{"gene":"TMEM216","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2010,"finding":"TMEM216 encodes a tetraspan transmembrane protein that localizes to the base of primary cilia (transition zone). Loss of TMEM216 in mutant fibroblasts or after siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled.","method":"Immunofluorescence localization, siRNA knockdown in fibroblasts, functional ciliogenesis assay, RhoA/Dishevelled activity assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, KD, pathway readouts) in a single rigorous study identifying the gene","pmids":["20512146"],"is_preprint":false},{"year":2010,"finding":"TMEM216 forms a protein complex with Meckelin (MKS3/TMEM67), a protein encoded by another gene mutated in Joubert and Meckel syndromes.","method":"Co-immunoprecipitation","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP reported in the discovery paper, not independently replicated in the corpus","pmids":["20512146"],"is_preprint":false},{"year":2010,"finding":"Disruption of tmem216 expression in zebrafish caused gastrulation defects consistent with ciliary dysfunction (similar to other ciliary morphants).","method":"Morpholino knockdown in zebrafish, phenotypic analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish morphant phenotype with defined readout, consistent with ciliary function","pmids":["20512146"],"is_preprint":false},{"year":2011,"finding":"TMEM216 is a component of a transition zone complex including Mks1, Tmem67, Cep290, B9d1, Tctn2, Cc2d2a, and Tctn1. Components of this complex co-localize at the transition zone. Loss of complex components causes tissue-specific defects in ciliogenesis and ciliary membrane composition (mislocalization of Arl13b, AC3, Smoothened, Pkd2).","method":"Co-immunoprecipitation complex assembly, immunofluorescence co-localization, genetic loss-of-function with ciliary membrane composition readouts","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP complex assembly plus multiple loss-of-function models with defined ciliary readouts, replicated across several complex members","pmids":["21725307"],"is_preprint":false},{"year":2012,"finding":"TMEM216 and TMEM138 are arranged head-to-tail on chromosome 11 and share a conserved cis-regulatory element in the intergenic region that mediates coordinated expression. Their coordinated expression is important for an interdependent cellular role in vesicular transport to primary cilia.","method":"Comparative genomics, reporter gene assays for shared regulatory element, cellular vesicular transport assays","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — functional reporter assays plus vesicular transport readout, multiple orthogonal methods in single study","pmids":["22282472"],"is_preprint":false},{"year":2011,"finding":"In C. elegans, MKS-2/TMEM216 functionally interacts with JBTS-14/TMEM237 to control basal body-transition zone anchoring to the membrane and ciliogenesis, as demonstrated by genetic interaction assays.","method":"C. elegans genetic interaction (double mutant analysis), ciliogenesis assay","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans with defined phenotypic readout, single study","pmids":["22152675"],"is_preprint":false},{"year":2020,"finding":"In Paramecium, depletion of MKS2/TMEM216 induces constitutive deciliation of some cilia, revealing a role for TMEM216 at the transition zone in controlling ciliary shedding. TMEM216 localizes with 9-fold symmetry at the most distal part of the transition zone in growing cilia.","method":"RNAi knockdown in Paramecium, live imaging of cilia, immunofluorescence localization with 9-fold symmetry analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization with structural detail plus functional consequence (deciliation) shown by KD with defined phenotypic readout","pmids":["32163404"],"is_preprint":false},{"year":2020,"finding":"TMEM216 deletion in zebrafish (CRISPR knockout) leads to shortened photoreceptor ciliary axoneme, mislocalization of outer segment proteins (rhodopsin, GNAT2, red opsin) to inner segments and cell bodies, abnormal outer segment disc morphology, and photoreceptor degeneration.","method":"CRISPR/Cas9 knockout zebrafish, immunofluorescence, electron microscopy, TUNEL assay","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple orthogonal readouts (IF, EM, TUNEL) in a single rigorous