{"gene":"TMEM237","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2011,"finding":"TMEM237 localizes to the ciliary transition zone (TZ) in mammalian cells, and its loss results in defective ciliogenesis and deregulation of Wnt signaling.","method":"Immunofluorescence localization, loss-of-function experiments in mammalian cells with ciliogenesis and Wnt signaling readouts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence (ciliogenesis defect), Wnt signaling deregulation, replicated across mammalian, zebrafish, and C. elegans models in same study","pmids":["22152675"],"is_preprint":false},{"year":2011,"finding":"C. elegans jbts-14 (TMEM237 ortholog) genetically interacts with nphp-4 to control basal body–transition zone anchoring to the membrane and ciliogenesis, establishing epistatic pathway placement.","method":"C. elegans genetic epistasis (double mutant analysis), ciliogenesis assays","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with defined phenotypic readout (basal body–TZ anchoring, ciliogenesis), multiple orthogonal methods across organisms in same study","pmids":["22152675"],"is_preprint":false},{"year":2011,"finding":"Both mammalian TMEM237 and C. elegans JBTS-14 require RPGRIP1L/MKS5 for proper transition zone localization, and JBTS-14 additionally shows functional interactions with MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2.","method":"C. elegans genetic and localization analyses; mammalian RPGRIP1L knockdown with TZ localization readout","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization dependency experiment with multiple genetic interaction partners confirmed across two model systems","pmids":["22152675"],"is_preprint":false},{"year":2011,"finding":"Disruption of zebrafish tmem237 expression produces gastrulation defects consistent with ciliary dysfunction.","method":"Morpholino knockdown in Danio rerio with gastrulation phenotype readout","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in zebrafish with defined phenotype, single study","pmids":["22152675"],"is_preprint":false},{"year":2015,"finding":"In C. elegans, TMEM-107 organizes recruitment of JBTS-14 (TMEM237) within the MKS module at the transition zone, placing TMEM237 in an intermediate layer of TZ subdomain architecture.","method":"C. elegans genetic analysis, fluorescence localization of TZ proteins in tmem-107 mutants","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization dependency experiments with super-resolution microscopy and genetic analysis, replicated across worms and mammalian cells in same study","pmids":["26595381"],"is_preprint":false},{"year":2010,"finding":"TMEM237 (Als2cr4) localizes to photoreceptor outer segments, the ciliary complex, and horizontal cells in the outer plexiform layer of the mouse retina, and immunoprecipitation/mass spectrometry identified interacting partners including vimentin, actin, myosin Va, myosin VI, myosin X, myosin XIV, kinesin 1, and lamin B-1.","method":"Immunohistochemistry, immunoelectron microscopy, immunoprecipitation followed by mass spectrometry","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by IEM and Co-IP/MS for interacting partners, single lab","pmids":["20375344"],"is_preprint":false},{"year":2019,"finding":"TMEM237 physically interacts with the intestinal riboflavin transporter RFVT-3 (hRFVT-3), co-localizes with it in intestinal epithelial cells, and its overexpression increases riboflavin uptake while knockdown reduces uptake; TMEM237 also enhances hRFVT-3 protein stability (increased protein half-life).","method":"Yeast two-hybrid screening, co-immunoprecipitation in HuTu-80 cells, confocal colocalization, siRNA knockdown with riboflavin uptake assay, protein half-life/stability assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, Y2H, functional uptake assay, and protein stability assay, multiple orthogonal methods in single study","pmids":["30892938"],"is_preprint":false},{"year":2021,"finding":"TMEM237 and TMEM67 are unique protein components of the photoreceptor outer segment plasma membrane, identified by quantitative proteomics (protein correlation profiling with label-free MS).","method":"Label-free quantitative mass spectrometry / protein correlation profiling on enriched OS plasma membrane vs. total OS membranes","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative MS-based subcellular fractionation with protein correlation profiling, single study","pmids":["33933680"],"is_preprint":false},{"year":2023,"finding":"HIF-1α directly binds the TMEM237 promoter to transactivate its expression under hypoxia; TMEM237 interacts with NPHP1 and strengthens the NPHP1–Pyk2 interaction, triggering phosphorylation of Pyk2 and