{"gene":"TMEM107","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"TMEM107 localizes to the transition zone (TZ) of cilia and occupies an intermediate layer of the TZ-localized MKS module, where it organizes recruitment of ciliopathy proteins MKS-1, TMEM-231 (JBTS20), and JBTS-14 (TMEM237). In C. elegans, TMEM-107 functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking, and assembly of membrane-to-microtubule Y-link connectors. Super-resolution microscopy revealed periodic localizations of MKS module membrane proteins within the TZ in both worms and mammalian cells.","method":"Genetic epistasis in C. elegans (double mutants with nphp-4), super-resolution microscopy, fluorescence imaging of TZ localization and protein recruitment","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (epistasis, super-resolution microscopy, protein localization assays) in a focused mechanistic study; independently consistent with findings from other labs","pmids":["26595381"],"is_preprint":false},{"year":2012,"finding":"Mouse Tmem107 (schlei mutant) is required for normal cilia formation and acts genetically in the Sonic hedgehog (Shh) signaling pathway; Tmem107 acts in combination with Gli2 and Gli3 to pattern ventral and intermediate neuronal cell types and determines digit number by regulating a subset of Shh target genes. Schlei mutants retain partial Gli activator and repressor function, unlike complete cilia-loss mutants.","method":"Forward genetics (ENU screen), mouse knockout/hypomorphic allele analysis, genetic epistasis with Gli2/Gli3, in situ hybridization for Shh pathway targets","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with defined pathway components, multiple phenotypic readouts, replicated across labs","pmids":["22698544"],"is_preprint":false},{"year":2015,"finding":"TMEM107 mutation in human patients causes a ciliogenesis defect with accompanying perturbation of Sonic hedgehog (Shh) signaling, as demonstrated in patient fibroblasts. Loss of TMEM107 leads to marked reduction in ciliated cells and is the cause of MKS13 (Meckel-Gruber syndrome locus 13); aberrant splicing and nonsense-mediated decay confirmed as the molecular mechanism for a homozygous splicing variant.","method":"Patient fibroblast analysis (ciliogenesis assay), RT-PCR for aberrant splicing/NMD, Shh signaling assay in patient cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays in patient fibroblasts with two orthogonal methods (ciliogenesis, splicing); single-lab study","pmids":["26123494"],"is_preprint":false},{"year":2015,"finding":"TMEM107 functions within cilia to regulate ciliary protein composition; key ciliary proteins fail to localize normally in cilia derived from Tmem107 mouse mutants and from a human OFD patient with TMEM107 mutation.","method":"Immunofluorescence of ciliary protein localization in mouse mutant cells and human patient fibroblasts","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in both mouse model and human patient, two independent biological systems","pmids":["26518474"],"is_preprint":false},{"year":2017,"finding":"Tmem107-/- mice exhibit craniofacial defects including cleft lip, cleft palate, exencephaly, and microphthalmia/anophthalmia. Palatal defects arise from increased mesenchymal proliferation and defective horizontalization of palatal shelves. Region-specific changes in ciliary morphology occur with altered acetylated tubulin and IFT88 expression. Shh and Gli1 expression is increased in Tmem107-/- animals, confirming upregulated Shh pathway activity upon TMEM107 loss.","method":"Mouse knockout (Tmem107-/-), histology, immunofluorescence, in situ hybridization for Shh/Gli1, BrdU proliferation assay","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype and pathway readout; single-lab study","pmids":["28954202"],"is_preprint":false},{"year":2020,"finding":"Depletion of TMEM107 (along with TMEM216/MKS2) in Paramecium induces constitutive deciliation of some cilia, establishing that TMEM107 controls ciliary shedding at the transition zone. All five TZ proteins studied (TMEM107, TMEM216, CEP290, RPGRIP1L, NPHP4) localize to the TZ with 9-fold symmetry at the most distal part of the TZ in growing cilia.","method":"RNAi depletion in Paramecium, live imaging of deciliation, super-resolution/electron microscopy of TZ localization","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined phenotypic readout and localization data; single-lab study in a ciliate