study","pmids":["32687549"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, a very close functional association exists between the B9D2-associated B9 complex and MKS-2/TMEM216 at the transition zone, as revealed by compound heterozygous allele knock-in experiments showing that B9D2 JBTS variants disrupt endogenous MKSR-2 organisation at the TZ and worsen MKS-2-related phenotypes.","method":"C. elegans CRISPR knock-in of patient variants, quantitative TZ/cilium structure assays, compound heterozygous genotype recapitulation","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene editing plus quantitative phenotypic assays, single lab","pmids":["33234550"],"is_preprint":false},{"year":2024,"finding":"TMEM216 interacts directly with SUFU (a negative regulator of Hedgehog signaling) and with GLI2/GLI3 transcription factors. TMEM216 competes with SUFU for binding to GLI2/GLI3, inhibiting their cleavage into repressor forms, resulting in nuclear accumulation of full-length GLI2 and decreased nuclear localization of cleaved GLI3, thereby activating Hedgehog signaling. Tmem216-deficient mice display impaired Hh signaling and ciliopathic phenotypes.","method":"Co-immunoprecipitation (TMEM216-SUFU, TMEM216-GLI2/GLI3), competition binding assay, nuclear fractionation, Tmem216 knockout mouse with Hh target gene expression readouts, cell-based Hh signaling assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, competition assay, nuclear fractionation, and in vivo mouse KO with pathway readouts, multiple orthogonal methods","pmids":["38261656"],"is_preprint":false},{"year":2016,"finding":"In C. elegans, mks-2 (TMEM216 ortholog) genetically interacts with nphp-4 to modulate ciliary defects, identified in a modifier screen; mks-2 mutations exacerbate nphp-4 ciliary phenotypes.","method":"C. elegans forward genetic modifier screen, double-mutant analysis, cilia phenotype assays (dye-filling, osmotic avoidance)","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined ciliary readouts, single study","pmids":["26863025"],"is_preprint":false}],"current_model":"TMEM216 is a tetraspan transmembrane protein that localizes to the ciliary transition zone (TZ), where it is part of a multi-protein MKS/Joubert syndrome complex (including Meckelin/TMEM67, Mks1, Cep290, Tctn1/2, B9d1, Cc2d2a) that regulates ciliogenesis, ciliary membrane composition, and ciliary shedding; it functions in vesicular transport to cilia in concert with TMEM138 (via a shared cis-regulatory module), and in the Hedgehog pathway by competing with SUFU for GLI2/GLI3 binding to promote full-length GLI2 nuclear accumulation and Hh pathway activation; loss of TMEM216 causes defective centrosomal docking and ciliogenesis with hyperactivation of RhoA and Dishevelled, mislocalization of outer segment proteins in photoreceptors, and constitutive ciliary shedding."},"narrative":{"mechanistic_narrative":"TMEM216 is a tetraspan transmembrane protein of the ciliary transition zone that governs ciliogenesis, ciliary membrane composition, and ciliary stability [PMID:20512146, PMID:21725307]. It assembles into the MKS/Joubert syndrome transition-zone complex together with Meckelin/TMEM67, Mks1, Cep290, B9d1, Tctn1/Tctn2, and Cc2d2a, where these components co-localize at the ciliary base and collectively maintain the membrane gate that controls entry of ciliary membrane proteins such as Arl13b, Smoothened, and Pkd2 [PMID:20512146, PMID:21725307]. Loss of TMEM216 disrupts centrosomal docking and ciliogenesis with downstream hyperactivation of RhoA and Dishevelled [PMID:20512146], and at the distal transition zone TMEM216 restrains constitutive ciliary shedding [PMID:32163404]. Beyond its structural role, TMEM216 acts in Hedgehog signaling by binding GLI2/GLI3 and competing with the repressor SUFU, thereby blocking GLI cleavage to promote nuclear accumulation of full-length GLI2 and pathway activation [PMID:38261656]. Its function is genetically and transcriptionally coordinated with TMEM138 through a shared cis-regulatory module that supports interdependent vesicular transport to cilia [PMID:22282472]. In vivo, loss causes photoreceptor outer-segment protein mislocalization and degeneration [PMID:32687549] and ciliopathic phenotypes consistent with its identification as a Joubert/Meckel syndrome gene [PMID:20512146].","teleology":[{"year":2010,"claim":"Established