ERK1/2 to promote hepatocellular carcinoma cell proliferation, migration, invasion, and EMT.","method":"ChIP assay, luciferase reporter assay, IP-MS, Co-IP, gain- and loss-of-function experiments in vitro and in vivo (mouse tumor models)","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP + luciferase for transcriptional regulation, IP-MS + Co-IP for protein interaction, functional gain/loss-of-function with signaling readout, multiple orthogonal methods","pmids":["37041420"],"is_preprint":false},{"year":2025,"finding":"Knockdown of CG14186 (Drosophila ortholog of TMEM237) potentiates maneb-induced dopaminergic neuron loss in Drosophila; adult-specific perturbation of Wnt signaling is sufficient to promote maneb-induced DA neuron loss, placing TMEM237/CG14186 in the Wnt signaling pathway in the context of DA neuron maintenance.","method":"RNAi knockdown in Drosophila, DGRP genome-wide association with dopamine neuron viability readout, Wnt pathway perturbation experiments","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with defined neurodegeneration phenotype and epistasis to Wnt pathway, single lab, single study","pmids":["40644377"],"is_preprint":false},{"year":2021,"finding":"A TMEM237 splice-site variant (c.553+1G>A) causes exon skipping, confirmed by RT-PCR on patient-derived RNA, establishing a splicing mechanism for loss-of-function in Joubert syndrome.","method":"RT-PCR on patient RNA demonstrating aberrant exon skipping","journal":"Zhonghua yi xue yi chuan xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct RT-PCR validation of splice mechanism, single family/single lab","pmids":["34839509"],"is_preprint":false}],"current_model":"TMEM237 is a transmembrane protein that localizes to the ciliary transition zone (TZ) where it functions within the MKS module—downstream of RPGRIP1L/MKS5 and organized by TMEM107—to maintain TZ architecture, a diffusion barrier, and ciliogenesis; loss of TMEM237 causes defective ciliogenesis and deregulated Wnt signaling across mammalian, zebrafish, and C. elegans models. Beyond the cilium, TMEM237 interacts with NPHP1 to activate the Pyk2/ERK1/2 pathway under HIF-1α–driven hypoxia, interacts with and stabilizes the intestinal riboflavin transporter RFVT-3, and is a unique component of the photoreceptor outer segment plasma membrane where it associates with cytoskeletal motor proteins."},"narrative":{"mechanistic_narrative":"TMEM237 is a transmembrane protein of the ciliary transition zone (TZ) that maintains TZ architecture, ciliogenesis, and Wnt signaling control, with loss-of-function producing defective ciliogenesis and deregulated Wnt signaling across mammalian, zebrafish, and C. elegans models [PMID:22152675]. Within the TZ, TMEM237 functions in the MKS module: its proper TZ localization requires RPGRIP1L/MKS5 [PMID:22152675], it is recruited within an intermediate TZ subdomain layer organized by TMEM107 [PMID:26595381], and it genetically interacts with NPHP4 and other MKS-module components to control basal body–TZ membrane anchoring [PMID:22152675]. A splice-site variant causing exon skipping establishes TMEM237 loss-of-function as a cause of Joubert syndrome [PMID:34839509]. Beyond the cilium, TMEM237 has context-specific roles: in intestinal epithelium it binds and stabilizes the riboflavin transporter RFVT-3 to promote riboflavin uptake [PMID:30892938], and under HIF-1α–driven hypoxia—where HIF-1α transactivates its promoter—it interacts with NPHP1 to strengthen the NPHP1–Pyk2 interaction and drive Pyk2/ERK1/2 phosphorylation, promoting hepatocellular carcinoma proliferation, migration, invasion, and EMT [PMID:37041420]. In the retina, TMEM237 localizes to photoreceptor outer segments and the outer-segment plasma membrane, where it associates with cytoskeletal and motor proteins [PMID:20375344, PMID:33933680].","teleology":[{"year":2011,"claim":"Established TMEM237 as a transition-zone protein whose loss disrupts ciliogenesis and Wnt signaling, and placed it epistatically within the MKS/NPHP TZ network downstream of RPGRIP1L/MKS5.","evidence":"Immunofluorescence localization plus loss-of-function in mammalian cells; C. elegans genetic epistasis with nphp-4 and MKS-module genes; RPGRIP1L knockdown; zebrafish morpholino","pmids":["22152675"],"confidence":"High","gaps":["Molecular mechanism by which TMEM237 maintains the diffusion barrier is not defined","Direct physical (vs. genetic) interactions among TZ components not mapped","How TMEM237 loss deregulates Wnt mechanistically is unresolved"]},{"year":2015,"claim":"Resolved where TMEM237 sits in TZ subdomain architecture, showing TMEM107 organizes its recruitment to an intermediate MKS-module layer.","evidence":"C. elegans