model","pmids":["32163404"],"is_preprint":false},{"year":2019,"finding":"Near-complete loss of cilia in Tmem107-null mice leads to left pulmonary isomerism due to failure of the midline barrier, while hypomorphic Tmem107schlei mutants with partially retained cilia can establish and maintain left-right asymmetry. Lefty1 expression and midline barrier formation require cilia but not necessarily Shh signaling, as revealed by comparing the two Tmem107 alleles.","method":"Mouse knockout and hypomorphic allele comparison, in situ hybridization for Lefty1 and Shh pathway genes, morphological analysis of L-R organ asymmetry","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis between two Tmem107 alleles with defined pathway readouts; single-lab study","pmids":["31887266"],"is_preprint":false},{"year":2023,"finding":"TMEM107 deficiency in retinal organoids results in loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knockout of TMEM107 in human ARPE-19 cells prevents primary cilia formation and impairs response to Smoothened agonist treatment due to ectopic activation of the SHH pathway, placing TMEM107 upstream of Smoothened/SHH pathway activation at the cilium.","method":"TMEM107 knockout in human ARPE-19 cells, retinal organoid culture, Smoothened agonist treatment, immunofluorescence for primary cilia, RT-qPCR for retinal genes","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR/KO with defined cellular phenotype and pharmacological rescue experiment; single-lab study","pmids":["37863656"],"is_preprint":false},{"year":2022,"finding":"TMEM107 expression is severely reduced in SCNM1-deficient cells due to defective minor intron (U12) splicing. Loss of TMEM107 expression contributes to abnormally elongated cilia in SCNM1-deficient fibroblasts; reintroduction of SCNM1 restores cilia length and TMEM107 expression, demonstrating that TMEM107 is regulated at the RNA processing level by the minor spliceosome.","method":"Transcriptome analysis of patient fibroblasts vs. controls, CRISPR-Cas9 SCNM1 knockout, siRNA knockdown, retroviral SCNM1 rescue, cilia length measurement","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (KO, KD, rescue) demonstrating TMEM107 as a downstream target of minor spliceosome; single-lab study","pmids":["36084634"],"is_preprint":false},{"year":2020,"finding":"TMEM107 forms tissue-specific protein complexes identifiable by pull-down from porcine retina tissue, demonstrating that its interaction partners vary in a tissue-specific manner relevant to ciliary function.","method":"Tagged TMEM107 pull-down from human HEK293T cell lysates used as bait against porcine retina tissue lysates, followed by mass spectrometry","journal":"Journal of proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown/MS experiment, no reciprocal validation, limited mechanistic follow-up","pmids":["32853754"],"is_preprint":false}],"current_model":"TMEM107 is a transmembrane protein that localizes to the transition zone (TZ) of primary cilia, where it occupies an intermediate layer of the MKS ciliopathy module and organizes recruitment of MKS-1, TMEM-231, and JBTS-14; loss of TMEM107 disrupts the ciliary diffusion barrier, impairs ciliary protein composition, causes constitutive deciliation, and leads to ectopic activation of the Sonic Hedgehog (SHH) pathway due to failure of proper cilium-mediated signal transduction."},"narrative":{"mechanistic_narrative":"TMEM107 is a transmembrane protein of the ciliary transition zone (TZ) that organizes the MKS ciliopathy module to control ciliary protein composition and Hedgehog signal transduction [PMID:26595381, PMID:26518474]. Within the TZ it occupies an intermediate layer of the MKS module and organizes recruitment of MKS-1, TMEM-231 (JBTS20), and TMEM237 (JBTS14), and in C. elegans functions redundantly with NPHP-4 to maintain cilium integrity, TZ docking, and assembly of membrane-to-microtubule Y-link connectors [PMID:26595381]. Loss of TMEM107 reduces ciliated cell numbers and disrupts normal localization of ciliary proteins [PMID:26123494, PMID:26518474], can drive constitutive deciliation at the TZ [PMID:32163404], and places TMEM107 upstream of Smoothened, where its absence causes ectopic activation of the Sonic Hedgehog (SHH) pathway [PMID:37863656]. In mice, Tmem107 acts genetically with Gli2 and Gli3 to pattern neuronal cell types and digit number, with hypomorphic schlei alleles retaining partial Gli activator/repressor function, and its loss elevates Shh/Gli1 