TMEM216 as a transition-zone protein whose loss disrupts ciliogenesis, answering whether it has a direct ciliary function and linking it to ciliopathy.","evidence":"Immunofluorescence localization plus siRNA knockdown and RhoA/Dishevelled activity assays in fibroblasts","pmids":["20512146"],"confidence":"High","gaps":["Molecular basis of RhoA/Dishevelled hyperactivation not resolved","Direct binding partners at the transition zone not defined in this study"]},{"year":2010,"claim":"First physical partner identified, placing TMEM216 in the same molecular machinery as another Joubert/Meckel gene product.","evidence":"Co-immunoprecipitation of TMEM216 with Meckelin/TMEM67","pmids":["20512146"],"confidence":"Medium","gaps":["Single Co-IP, not reciprocally validated in the corpus","Stoichiometry and direct vs. indirect interaction unclear"]},{"year":2010,"claim":"Provided in vivo evidence of ciliary dysfunction from TMEM216 loss in a vertebrate model.","evidence":"Morpholino knockdown in zebrafish with gastrulation/ciliary phenotype analysis","pmids":["20512146"],"confidence":"Medium","gaps":["Morpholino off-target effects not excluded","Tissue-specific requirements not addressed"]},{"year":2011,"claim":"Defined TMEM216 as a member of a multi-protein transition-zone complex that controls ciliary membrane composition, establishing the gate function.","evidence":"Reciprocal co-IP complex assembly, co-localization, and loss-of-function with ciliary membrane readouts (Arl13b, AC3, Smoothened, Pkd2) across complex members","pmids":["21725307"],"confidence":"High","gaps":["Spatial architecture of TMEM216 within the complex not resolved","Mechanism of selective membrane protein exclusion not defined"]},{"year":2011,"claim":"Showed functional cooperation between TMEM216 and TMEM237 in anchoring the basal body/transition zone to the membrane.","evidence":"C. elegans double-mutant genetic interaction and ciliogenesis assays","pmids":["22152675"],"confidence":"Medium","gaps":["Genetic interaction does not establish direct physical contact","Single model organism"]},{"year":2012,"claim":"Revealed a shared cis-regulatory mechanism coordinating TMEM216 with TMEM138 and linked both to vesicular transport to cilia.","evidence":"Comparative genomics, reporter assays for the shared intergenic element, and vesicular transport assays","pmids":["22282472"],"confidence":"High","gaps":["Molecular cargo of the vesicular transport pathway not identified","Whether TMEM216 and TMEM138 physically interact not established"]},{"year":2016,"claim":"Identified TMEM216 as a genetic modifier of nphp-4-related ciliary phenotypes, broadening its functional network.","evidence":"C. elegans forward modifier screen with dye-filling and osmotic avoidance assays","pmids":["26863025"],"confidence":"Medium","gaps":["Mechanism of interaction with NPHP module unresolved","Genetic, not physical, interaction"]},{"year":2020,"claim":"Demonstrated that TMEM216 restrains ciliary shedding and pinpointed its distal transition-zone localization with 9-fold symmetry.","evidence":"RNAi in Paramecium, live cilia imaging, and symmetry-resolved immunofluorescence","pmids":["32163404"],"confidence":"High","gaps":["Molecular trigger of deciliation upon loss not defined","Conservation of shedding role in mammalian cilia not tested here"]},{"year":2020,"claim":"Established a tissue-specific requirement in photoreceptors, connecting TMEM216 loss to outer-segment protein trafficking and degeneration.","evidence":"CRISPR knockout zebrafish with immunofluorescence, electron microscopy, and TUNEL","pmids":["32687549"],"confidence":"High","gaps":["Mechanism of outer-segment protein mislocalization not resolved","Whether degeneration is cell-autonomous not addressed"]},{"year":2021,"claim":"Defined a close functional association between TMEM216 and the B9 complex at the transition zone using patient-variant knock-ins.","evidence":"C. elegans CRISPR knock-in of B9D2 JBTS variants with quantitative TZ structure assays and compound-heterozygous recapitulation","pmids":["33234550"],"confidence":"Medium","gaps":["Direct biochemical interaction with B9 complex not shown","Findings in invertebrate model"]},{"year":2024,"claim":"Extended TMEM216 beyond a structural transition-zone role to a direct regulator of Hedgehog signaling through SUFU/GLI competition.","evidence":"Reciprocal Co-IP (SUFU, GLI2/GLI3), competition binding, nuclear fractionation, and Tmem216 knockout mouse Hh readouts","pmids":["38261656"],"confidence":"High","gaps":["How a transition-zone transmembrane protein accesses cytoplasmic GLI/SUFU not mechanistically explained","Structural basis of GLI binding not defined"]},{"year":null,"claim":"How TMEM216's transition-zone gating function is mechanistically coupled to its Hedgehog-regulatory role, and the structural basis of its protein interactions, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of TMEM216 or its complexes","Mechanism linking membrane gate integrity to GLI regulation unknown","Direct cargo of TMEM216/TMEM138 vesicular transport unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4]}],"complexes":["MKS/Joubert transition-zone complex"],"partners":["TMEM67","MKS1","CEP290","B9D1","TCTN1","TCTN2","CC2D2A","SUFU"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0N5","full_name":"Transmembrane protein 216","aliases":[],"length_aa":145,"mass_kda":16.5,"function":"Essential for primary ciliogenesis and embryonic development, facilitating the activation of Hedgehog (Hh) signaling pathway. Disrupts the interaction of GLI2 and GLI3 with the negative regulator SUFU. Inhibiting SUFU's interaction with GLI2 promotes the entry of GLI2 into the nucleus, allowing it to activate Hh target gene expression. Disrupting SUFU's interaction with GLI3 prevents its conversion into the repressor form, leading to increased nuclear GLI3 and enhanced Hh signaling. Required for the proper development and structural integrity of photoreceptor outer segment disks, ensuring normal outer segment morphogenesis and survival of photoreceptors","subcellular_location":"Membrane; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q9P0N5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM216","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM216","total_profiled":1310},"omim":[{"mim_id":"620996","title":"RETINITIS PIGMENTOSA 98; RP98","url":"https://www.omim.org/entry/620996"},{"mim_id":"620248","title":"TRANSMEMBRANE PROTEIN 80; TMEM80","url":"https://www.omim.org/entry/620248"},{"mim_id":"614465","title":"JOUBERT SYNDROME 16; JBTS16","url":"https://www.omim.org/entry/614465"},{"mim_id":"614459","title":"TRANSMEMBRANE PROTEIN 138; TMEM138","url":"https://www.omim.org/entry/614459"},{"mim_id":"614423","title":"TRANSMEMBRANE PROTEIN 237; TMEM237","url":"https://www.omim.org/entry/614423"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM216"},"hgnc":{"alias_symbol":["MGC13379","HSPC244","JBTS2"],"prev_symbol":["CORS2","MKS2"]},"alphafold":{"accession":"Q9P0N5","domains":[{"cath_id":"1.20.1440","chopping":"17-143","consensus_level":"high","plddt":92.9053,"start":17,"end":143}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0N5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0N5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0N5-F1-predicted_aligned_error_v6.png","plddt_mean":89.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM216","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM216"},"sequence":{"accession":"Q9P0N5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0N5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0N5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0N5"}},"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":"20512146","id":"PMC_20512146","title":"Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.","date":"2010","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20512146","citation_count":227,"is_preprint":false},{"pmid":"16415887","id":"PMC_16415887","title":"The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16415887","citation_count":219,"is_preprint":false},{"pmid":"17564974","id":"PMC_17564974","title":"Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome.","date":"2007","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17564974","citation_count":215,"is_preprint":false},{"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":"6371496","id":"PMC_6371496","title":"Superkiller mutations in Saccharomyces cerevisiae suppress exclusion of M2 double-stranded RNA by L-A-HN and confer cold sensitivity in the presence of M and L-A-HN.","date":"1984","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/6371496","citation_count":122,"is_preprint":false},{"pmid":"21068128","id":"PMC_21068128","title":"Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy.","date":"2010","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21068128","citation_count":113,"is_preprint":false},{"pmid":"22038610","id":"PMC_22038610","title":"Engineering of bacterial methyl ketone synthesis for biofuels.","date":"2011","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22038610","citation_count":91,"is_preprint":false},{"pmid":"19004860","id":"PMC_19004860","title":"C2cd3 is required for cilia formation and Hedgehog signaling in mouse.