genetics and super-resolution fluorescence localization of TZ proteins in tmem-107 mutants, with mammalian validation","pmids":["26595381"],"confidence":"High","gaps":["Direct binding interface between TMEM107 and TMEM237 not characterized","Stoichiometry and assembly order of the full MKS module remain incomplete"]},{"year":2010,"claim":"Demonstrated a retinal localization for TMEM237 (photoreceptor outer segments, ciliary complex, horizontal cells) and catalogued candidate cytoskeletal/motor interactors.","evidence":"Immunohistochemistry, immunoelectron microscopy, and Co-IP/mass spectrometry in mouse retina","pmids":["20375344"],"confidence":"Medium","gaps":["Co-IP/MS interactors (vimentin, actin, myosins, kinesin 1, lamin B-1) lack reciprocal validation","Functional consequence of motor-protein association is untested"]},{"year":2019,"claim":"Revealed a non-ciliary function: TMEM237 binds and stabilizes the intestinal riboflavin transporter RFVT-3 to regulate vitamin uptake.","evidence":"Yeast two-hybrid, reciprocal co-IP in HuTu-80 cells, confocal colocalization, siRNA knockdown with riboflavin uptake assay, and protein half-life assay","pmids":["30892938"],"confidence":"High","gaps":["Mechanism of RFVT-3 stabilization (e.g., trafficking vs. degradation protection) not defined","Whether this function depends on TMEM237 transmembrane topology is unknown"]},{"year":2021,"claim":"Confirmed TMEM237 as a unique component of the photoreceptor outer-segment plasma membrane and a disease-causing splicing target in Joubert syndrome.","evidence":"Label-free quantitative MS / protein correlation profiling of OS plasma membrane; RT-PCR on patient RNA demonstrating exon skipping from a splice-site variant","pmids":["33933680","34839509"],"confidence":"Medium","gaps":["OS plasma-membrane function of TMEM237 is not established","Patient/splicing evidence is from a single family"]},{"year":2023,"claim":"Defined a hypoxia-driven oncogenic axis: HIF-1α transactivates TMEM237, which binds NPHP1 to potentiate NPHP1–Pyk2 coupling and Pyk2/ERK1/2 signaling driving hepatocellular carcinoma progression.","evidence":"ChIP and luciferase reporter assays, IP-MS, Co-IP, and gain/loss-of-function in vitro and in mouse tumor models","pmids":["37041420"],"confidence":"High","gaps":["Whether this signaling role requires ciliary localization is unclear","Structural basis of TMEM237 enhancement of NPHP1–Pyk2 binding unknown"]},{"year":2025,"claim":"Linked TMEM237/Wnt function to neuronal maintenance, showing its loss sensitizes dopaminergic neurons to toxicant-induced degeneration.","evidence":"RNAi knockdown of the Drosophila ortholog CG14186, DGRP association with DA neuron viability, and Wnt-pathway perturbation","pmids":["40644377"],"confidence":"Medium","gaps":["Direct relevance to mammalian neurodegeneration untested","Mechanistic link between TMEM237, Wnt, and DA neuron survival not resolved"]},{"year":null,"claim":"How TMEM237's distinct activities—TZ barrier maintenance, RFVT-3 stabilization, and NPHP1/Pyk2 signaling—relate to a single biochemical function remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model or defined molecular activity for TMEM237","Whether ciliary and non-ciliary roles share a common mechanism is undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]}],"complexes":["MKS module (ciliary transition zone)"],"partners":["RPGRIP1L","TMEM107","NPHP1","NPHP4","RFVT-3","TMEM216","B9D1","B9D2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96Q45","full_name":"Transmembrane protein 237","aliases":["Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 4 protein"],"length_aa":408,"mass_kda":45.5,"function":"Component of the transition zone in primary cilia. Required for ciliogenesis","subcellular_location":"Membrane; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q96Q45/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM237","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":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMEM237","total_profiled":1310},"omim":[{"mim_id":"614424","title":"JOUBERT SYNDROME 14; JBTS14","url":"https://www.omim.org/entry/614424"},{"mim_id":"614423","title":"TRANSMEMBRANE PROTEIN 237; TMEM237","url":"https://www.omim.org/entry/614423"},{"mim_id":"213300","title":"JOUBERT SYNDROME 1; JBTS1","url":"https://www.omim.org/entry/213300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Microtubules","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium transition zone","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":71.7}],"url":"https://www.proteinatlas.org/search/TMEM237"},"hgnc":{"alias_symbol":["JBTS14"],"prev_symbol":["ALS2CR4"]},"alphafold":{"accession":"Q96Q45","domains":[{"cath_id":"1.20.120","chopping":"217-340_347-387","consensus_level":"high","plddt":84.6251,"start":217,"end":387}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q45","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q45-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q45-F1-predicted_aligned_error_v6.png","plddt_mean":63.