activity and produces craniofacial and laterality defects reflecting cilium-dependent developmental signaling [PMID:22698544, PMID:28954202, PMID:31887266]. In humans, TMEM107 mutation causes Meckel-Gruber syndrome (MKS13) through a ciliogenesis defect with perturbed SHH signaling [PMID:26123494]. TMEM107 expression is itself controlled at the RNA-processing level by the minor (U12) spliceosome via SCNM1 [PMID:36084634].","teleology":[{"year":2012,"claim":"Established that Tmem107 is required for cilia formation and functions within the Shh pathway to control vertebrate patterning, distinguishing it from complete cilia-loss mutants by its partial retention of Gli function.","evidence":"ENU forward genetics in mouse (schlei allele), genetic epistasis with Gli2/Gli3, in situ hybridization for Shh targets","pmids":["22698544"],"confidence":"High","gaps":["Did not define molecular localization of TMEM107 within the cilium","Did not identify direct protein partners"]},{"year":2015,"claim":"Defined TMEM107's molecular role at the transition zone as an intermediate-layer organizer of the MKS module that recruits other ciliopathy proteins, explaining how it maintains cilium integrity.","evidence":"C. elegans genetic epistasis (nphp-4 double mutants) and super-resolution microscopy of TZ protein localization in worms and mammalian cells","pmids":["26595381"],"confidence":"High","gaps":["Direct biochemical interaction with MKS-1/TMEM-231/JBTS-14 not resolved at residue level","Mechanism of redundancy with NPHP-4 not fully defined"]},{"year":2015,"claim":"Connected TMEM107 to human disease by showing mutation causes a ciliogenesis defect with perturbed Shh signaling and underlies Meckel-Gruber syndrome (MKS13).","evidence":"Patient fibroblast ciliogenesis and Shh assays, RT-PCR confirming aberrant splicing and NMD of a homozygous splicing variant","pmids":["26123494"],"confidence":"Medium","gaps":["Single-lab patient cohort","Genotype-phenotype range across ciliopathies not delineated"]},{"year":2015,"claim":"Showed TMEM107 is required for correct ciliary protein composition, demonstrating its loss mislocalizes ciliary proteins across mouse and human systems.","evidence":"Immunofluorescence of ciliary protein localization in Tmem107 mouse mutant cells and an OFD patient fibroblast","pmids":["26518474"],"confidence":"Medium","gaps":["Which specific proteins depend on TMEM107 not comprehensively cataloged","Mechanism of selective gating not resolved"]},{"year":2017,"claim":"Linked TMEM107 loss to specific developmental phenotypes and confirmed upregulated Shh activity, tying ciliary dysfunction to craniofacial morphogenesis.","evidence":"Tmem107-/- mouse histology, BrdU proliferation, immunofluorescence, and in situ hybridization for Shh/Gli1","pmids":["28954202"],"confidence":"Medium","gaps":["Cell-type-specific basis of region-specific ciliary changes unclear","Direct link between altered IFT88/acetylated tubulin and TMEM107 loss not mechanistically dissected"]},{"year":2019,"claim":"Used graded Tmem107 alleles to separate cilium-dependent from Shh-dependent requirements in left-right patterning, showing midline barrier formation needs cilia but not necessarily Shh.","evidence":"Comparison of Tmem107-null vs. hypomorphic schlei mice with in situ hybridization for Lefty1/Shh genes and L-R organ analysis","pmids":["31887266"],"confidence":"Medium","gaps":["Molecular basis of allelic dose-dependence on cilia number not defined","Single-lab study"]},{"year":2020,"claim":"Established that TMEM107 controls ciliary shedding at the transition zone, with loss inducing constitutive deciliation, in an evolutionarily conserved ciliate model.","evidence":"RNAi depletion in Paramecium with live imaging of deciliation and super-resolution/EM localization showing 9-fold TZ symmetry","pmids":["32163404"],"confidence":"Medium","gaps":["Molecular trigger of deciliation downstream of TMEM107 loss unknown","Conservation of the shedding role in mammals not directly tested"]},{"year":2020,"claim":"Indicated that TMEM107 assembles tissue-specific protein complexes relevant to ciliary function.","evidence":"Tagged TMEM107 pull-down from HEK293T lysate against porcine retina lysate followed by mass spectrometry","pmids":["32853754"],"confidence":"Low","gaps":["Single pulldown/MS without reciprocal validation","Specific tissue-specific partners not functionally confirmed","No follow-up on functional consequence of identified