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19004860","citation_count":85,"is_preprint":false},{"pmid":"20036350","id":"PMC_20036350","title":"Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20036350","citation_count":82,"is_preprint":false},{"pmid":"12917796","id":"PMC_12917796","title":"Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12917796","citation_count":74,"is_preprint":false},{"pmid":"17397051","id":"PMC_17397051","title":"Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. 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evolution","url":"https://pubmed.ncbi.nlm.nih.gov/22936720","citation_count":4,"is_preprint":false},{"pmid":"30498907","id":"PMC_30498907","title":"Thumb duplication: molecular analysis of different clinical types.","date":"2018","source":"European journal of orthopaedic surgery & traumatology : orthopedie traumatologie","url":"https://pubmed.ncbi.nlm.nih.gov/30498907","citation_count":3,"is_preprint":false},{"pmid":"31597241","id":"PMC_31597241","title":"Identification and Functional Characterization of a Soybean (Glycine max) Thioesterase that Acts on Intermediates of Fatty Acid Biosynthesis.","date":"2019","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31597241","citation_count":3,"is_preprint":false},{"pmid":"41230208","id":"PMC_41230208","title":"Novel PIBF1 Pathogenic Variant in Three Siblings with Joubert Syndrome Type 33.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/41230208","citation_count":1,"is_preprint":false},{"pmid":"40938124","id":"PMC_40938124","title":"Identification of a Sinorhizobium meliloti YbgC-like thioesterase that contributes to the production of the infochemical 2-tridecanone.","date":"2025","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/40938124","citation_count":1,"is_preprint":false},{"pmid":"40365501","id":"PMC_40365501","title":"Renal insufficiency caused by TMEM216 gene mutation: Case Report.","date":"2025","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40365501","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23822,"output_tokens":2622,"usd":0.055398,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9818,"output_tokens":3291,"usd":0.065683,"stage2_stop_reason":"end_turn"},"total_usd":0.121081,"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\": 2010,\n      \"finding\": \"TMEM216 encodes a tetraspan transmembrane protein that localizes to the base of primary cilia (transition zone). Loss of TMEM216 in mutant fibroblasts or after siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled.\",\n      \"method\": \"Immunofluorescence localization, siRNA knockdown in fibroblasts, functional ciliogenesis assay, RhoA/Dishevelled activity assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, KD, pathway readouts) in a single rigorous study identifying the gene\",\n      \"pmids\": [\"20512146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TMEM216 forms a protein complex with Meckelin (MKS3/TMEM67), a protein encoded by another gene mutated in Joubert and Meckel syndromes.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP reported in the discovery paper, not independently replicated in the corpus\",\n      \"pmids\": [\"20512146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Disruption of tmem216 expression in zebrafish caused gastrulation defects consistent with ciliary dysfunction (similar to other ciliary morphants).\",\n      \"method\": \"Morpholino knockdown in zebrafish, phenotypic analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish morphant phenotype with defined readout, consistent with ciliary function\",\n      \"pmids\": [\"20512146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TMEM216 is a component of a transition zone complex including Mks1, Tmem67, Cep290, B9d1, Tctn2, Cc2d2a, and Tctn1. Components of this complex co-localize at the transition zone. Loss of complex components causes tissue-specific defects in ciliogenesis and ciliary membrane composition (mislocalization of Arl13b, AC3, Smoothened, Pkd2).