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM237","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM237"},"sequence":{"accession":"Q96Q45","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96Q45.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96Q45/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q45"}},"corpus_meta":[{"pmid":"22152675","id":"PMC_22152675","title":"TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22152675","citation_count":165,"is_preprint":false},{"pmid":"26595381","id":"PMC_26595381","title":"TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome.","date":"2015","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26595381","citation_count":108,"is_preprint":false},{"pmid":"35238134","id":"PMC_35238134","title":"Genotype-phenotype correlates in Joubert syndrome: A review.","date":"2022","source":"American journal of medical genetics. Part C, Seminars in medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35238134","citation_count":88,"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":"22693042","id":"PMC_22693042","title":"Molecular characterization of Joubert syndrome in Saudi Arabia.","date":"2012","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/22693042","citation_count":53,"is_preprint":false},{"pmid":"26729329","id":"PMC_26729329","title":"Enhanced diagnostic yield in Meckel-Gruber and Joubert syndrome through exome sequencing supplemented with split-read mapping.","date":"2016","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26729329","citation_count":44,"is_preprint":false},{"pmid":"31238879","id":"PMC_31238879","title":"Novel pathogenic variants and multiple molecular diagnoses in neurodevelopmental disorders.","date":"2019","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/31238879","citation_count":44,"is_preprint":false},{"pmid":"23351400","id":"PMC_23351400","title":"Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies.","date":"2012","source":"Cilia","url":"https://pubmed.ncbi.nlm.nih.gov/23351400","citation_count":43,"is_preprint":false},{"pmid":"28236344","id":"PMC_28236344","title":"Integration of high-risk human papillomavirus into cellular cancer-related genes in head and neck cancer cell lines.","date":"2017","source":"Head & neck","url":"https://pubmed.ncbi.nlm.nih.gov/28236344","citation_count":35,"is_preprint":false},{"pmid":"28596487","id":"PMC_28596487","title":"ZNF131 suppresses centrosome fragmentation in glioblastoma stem-like cells through regulation of HAUS5.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28596487","citation_count":15,"is_preprint":false},{"pmid":"33933680","id":"PMC_33933680","title":"TMEM67, TMEM237, and Embigin in Complex With Monocarboxylate Transporter MCT1 Are Unique Components of the Photoreceptor Outer Segment Plasma Membrane.","date":"2021","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/33933680","citation_count":14,"is_preprint":false},{"pmid":"20375344","id":"PMC_20375344","title":"Deciphering the structure and function of Als2cr4 in the mouse retina.","date":"2010","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/20375344","citation_count":12,"is_preprint":false},{"pmid":"30892938","id":"PMC_30892938","title":"Identification of transmembrane protein 237 as a novel interactor with the intestinal riboflavin transporter-3 (RFVT-3): role in functionality and cell biology.","date":"2019","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30892938","citation_count":10,"is_preprint":false},{"pmid":"37041420","id":"PMC_37041420","title":"HIF-1α-activated TMEM237 promotes hepatocellular carcinoma progression via the NPHP1/Pyk2/ERK pathway.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37041420","citation_count":9,"is_preprint":false},{"pmid":"36797544","id":"PMC_36797544","title":"Function of TRPC1 in modulating hepatocellular carcinoma progression.","date":"2023","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36797544","citation_count":9,"is_preprint":false},{"pmid":"34839509","id":"PMC_34839509","title":"[Phenotype and genotype analysis of a pedigree affected with Joubert syndrome due to variant of TMEM237 gene].","date":"2021","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34839509","citation_count":1,"is_preprint":false},{"pmid":"40644377","id":"PMC_40644377","title":"Genetic basis of maneb-induced dopaminergic neurodegeneration