interactions"]},{"year":2022,"claim":"Revealed that TMEM107 expression is governed at the RNA-processing level by the minor spliceosome, connecting U12 splicing to ciliary length control.","evidence":"Transcriptomics of SCNM1-deficient fibroblasts, CRISPR KO, siRNA, and retroviral SCNM1 rescue with cilia length measurement","pmids":["36084634"],"confidence":"Medium","gaps":["Whether minor-intron mis-splicing of TMEM107 contributes to specific disease phenotypes not established","Other minor-spliceosome targets affecting cilia not separated"]},{"year":2023,"claim":"Placed TMEM107 upstream of Smoothened/SHH activation at the cilium and demonstrated its loss causes ectopic SHH activation and retinal defects in human cell and organoid models.","evidence":"CRISPR TMEM107 knockout in ARPE-19 cells and retinal organoids, Smoothened agonist treatment, immunofluorescence and RT-qPCR","pmids":["37863656"],"confidence":"Medium","gaps":["Direct molecular link between TZ gating and Smoothened regulation not resolved","Single-lab study"]},{"year":null,"claim":"How TMEM107 biochemically gates the transition zone barrier and mechanistically restrains Smoothened/SHH activation remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TMEM107 within the MKS module","Direct binding interfaces with MKS-1/TMEM-231/TMEM237 not mapped","Mechanism coupling diffusion barrier integrity to Smoothened control unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,3,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,6]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,5]}],"complexes":["MKS module / transition zone"],"partners":["MKS1","TMEM231","TMEM237","NPHP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UX40","full_name":"Transmembrane protein 107","aliases":[],"length_aa":140,"mass_kda":15.5,"function":"Plays a role in cilia formation and embryonic patterning. Requires for normal Sonic hedgehog (Shh) signaling in the neural tube and acts in combination with GLI2 and GLI3 to pattern ventral and intermediate neuronal cell types (By similarity). During ciliogenesis regulates the ciliary transition zone localization of some MKS complex proteins (PubMed:26518474)","subcellular_location":"Membrane; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q6UX40/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM107","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM107","total_profiled":1310},"omim":[{"mim_id":"620107","title":"OROFACIODIGITAL SYNDROME XIX; OFD19","url":"https://www.omim.org/entry/620107"},{"mim_id":"617563","title":"OROFACIODIGITAL SYNDROME XVI; OFD16","url":"https://www.omim.org/entry/617563"},{"mim_id":"617562","title":"MECKEL SYNDROME 13; MKS13","url":"https://www.omim.org/entry/617562"},{"mim_id":"616663","title":"SMALL NUCLEOLAR RNA, C/D BOX, 118; SNORD118","url":"https://www.omim.org/entry/616663"},{"mim_id":"616183","title":"TRANSMEMBRANE PROTEIN 107; TMEM107","url":"https://www.omim.org/entry/616183"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":53.5}],"url":"https://www.proteinatlas.org/search/TMEM107"},"hgnc":{"alias_symbol":["MGC10744","JBTS29","MKS13"],"prev_symbol":[]},"alphafold":{"accession":"Q6UX40","domains":[{"cath_id":"1.20.1260","chopping":"7-134","consensus_level":"high","plddt":96.31,"start":7,"end":134}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX40","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX40-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX40-F1-predicted_aligned_error_v6.png","plddt_mean":94.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM107","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM107"},"sequence":{"accession":"Q6UX40","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UX40.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UX40/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX40"}},"corpus_meta":[{"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":"28289185","id":"PMC_28289185","title":"Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.","date":"2017","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28289185","citation_count":87,"is_preprint":false},{"pmid":"22698544","id":"PMC_22698544","title":"Forward genetics uncovers Transmembrane protein 107 as a novel factor required for ciliogenesis and Sonic hedgehog signaling.","date":"2012","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22698544","citation_count":39,"is_preprint":false},{"pmid":"26123494","id":"PMC_26123494","title":"Identification of a novel MKS locus defined by TMEM107 mutation.