\",\n      \"method\": \"Co-immunoprecipitation complex assembly, immunofluorescence co-localization, genetic loss-of-function with ciliary membrane composition readouts\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP complex assembly plus multiple loss-of-function models with defined ciliary readouts, replicated across several complex members\",\n      \"pmids\": [\"21725307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TMEM216 and TMEM138 are arranged head-to-tail on chromosome 11 and share a conserved cis-regulatory element in the intergenic region that mediates coordinated expression. Their coordinated expression is important for an interdependent cellular role in vesicular transport to primary cilia.\",\n      \"method\": \"Comparative genomics, reporter gene assays for shared regulatory element, cellular vesicular transport assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — functional reporter assays plus vesicular transport readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22282472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In C. elegans, MKS-2/TMEM216 functionally interacts with JBTS-14/TMEM237 to control basal body-transition zone anchoring to the membrane and ciliogenesis, as demonstrated by genetic interaction assays.\",\n      \"method\": \"C. elegans genetic interaction (double mutant analysis), ciliogenesis assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans with defined phenotypic readout, single study\",\n      \"pmids\": [\"22152675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Paramecium, depletion of MKS2/TMEM216 induces constitutive deciliation of some cilia, revealing a role for TMEM216 at the transition zone in controlling ciliary shedding. TMEM216 localizes with 9-fold symmetry at the most distal part of the transition zone in growing cilia.\",\n      \"method\": \"RNAi knockdown in Paramecium, live imaging of cilia, immunofluorescence localization with 9-fold symmetry analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with structural detail plus functional consequence (deciliation) shown by KD with defined phenotypic readout\",\n      \"pmids\": [\"32163404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM216 deletion in zebrafish (CRISPR knockout) leads to shortened photoreceptor ciliary axoneme, mislocalization of outer segment proteins (rhodopsin, GNAT2, red opsin) to inner segments and cell bodies, abnormal outer segment disc morphology, and photoreceptor degeneration.\",\n      \"method\": \"CRISPR/Cas9 knockout zebrafish, immunofluorescence, electron microscopy, TUNEL assay\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple orthogonal readouts (IF, EM, TUNEL) in a single rigorous study\",\n      \"pmids\": [\"32687549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, a very close functional association exists between the B9D2-associated B9 complex and MKS-2/TMEM216 at the transition zone, as revealed by compound heterozygous allele knock-in experiments showing that B9D2 JBTS variants disrupt endogenous MKSR-2 organisation at the TZ and worsen MKS-2-related phenotypes.\",\n      \"method\": \"C. elegans CRISPR knock-in of patient variants, quantitative TZ/cilium structure assays, compound heterozygous genotype recapitulation\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene editing plus quantitative phenotypic assays, single lab\",\n      \"pmids\": [\"33234550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM216 interacts directly with SUFU (a negative regulator of Hedgehog signaling) and with GLI2/GLI3 transcription factors. TMEM216 competes with SUFU for binding to GLI2/GLI3, inhibiting their cleavage into repressor forms, resulting in nuclear accumulation of full-length GLI2 and decreased nuclear localization of cleaved GLI3, thereby activating Hedgehog signaling. Tmem216-deficient mice display impaired Hh signaling and ciliopathic phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (TMEM216-SUFU, TMEM216-GLI2/GLI3), competition binding assay, nuclear fractionation, Tmem216 knockout mouse with Hh target gene expression readouts, cell-based Hh signaling assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, competition assay, nuclear fractionation, and in vivo mouse KO with pathway readouts, multiple orthogonal methods\",\n      \"pmids\": [\"38261656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C. elegans, mks-2 (TMEM216 ortholog) genetically interacts with nphp-4 to modulate ciliary defects, identified in a modifier screen; mks-2 mutations exacerbate nphp-4 ciliary phenotypes.