in Drosophila.","date":"2025","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/40644377","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.07.652747","title":"Genetic basis of maneb-induced dopaminergic neurodegeneration in  <i>Drosophila</i>","date":"2025-05-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.07.652747","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11189,"output_tokens":2593,"usd":0.036231,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9783,"output_tokens":2889,"usd":0.06057,"stage2_stop_reason":"end_turn"},"total_usd":0.096801,"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\": \"TMEM237 localizes to the ciliary transition zone (TZ) in mammalian cells, and its loss results in defective ciliogenesis and deregulation of Wnt signaling.\",\n      \"method\": \"Immunofluorescence localization, loss-of-function experiments in mammalian cells with ciliogenesis and Wnt signaling readouts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence (ciliogenesis defect), Wnt signaling deregulation, replicated across mammalian, zebrafish, and C. elegans models in same study\",\n      \"pmids\": [\"22152675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans jbts-14 (TMEM237 ortholog) genetically interacts with nphp-4 to control basal body–transition zone anchoring to the membrane and ciliogenesis, establishing epistatic pathway placement.\",\n      \"method\": \"C. elegans genetic epistasis (double mutant analysis), ciliogenesis assays\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with defined phenotypic readout (basal body–TZ anchoring, ciliogenesis), multiple orthogonal methods across organisms in same study\",\n      \"pmids\": [\"22152675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Both mammalian TMEM237 and C. elegans JBTS-14 require RPGRIP1L/MKS5 for proper transition zone localization, and JBTS-14 additionally shows functional interactions with MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2.\",\n      \"method\": \"C. elegans genetic and localization analyses; mammalian RPGRIP1L knockdown with TZ localization readout\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization dependency experiment with multiple genetic interaction partners confirmed across two model systems\",\n      \"pmids\": [\"22152675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Disruption of zebrafish tmem237 expression produces gastrulation defects consistent with ciliary dysfunction.\",\n      \"method\": \"Morpholino knockdown in Danio rerio with gastrulation phenotype readout\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in zebrafish with defined phenotype, single study\",\n      \"pmids\": [\"22152675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In C. elegans, TMEM-107 organizes recruitment of JBTS-14 (TMEM237) within the MKS module at the transition zone, placing TMEM237 in an intermediate layer of TZ subdomain architecture.\",\n      \"method\": \"C. elegans genetic analysis, fluorescence localization of TZ proteins in tmem-107 mutants\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization dependency experiments with super-resolution microscopy and genetic analysis, replicated across worms and mammalian cells in same study\",\n      \"pmids\": [\"26595381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TMEM237 (Als2cr4) localizes to photoreceptor outer segments, the ciliary complex, and horizontal cells in the outer plexiform layer of the mouse retina, and immunoprecipitation/mass spectrometry identified interacting partners including vimentin, actin, myosin Va, myosin VI, myosin X, myosin XIV, kinesin 1, and lamin B-1.\",\n      \"method\": \"Immunohistochemistry, immunoelectron microscopy, immunoprecipitation followed by mass spectrometry\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by IEM and Co-IP/MS for interacting partners, single lab\",\n      \"pmids\": [\"20375344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMEM237 physically interacts with the intestinal riboflavin transporter RFVT-3 (hRFVT-3), co-localizes with it in intestinal epithelial cells, and its overexpression increases riboflavin uptake while knockdown reduces uptake; TMEM237 also enhances hRFVT-3 protein stability (increased protein half-life).\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation in HuTu-80 cells, confocal colocalization, siRNA knockdown with riboflavin uptake assay, protein half-life/stability assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, Y2H, functional uptake assay, and protein stability assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30892938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM237 and TMEM67 are unique protein components of the photoreceptor outer segment plasma membrane, identified by quantitative proteomics (protein correlation profiling with label-free MS).