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26123494","citation_count":38,"is_preprint":false},{"pmid":"34294125","id":"PMC_34294125","title":"EGR1 dysregulation defines an inflammatory and leukemic program in cell trajectory of human-aged hematopoietic stem cells (HSC).","date":"2021","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34294125","citation_count":33,"is_preprint":false},{"pmid":"32163404","id":"PMC_32163404","title":"MKS-NPHP module proteins control ciliary shedding at the transition zone.","date":"2020","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/32163404","citation_count":31,"is_preprint":false},{"pmid":"25213383","id":"PMC_25213383","title":"Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors.","date":"2014","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25213383","citation_count":31,"is_preprint":false},{"pmid":"28954202","id":"PMC_28954202","title":"Ciliopathy Protein Tmem107 Plays Multiple Roles in Craniofacial Development.","date":"2017","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/28954202","citation_count":26,"is_preprint":false},{"pmid":"17437276","id":"PMC_17437276","title":"Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber syndrome.","date":"2007","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/17437276","citation_count":21,"is_preprint":false},{"pmid":"26518474","id":"PMC_26518474","title":"TMEM107 Is a Critical Regulator of Ciliary Protein Composition and Is Mutated in Orofaciodigital Syndrome.","date":"2015","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/26518474","citation_count":19,"is_preprint":false},{"pmid":"33124203","id":"PMC_33124203","title":"TMEM107 inhibits EMT and invasion of NSCLC through regulating the Hedgehog pathway.","date":"2020","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33124203","citation_count":17,"is_preprint":false},{"pmid":"36084634","id":"PMC_36084634","title":"Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36084634","citation_count":14,"is_preprint":false},{"pmid":"32853754","id":"PMC_32853754","title":"Tissue- and isoform-specific protein complex analysis with natively processed bait proteins.","date":"2020","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32853754","citation_count":11,"is_preprint":false},{"pmid":"37863656","id":"PMC_37863656","title":"Role of ciliopathy protein TMEM107 in eye development: insights from a mouse model and retinal organoid.","date":"2023","source":"Life science 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In C. elegans, TMEM-107 functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking, and assembly of membrane-to-microtubule Y-link connectors. Super-resolution microscopy revealed periodic localizations of MKS module membrane proteins within the TZ in both worms and mammalian cells.\",\n      \"method\": \"Genetic epistasis in C. elegans (double mutants with nphp-4), super-resolution microscopy, fluorescence imaging of TZ localization and protein recruitment\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (epistasis, super-resolution microscopy, protein localization assays) in a focused mechanistic study; independently consistent with findings from other labs\",\n      \"pmids\": [\"26595381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mouse Tmem107 (schlei mutant) is required for normal cilia formation and acts genetically in the Sonic hedgehog (Shh) signaling pathway; Tmem107 acts in combination with Gli2 and Gli3 to pattern ventral and intermediate neuronal cell types and determines digit number by regulating a subset of Shh target genes. Schlei mutants retain partial Gli activator and repressor function, unlike complete cilia-loss mutants.\",\n      \"method\": \"Forward genetics (ENU screen), mouse knockout/hypomorphic allele analysis, genetic epistasis with Gli2/Gli3, in situ hybridization for Shh pathway targets\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with defined pathway components, multiple phenotypic readouts, replicated across labs\",\n      \"pmids\": [\"22698544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMEM107 mutation in human patients causes a ciliogenesis defect with accompanying perturbation of Sonic hedgehog (Shh) signaling, as demonstrated in patient fibroblasts. Loss of TMEM107 leads to marked reduction in ciliated cells and is the cause of MKS13 (Meckel-Gruber syndrome locus 13); aberrant splicing and nonsense-mediated decay confirmed as the molecular mechanism for a homozygous splicing variant.