation.\",\n      \"method\": \"Chromatin binding assay (MXI1 binding to TCTN2 promoter), loss- and gain-of-function experiments in CD4+ T cells and OA mouse model, flow cytometry for Th17/Treg proportions\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, promoter binding and epistasis assays without full mechanistic resolution of how TCTN2 protein mediates T cell effects; context is unusual relative to canonical TCTN2 ciliary function\",\n      \"pmids\": [\"36049372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In human neural tube organoids, TCTN2 deficiency causes dorsal-ventral patterning defects, and this phenotype could be modeled and rescued, demonstrating a role for TCTN2 in SHH-dependent D-V neural tube patterning in a human cellular context.\",\n      \"method\": \"hPSC-derived neural tube organoids with TCTN2 mutation, single-cell transcriptomics, rescue assays\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human organoid model with transcriptomic readout and rescue, single lab; novel human-context evidence for known ciliary HH-signaling role\",\n      \"pmids\": [\"40373768\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TCTN2 is a transmembrane protein that localizes to the transition zone (TZ) of primary cilia as part of a large MKS/JBTS protein complex (including MKS1, TMEM216, TMEM67, CEP290, B9D1, TCTN1, CC2D2A); it is required for structural integrity of the TZ gate, the correct localization of ciliary membrane proteins (ARL13B, SMO, PKD2, AC3), and proper IFT88 confinement to the ciliary lumen, and acts upstream of Hedgehog (SHH) pathway activation to regulate tissue-specific ciliogenesis, neural tube and facial midline patterning, Gli3 processing, and left-right axis specification.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TCTN2 is a transmembrane component of the ciliary transition-zone (TZ) gating apparatus that controls the protein composition of the primary cilium and thereby enables Hedgehog signaling during development [#0, #4]. It assembles into a large TZ complex with ciliopathy proteins MKS1, TMEM216, TMEM67, CEP290, B9D1, TCTN1, and CC2D2A, occupying a defined axial level of the TZ coincident with MKS1 and RPGRIP1L and distinct from CEP290 [#0, #1]. This complex is required for the selective ciliary localization of membrane-associated proteins, including ARL13B, Smoothened, PKD2, and AC3, and for confining the intraflagellar transport protein IFT88 to the ciliary lumen; loss of TCTN2 damages the TZ gate, disrupts the nested ninefold ring architecture of NPHP and MKS complex components, and produces shortened, curved cilia [#0, #2, #4]. Through this gating function TCTN2 acts upstream of Hedgehog pathway activation, where it has a non-redundant role not substitutable by its paralogs TCTN1 or TCTN3: Tctn2 loss reduces Hh signaling and ciliogenesis, alters Gli3 processing, and causes holoprosencephaly, hypotelorism, floor-plate loss, and randomized heart looping, with midface defects rescuable by reducing dosage of the Hh negative regulator Ptch1 [#3, #5]. Its requirement for SHH-dependent dorsoventral and left-right patterning is conserved in zebrafish and in human neural tube organoids [#7, #9]. Mutations in TCTN2 cause Joubert syndrome, where they displace TZ proteins from their normal positions [#2].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that TCTN2 is not an isolated ciliary protein but a member of a defined transition-zone ciliopathy complex whose loss selectively alters ciliary membrane composition, framing it as a gate component rather than a structural axoneme protein.\",\n      \"evidence\": \"Co-immunoprecipitation, transition-zone co-localization, and loss-of-function mouse models with ciliary membrane composition analysis\",\n      \"pmids\": [\"21725307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular topology or stoichiometry of TCTN2 within the complex\", \"Mechanism by which the complex selects specific membrane proteins (ARL13B, SMO, PKD2, AC3) unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed the Tectonic complex (TCTN1/2/3) collectively transduces SHH signaling via GLI3 processing, placing TCTN2's complex in the Hedgehog output pathway.\",\n      \"evidence\": \"Patient-cell GLI3 processing assay and complex co-localization for the paralog TCTN3\",\n      \"pmids\": [\"22883145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Evidence is on TCTN3, providing only indirect context for TCTN2\", \"No direct demonstration that TCTN2 itself drives GLI3 processing in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Pinpointed the axial position of TCTN2 within the transition zone, distinguishing its location from CEP290 and aligning it with MKS1/RPGRIP1L, refining the architectural map of the gate.