\",\n      \"method\": \"Label-free quantitative mass spectrometry / protein correlation profiling on enriched OS plasma membrane vs. total OS membranes\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS-based subcellular fractionation with protein correlation profiling, single study\",\n      \"pmids\": [\"33933680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIF-1α directly binds the TMEM237 promoter to transactivate its expression under hypoxia; TMEM237 interacts with NPHP1 and strengthens the NPHP1–Pyk2 interaction, triggering phosphorylation of Pyk2 and ERK1/2 to promote hepatocellular carcinoma cell proliferation, migration, invasion, and EMT.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, IP-MS, Co-IP, gain- and loss-of-function experiments in vitro and in vivo (mouse tumor models)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP + luciferase for transcriptional regulation, IP-MS + Co-IP for protein interaction, functional gain/loss-of-function with signaling readout, multiple orthogonal methods\",\n      \"pmids\": [\"37041420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of CG14186 (Drosophila ortholog of TMEM237) potentiates maneb-induced dopaminergic neuron loss in Drosophila; adult-specific perturbation of Wnt signaling is sufficient to promote maneb-induced DA neuron loss, placing TMEM237/CG14186 in the Wnt signaling pathway in the context of DA neuron maintenance.\",\n      \"method\": \"RNAi knockdown in Drosophila, DGRP genome-wide association with dopamine neuron viability readout, Wnt pathway perturbation experiments\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with defined neurodegeneration phenotype and epistasis to Wnt pathway, single lab, single study\",\n      \"pmids\": [\"40644377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A TMEM237 splice-site variant (c.553+1G>A) causes exon skipping, confirmed by RT-PCR on patient-derived RNA, establishing a splicing mechanism for loss-of-function in Joubert syndrome.\",\n      \"method\": \"RT-PCR on patient RNA demonstrating aberrant exon skipping\",\n      \"journal\": \"Zhonghua yi xue yi chuan xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct RT-PCR validation of splice mechanism, single family/single lab\",\n      \"pmids\": [\"34839509\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM237 is a transmembrane protein that localizes to the ciliary transition zone (TZ) where it functions within the MKS module—downstream of RPGRIP1L/MKS5 and organized by TMEM107—to maintain TZ architecture, a diffusion barrier, and ciliogenesis; loss of TMEM237 causes defective ciliogenesis and deregulated Wnt signaling across mammalian, zebrafish, and C. elegans models. Beyond the cilium, TMEM237 interacts with NPHP1 to activate the Pyk2/ERK1/2 pathway under HIF-1α–driven hypoxia, interacts with and stabilizes the intestinal riboflavin transporter RFVT-3, and is a unique component of the photoreceptor outer segment plasma membrane where it associates with cytoskeletal motor proteins.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMEM237 is a transmembrane protein of the ciliary transition zone (TZ) that maintains TZ architecture, ciliogenesis, and Wnt signaling control, with loss-of-function producing defective ciliogenesis and deregulated Wnt signaling across mammalian, zebrafish, and C. elegans models [#0, #1]. Within the TZ, TMEM237 functions in the MKS module: its proper TZ localization requires RPGRIP1L/MKS5 [#2], it is recruited within an intermediate TZ subdomain layer organized by TMEM107 [#4], and it genetically interacts with NPHP4 and other MKS-module components to control basal body\\u2013TZ membrane anchoring [#1, #2]. A splice-site variant causing exon skipping establishes TMEM237 loss-of-function as a cause of Joubert syndrome [#10]. Beyond the cilium, TMEM237 has context-specific roles: in intestinal epithelium it binds and stabilizes the riboflavin transporter RFVT-3 to promote riboflavin uptake [#6], and under HIF-1\\u03b1\\u2013driven hypoxia\\u2014where HIF-1\\u03b1 transactivates its promoter\\u2014it interacts with NPHP1 to strengthen the NPHP1\\u2013Pyk2 interaction and drive Pyk2/ERK1/2 phosphorylation, promoting hepatocellular carcinoma proliferation, migration, invasion, and EMT [#8]. In the retina, TMEM237 localizes to photoreceptor outer segments and the outer-segment plasma membrane, where it associates with cytoskeletal and motor proteins [#5, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established TMEM237 as a transition-zone protein whose loss disrupts ciliogenesis and Wnt signaling, and placed it epistatically within the MKS/NPHP TZ network downstream of RPGRIP1L/MKS5.