\",\n      \"method\": \"Patient fibroblast analysis (ciliogenesis assay), RT-PCR for aberrant splicing/NMD, Shh signaling assay in patient cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays in patient fibroblasts with two orthogonal methods (ciliogenesis, splicing); single-lab study\",\n      \"pmids\": [\"26123494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMEM107 functions within cilia to regulate ciliary protein composition; key ciliary proteins fail to localize normally in cilia derived from Tmem107 mouse mutants and from a human OFD patient with TMEM107 mutation.\",\n      \"method\": \"Immunofluorescence of ciliary protein localization in mouse mutant cells and human patient fibroblasts\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in both mouse model and human patient, two independent biological systems\",\n      \"pmids\": [\"26518474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tmem107-/- mice exhibit craniofacial defects including cleft lip, cleft palate, exencephaly, and microphthalmia/anophthalmia. Palatal defects arise from increased mesenchymal proliferation and defective horizontalization of palatal shelves. Region-specific changes in ciliary morphology occur with altered acetylated tubulin and IFT88 expression. Shh and Gli1 expression is increased in Tmem107-/- animals, confirming upregulated Shh pathway activity upon TMEM107 loss.\",\n      \"method\": \"Mouse knockout (Tmem107-/-), histology, immunofluorescence, in situ hybridization for Shh/Gli1, BrdU proliferation assay\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype and pathway readout; single-lab study\",\n      \"pmids\": [\"28954202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Depletion of TMEM107 (along with TMEM216/MKS2) in Paramecium induces constitutive deciliation of some cilia, establishing that TMEM107 controls ciliary shedding at the transition zone. All five TZ proteins studied (TMEM107, TMEM216, CEP290, RPGRIP1L, NPHP4) localize to the TZ with 9-fold symmetry at the most distal part of the TZ in growing cilia.\",\n      \"method\": \"RNAi depletion in Paramecium, live imaging of deciliation, super-resolution/electron microscopy of TZ localization\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined phenotypic readout and localization data; single-lab study in a ciliate model\",\n      \"pmids\": [\"32163404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Near-complete loss of cilia in Tmem107-null mice leads to left pulmonary isomerism due to failure of the midline barrier, while hypomorphic Tmem107schlei mutants with partially retained cilia can establish and maintain left-right asymmetry. Lefty1 expression and midline barrier formation require cilia but not necessarily Shh signaling, as revealed by comparing the two Tmem107 alleles.\",\n      \"method\": \"Mouse knockout and hypomorphic allele comparison, in situ hybridization for Lefty1 and Shh pathway genes, morphological analysis of L-R organ asymmetry\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis between two Tmem107 alleles with defined pathway readouts; single-lab study\",\n      \"pmids\": [\"31887266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM107 deficiency in retinal organoids results in loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knockout of TMEM107 in human ARPE-19 cells prevents primary cilia formation and impairs response to Smoothened agonist treatment due to ectopic activation of the SHH pathway, placing TMEM107 upstream of Smoothened/SHH pathway activation at the cilium.\",\n      \"method\": \"TMEM107 knockout in human ARPE-19 cells, retinal organoid culture, Smoothened agonist treatment, immunofluorescence for primary cilia, RT-qPCR for retinal genes\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR/KO with defined cellular phenotype and pharmacological rescue experiment; single-lab study\",\n      \"pmids\": [\"37863656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM107 expression is severely reduced in SCNM1-deficient cells due to defective minor intron (U12) splicing. Loss of TMEM107 expression contributes to abnormally elongated cilia in SCNM1-deficient fibroblasts; reintroduction of SCNM1 restores cilia length and TMEM107 expression, demonstrating that TMEM107 is regulated at the RNA processing level by the minor spliceosome.