\",\n      \"method\": \"C. elegans forward genetic modifier screen, double-mutant analysis, cilia phenotype assays (dye-filling, osmotic avoidance)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined ciliary readouts, single study\",\n      \"pmids\": [\"26863025\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM216 is a tetraspan transmembrane protein that localizes to the ciliary transition zone (TZ), where it is part of a multi-protein MKS/Joubert syndrome complex (including Meckelin/TMEM67, Mks1, Cep290, Tctn1/2, B9d1, Cc2d2a) that regulates ciliogenesis, ciliary membrane composition, and ciliary shedding; it functions in vesicular transport to cilia in concert with TMEM138 (via a shared cis-regulatory module), and in the Hedgehog pathway by competing with SUFU for GLI2/GLI3 binding to promote full-length GLI2 nuclear accumulation and Hh pathway activation; loss of TMEM216 causes defective centrosomal docking and ciliogenesis with hyperactivation of RhoA and Dishevelled, mislocalization of outer segment proteins in photoreceptors, and constitutive ciliary shedding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM216 is a tetraspan transmembrane protein of the ciliary transition zone that governs ciliogenesis, ciliary membrane composition, and ciliary stability [#0, #3]. It assembles into the MKS/Joubert syndrome transition-zone complex together with Meckelin/TMEM67, Mks1, Cep290, B9d1, Tctn1/Tctn2, and Cc2d2a, where these components co-localize at the ciliary base and collectively maintain the membrane gate that controls entry of ciliary membrane proteins such as Arl13b, Smoothened, and Pkd2 [#1, #3]. Loss of TMEM216 disrupts centrosomal docking and ciliogenesis with downstream hyperactivation of RhoA and Dishevelled [#0], and at the distal transition zone TMEM216 restrains constitutive ciliary shedding [#6]. Beyond its structural role, TMEM216 acts in Hedgehog signaling by binding GLI2/GLI3 and competing with the repressor SUFU, thereby blocking GLI cleavage to promote nuclear accumulation of full-length GLI2 and pathway activation [#9]. Its function is genetically and transcriptionally coordinated with TMEM138 through a shared cis-regulatory module that supports interdependent vesicular transport to cilia [#4]. In vivo, loss causes photoreceptor outer-segment protein mislocalization and degeneration [#7] and ciliopathic phenotypes consistent with its identification as a Joubert/Meckel syndrome gene [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established TMEM216 as a transition-zone protein whose loss disrupts ciliogenesis, answering whether it has a direct ciliary function and linking it to ciliopathy.\",\n      \"evidence\": \"Immunofluorescence localization plus siRNA knockdown and RhoA/Dishevelled activity assays in fibroblasts\",\n      \"pmids\": [\"20512146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of RhoA/Dishevelled hyperactivation not resolved\", \"Direct binding partners at the transition zone not defined in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"First physical partner identified, placing TMEM216 in the same molecular machinery as another Joubert/Meckel gene product.\",\n      \"evidence\": \"Co-immunoprecipitation of TMEM216 with Meckelin/TMEM67\",\n      \"pmids\": [\"20512146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP, not reciprocally validated in the corpus\", \"Stoichiometry and direct vs. indirect interaction unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided in vivo evidence of ciliary dysfunction from TMEM216 loss in a vertebrate model.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with gastrulation/ciliary phenotype analysis\",\n      \"pmids\": [\"20512146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not excluded\", \"Tissue-specific requirements not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined TMEM216 as a member of a multi-protein transition-zone complex that controls ciliary membrane composition, establishing the gate function.