\",\n      \"evidence\": \"Immunofluorescence localization plus loss-of-function in mammalian cells; C. elegans genetic epistasis with nphp-4 and MKS-module genes; RPGRIP1L knockdown; zebrafish morpholino\",\n      \"pmids\": [\"22152675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which TMEM237 maintains the diffusion barrier is not defined\", \"Direct physical (vs. genetic) interactions among TZ components not mapped\", \"How TMEM237 loss deregulates Wnt mechanistically is unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved where TMEM237 sits in TZ subdomain architecture, showing TMEM107 organizes its recruitment to an intermediate MKS-module layer.\",\n      \"evidence\": \"C. elegans genetics and super-resolution fluorescence localization of TZ proteins in tmem-107 mutants, with mammalian validation\",\n      \"pmids\": [\"26595381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between TMEM107 and TMEM237 not characterized\", \"Stoichiometry and assembly order of the full MKS module remain incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated a retinal localization for TMEM237 (photoreceptor outer segments, ciliary complex, horizontal cells) and catalogued candidate cytoskeletal/motor interactors.\",\n      \"evidence\": \"Immunohistochemistry, immunoelectron microscopy, and Co-IP/mass spectrometry in mouse retina\",\n      \"pmids\": [\"20375344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP/MS interactors (vimentin, actin, myosins, kinesin 1, lamin B-1) lack reciprocal validation\", \"Functional consequence of motor-protein association is untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-ciliary function: TMEM237 binds and stabilizes the intestinal riboflavin transporter RFVT-3 to regulate vitamin uptake.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP in HuTu-80 cells, confocal colocalization, siRNA knockdown with riboflavin uptake assay, and protein half-life assay\",\n      \"pmids\": [\"30892938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of RFVT-3 stabilization (e.g., trafficking vs. degradation protection) not defined\", \"Whether this function depends on TMEM237 transmembrane topology is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed TMEM237 as a unique component of the photoreceptor outer-segment plasma membrane and a disease-causing splicing target in Joubert syndrome.\",\n      \"evidence\": \"Label-free quantitative MS / protein correlation profiling of OS plasma membrane; RT-PCR on patient RNA demonstrating exon skipping from a splice-site variant\",\n      \"pmids\": [\"33933680\", \"34839509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"OS plasma-membrane function of TMEM237 is not established\", \"Patient/splicing evidence is from a single family\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a hypoxia-driven oncogenic axis: HIF-1\\u03b1 transactivates TMEM237, which binds NPHP1 to potentiate NPHP1\\u2013Pyk2 coupling and Pyk2/ERK1/2 signaling driving hepatocellular carcinoma progression.\",\n      \"evidence\": \"ChIP and luciferase reporter assays, IP-MS, Co-IP, and gain/loss-of-function in vitro and in mouse tumor models\",\n      \"pmids\": [\"37041420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this signaling role requires ciliary localization is unclear\", \"Structural basis of TMEM237 enhancement of NPHP1\\u2013Pyk2 binding unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked TMEM237/Wnt function to neuronal maintenance, showing its loss sensitizes dopaminergic neurons to toxicant-induced degeneration.\",\n      \"evidence\": \"RNAi knockdown of the Drosophila ortholog CG14186, DGRP association with DA neuron viability, and Wnt-pathway perturbation\",\n      \"pmids\": [\"40644377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct relevance to mammalian neurodegeneration untested\", \"Mechanistic link between TMEM237, Wnt, and DA neuron survival not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM237's distinct activities\\u2014TZ barrier maintenance, RFVT-3 stabilization, and NPHP1/Pyk2 signaling\\u2014relate to a single biochemical function remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model or defined molecular activity for TMEM237\", \"Whether ciliary and non-ciliary roles share a common mechanism is undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"MKS module (ciliary transition zone)\"],\n    \"partners\": [\"RPGRIP1L\", \"TMEM107\", \"NPHP1\", \"NPHP4\", \"RFVT-3\", \"TMEM216\", \"B9D1\", \"B9D2\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}