\",\n      \"method\": \"Transcriptome analysis of patient fibroblasts vs. controls, CRISPR-Cas9 SCNM1 knockout, siRNA knockdown, retroviral SCNM1 rescue, cilia length measurement\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (KO, KD, rescue) demonstrating TMEM107 as a downstream target of minor spliceosome; single-lab study\",\n      \"pmids\": [\"36084634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM107 forms tissue-specific protein complexes identifiable by pull-down from porcine retina tissue, demonstrating that its interaction partners vary in a tissue-specific manner relevant to ciliary function.\",\n      \"method\": \"Tagged TMEM107 pull-down from human HEK293T cell lysates used as bait against porcine retina tissue lysates, followed by mass spectrometry\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/MS experiment, no reciprocal validation, limited mechanistic follow-up\",\n      \"pmids\": [\"32853754\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM107 is a transmembrane protein that localizes to the transition zone (TZ) of primary cilia, where it occupies an intermediate layer of the MKS ciliopathy module and organizes recruitment of MKS-1, TMEM-231, and JBTS-14; loss of TMEM107 disrupts the ciliary diffusion barrier, impairs ciliary protein composition, causes constitutive deciliation, and leads to ectopic activation of the Sonic Hedgehog (SHH) pathway due to failure of proper cilium-mediated signal transduction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM107 is a transmembrane protein of the ciliary transition zone (TZ) that organizes the MKS ciliopathy module to control ciliary protein composition and Hedgehog signal transduction [#0, #3]. Within the TZ it occupies an intermediate layer of the MKS module and organizes recruitment of MKS-1, TMEM-231 (JBTS20), and TMEM237 (JBTS14), and in C. elegans functions redundantly with NPHP-4 to maintain cilium integrity, TZ docking, and assembly of membrane-to-microtubule Y-link connectors [#0]. Loss of TMEM107 reduces ciliated cell numbers and disrupts normal localization of ciliary proteins [#2, #3], can drive constitutive deciliation at the TZ [#5], and places TMEM107 upstream of Smoothened, where its absence causes ectopic activation of the Sonic Hedgehog (SHH) pathway [#7]. In mice, Tmem107 acts genetically with Gli2 and Gli3 to pattern neuronal cell types and digit number, with hypomorphic schlei alleles retaining partial Gli activator/repressor function, and its loss elevates Shh/Gli1 activity and produces craniofacial and laterality defects reflecting cilium-dependent developmental signaling [#1, #4, #6]. In humans, TMEM107 mutation causes Meckel-Gruber syndrome (MKS13) through a ciliogenesis defect with perturbed SHH signaling [#2]. TMEM107 expression is itself controlled at the RNA-processing level by the minor (U12) spliceosome via SCNM1 [#8].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that Tmem107 is required for cilia formation and functions within the Shh pathway to control vertebrate patterning, distinguishing it from complete cilia-loss mutants by its partial retention of Gli function.\",\n      \"evidence\": \"ENU forward genetics in mouse (schlei allele), genetic epistasis with Gli2/Gli3, in situ hybridization for Shh targets\",\n      \"pmids\": [\"22698544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define molecular localization of TMEM107 within the cilium\", \"Did not identify direct protein partners\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined TMEM107's molecular role at the transition zone as an intermediate-layer organizer of the MKS module that recruits other ciliopathy proteins, explaining how it maintains cilium integrity.\",\n      \"evidence\": \"C. elegans genetic epistasis (nphp-4 double mutants) and super-resolution microscopy of TZ protein localization in worms and mammalian cells\",\n      \"pmids\": [\"26595381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical interaction with MKS-1/TMEM-231/JBTS-14 not resolved at residue level\", \"Mechanism of redundancy with NPHP-4 not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected TMEM107 to human disease by showing mutation causes a ciliogenesis defect with perturbed Shh signaling and underlies Meckel-Gruber syndrome (MKS13).