\",\n      \"evidence\": \"STED super-resolution microscopy with positional averaging\",\n      \"pmids\": [\"26365165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Positional data without functional consequence of the position\", \"Single-lab structural measurement\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked TCTN2 disease mutations directly to physical disorganization of the transition-zone architecture, connecting genotype to a structural defect in the gate.\",\n      \"evidence\": \"Two-colour STORM super-resolution microscopy in mutant/patient-derived cells\",\n      \"pmids\": [\"28846093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish which interaction surface of TCTN2 maintains protein positioning\", \"Quantitative link between architectural disruption and signaling failure not resolved here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated TCTN2 has a non-redundant, paralog-specific role in ciliogenesis and Hedgehog signaling that cannot be substituted by TCTN1 or TCTN3, separating ciliogenic function from neural-tube patterning function.\",\n      \"evidence\": \"Mouse knockouts, gene replacement at the endogenous locus, Gli3 processing assays, and neural tube patterning markers\",\n      \"pmids\": [\"28800946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for TCTN2's unique non-redundancy not identified\", \"How Gli3 processing is partially rescued by paralogs while ciliogenesis is not remains unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided direct cell-biological proof that TCTN2 is required for the structural integrity of the TZ gate, showing IFT88 leakage and cilium geometry defects upon clean knockout.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in human RPE cells with super-resolution and quantitative geometric localization analysis\",\n      \"pmids\": [\"29866362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single cell type (RPE); tissue specificity of the gate defect not addressed\", \"Does not define the physical barrier mechanism preventing IFT88 escape\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended TCTN2's developmental role to left-right axis specification in a second vertebrate, linking the gate to laterality marker expression.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with cardiac looping assay and lefty2/pitx2 in situ hybridization\",\n      \"pmids\": [\"29843777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino-based knockdown without genetic confirmation\", \"Ciliary mechanism in the laterality organ not directly shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the temporal and epistatic placement of TCTN2 in facial development, showing it acts upstream of Ptch1/Hh-mediated cell survival in the prechordal plate before neurectoderm Shh changes.\",\n      \"evidence\": \"Mouse genetic epistasis (Tctn2 × Ptch1 heterozygous), HH reporters, cell death assays with temporal staging\",\n      \"pmids\": [\"34672258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how the TZ gate defect translates into reduced prechordal-plate Hh activation\", \"Cell-survival readout downstream; direct ciliary signaling state in prechordal plate not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported a non-ciliary context in which TCTN2 is transcriptionally activated by MXI1 and mediates Th17/Treg imbalance in osteoarthritis.\",\n      \"evidence\": \"MXI1–TCTN2 promoter binding, loss/gain-of-function in CD4+ T cells and OA mouse model, flow cytometry\",\n      \"pmids\": [\"36049372\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab and not independently confirmed\", \"Mechanism by which TCTN2 protein influences T-cell differentiation undefined and disconnected from its ciliary role\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed TCTN2's requirement for SHH-dependent dorsoventral neural tube patterning in a human cellular system, with rescue validating causality.\",\n      \"evidence\": \"hPSC-derived neural tube organoids with TCTN2 mutation, single-cell transcriptomics, and rescue assays\",\n      \"pmids\": [\"40373768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab human organoid model\", \"Does not resolve the molecular step linking TZ gate integrity to D-V SHH gradient interpretation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the TCTN2-containing transition-zone complex physically discriminates which membrane proteins cross the gate, and how this selective gating is mechanistically coupled to Hedgehog pathway activation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the gating barrier or TCTN2's role within it\", \"Molecular link between gate integrity and Gli3 processing / Hh activation undefined\", \"Basis of TCTN2's non-redundancy with paralogs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\"MKS/Tectonic transition-zone complex\"],\n    \"partners\": [\"MKS1\", \"TMEM216\", \"TMEM67\", \"CEP290\", \"B9D1\", \"TCTN1\", \"CC2D2A\", \"TCTN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}