\",\n      \"evidence\": \"Reciprocal co-IP complex assembly, co-localization, and loss-of-function with ciliary membrane readouts (Arl13b, AC3, Smoothened, Pkd2) across complex members\",\n      \"pmids\": [\"21725307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial architecture of TMEM216 within the complex not resolved\", \"Mechanism of selective membrane protein exclusion not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed functional cooperation between TMEM216 and TMEM237 in anchoring the basal body/transition zone to the membrane.\",\n      \"evidence\": \"C. elegans double-mutant genetic interaction and ciliogenesis assays\",\n      \"pmids\": [\"22152675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic interaction does not establish direct physical contact\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a shared cis-regulatory mechanism coordinating TMEM216 with TMEM138 and linked both to vesicular transport to cilia.\",\n      \"evidence\": \"Comparative genomics, reporter assays for the shared intergenic element, and vesicular transport assays\",\n      \"pmids\": [\"22282472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cargo of the vesicular transport pathway not identified\", \"Whether TMEM216 and TMEM138 physically interact not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified TMEM216 as a genetic modifier of nphp-4-related ciliary phenotypes, broadening its functional network.\",\n      \"evidence\": \"C. elegans forward modifier screen with dye-filling and osmotic avoidance assays\",\n      \"pmids\": [\"26863025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of interaction with NPHP module unresolved\", \"Genetic, not physical, interaction\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that TMEM216 restrains ciliary shedding and pinpointed its distal transition-zone localization with 9-fold symmetry.\",\n      \"evidence\": \"RNAi in Paramecium, live cilia imaging, and symmetry-resolved immunofluorescence\",\n      \"pmids\": [\"32163404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of deciliation upon loss not defined\", \"Conservation of shedding role in mammalian cilia not tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a tissue-specific requirement in photoreceptors, connecting TMEM216 loss to outer-segment protein trafficking and degeneration.\",\n      \"evidence\": \"CRISPR knockout zebrafish with immunofluorescence, electron microscopy, and TUNEL\",\n      \"pmids\": [\"32687549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of outer-segment protein mislocalization not resolved\", \"Whether degeneration is cell-autonomous not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a close functional association between TMEM216 and the B9 complex at the transition zone using patient-variant knock-ins.\",\n      \"evidence\": \"C. elegans CRISPR knock-in of B9D2 JBTS variants with quantitative TZ structure assays and compound-heterozygous recapitulation\",\n      \"pmids\": [\"33234550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical interaction with B9 complex not shown\", \"Findings in invertebrate model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended TMEM216 beyond a structural transition-zone role to a direct regulator of Hedgehog signaling through SUFU/GLI competition.\",\n      \"evidence\": \"Reciprocal Co-IP (SUFU, GLI2/GLI3), competition binding, nuclear fractionation, and Tmem216 knockout mouse Hh readouts\",\n      \"pmids\": [\"38261656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a transition-zone transmembrane protein accesses cytoplasmic GLI/SUFU not mechanistically explained\", \"Structural basis of GLI binding not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM216's transition-zone gating function is mechanistically coupled to its Hedgehog-regulatory role, and the structural basis of its protein interactions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of TMEM216 or its complexes\", \"Mechanism linking membrane gate integrity to GLI regulation unknown\", \"Direct cargo of TMEM216/TMEM138 vesicular transport unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"MKS/Joubert transition-zone complex\"],\n    \"partners\": [\"TMEM67\", \"MKS1\", \"CEP290\", \"B9D1\", \"TCTN1\", \"TCTN2\", \"CC2D2A\", \"SUFU\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}