\",\n      \"evidence\": \"Patient fibroblast ciliogenesis and Shh assays, RT-PCR confirming aberrant splicing and NMD of a homozygous splicing variant\",\n      \"pmids\": [\"26123494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab patient cohort\", \"Genotype-phenotype range across ciliopathies not delineated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed TMEM107 is required for correct ciliary protein composition, demonstrating its loss mislocalizes ciliary proteins across mouse and human systems.\",\n      \"evidence\": \"Immunofluorescence of ciliary protein localization in Tmem107 mouse mutant cells and an OFD patient fibroblast\",\n      \"pmids\": [\"26518474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific proteins depend on TMEM107 not comprehensively cataloged\", \"Mechanism of selective gating not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked TMEM107 loss to specific developmental phenotypes and confirmed upregulated Shh activity, tying ciliary dysfunction to craniofacial morphogenesis.\",\n      \"evidence\": \"Tmem107-/- mouse histology, BrdU proliferation, immunofluorescence, and in situ hybridization for Shh/Gli1\",\n      \"pmids\": [\"28954202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type-specific basis of region-specific ciliary changes unclear\", \"Direct link between altered IFT88/acetylated tubulin and TMEM107 loss not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Used graded Tmem107 alleles to separate cilium-dependent from Shh-dependent requirements in left-right patterning, showing midline barrier formation needs cilia but not necessarily Shh.\",\n      \"evidence\": \"Comparison of Tmem107-null vs. hypomorphic schlei mice with in situ hybridization for Lefty1/Shh genes and L-R organ analysis\",\n      \"pmids\": [\"31887266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of allelic dose-dependence on cilia number not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that TMEM107 controls ciliary shedding at the transition zone, with loss inducing constitutive deciliation, in an evolutionarily conserved ciliate model.\",\n      \"evidence\": \"RNAi depletion in Paramecium with live imaging of deciliation and super-resolution/EM localization showing 9-fold TZ symmetry\",\n      \"pmids\": [\"32163404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger of deciliation downstream of TMEM107 loss unknown\", \"Conservation of the shedding role in mammals not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Indicated that TMEM107 assembles tissue-specific protein complexes relevant to ciliary function.\",\n      \"evidence\": \"Tagged TMEM107 pull-down from HEK293T lysate against porcine retina lysate followed by mass spectrometry\",\n      \"pmids\": [\"32853754\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pulldown/MS without reciprocal validation\", \"Specific tissue-specific partners not functionally confirmed\", \"No follow-up on functional consequence of identified interactions\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that TMEM107 expression is governed at the RNA-processing level by the minor spliceosome, connecting U12 splicing to ciliary length control.\",\n      \"evidence\": \"Transcriptomics of SCNM1-deficient fibroblasts, CRISPR KO, siRNA, and retroviral SCNM1 rescue with cilia length measurement\",\n      \"pmids\": [\"36084634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether minor-intron mis-splicing of TMEM107 contributes to specific disease phenotypes not established\", \"Other minor-spliceosome targets affecting cilia not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed TMEM107 upstream of Smoothened/SHH activation at the cilium and demonstrated its loss causes ectopic SHH activation and retinal defects in human cell and organoid models.\",\n      \"evidence\": \"CRISPR TMEM107 knockout in ARPE-19 cells and retinal organoids, Smoothened agonist treatment, immunofluorescence and RT-qPCR\",\n      \"pmids\": [\"37863656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between TZ gating and Smoothened regulation not resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM107 biochemically gates the transition zone barrier and mechanistically restrains Smoothened/SHH activation remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TMEM107 within the MKS module\", \"Direct binding interfaces with MKS-1/TMEM-231/TMEM237 not mapped\", \"Mechanism coupling diffusion barrier integrity to Smoothened control unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [\"MKS module / transition zone\"],\n    \"partners\": [\"MKS1\", \"TMEM231\", \"TMEM237\", \"NPHP4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}