{"gene":"INTU","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2010,"finding":"Mouse Intu null mutants exhibit severe ciliogenesis defects (loss of primary cilia in embryos and cultured fibroblasts), disrupted Gli3 proteolytic processing, and downregulated Hh target genes Gli1 and Ptch1, establishing Intu as an essential regulator of ciliogenesis and Hedgehog signal transduction. A cytoplasmic GFP-Intu fusion protein efficiently rescues ciliogenic defects in Intu mutant cells.","method":"Gene-targeted null mutation in mice, immunofluorescence for cilia, qRT-PCR and Western blot for Hh pathway components, rescue with GFP-Intu in cultured fibroblasts","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype (ciliogenesis), pathway placement (Hh/Gli3 processing), and genetic rescue experiment; replicated across multiple readouts in one study","pmids":["20067783"],"is_preprint":false},{"year":2009,"finding":"Fuz (a PCP effector functionally linked to Intu in the same pathway) is essential for trafficking of cargo to basal bodies and to apical cilia tips, and for exocytosis in secretory cells; a Rab-related small GTPase was identified as a Fuz interaction partner also required for ciliogenesis and secretion, placing the PCP effector module at the interface of vesicle trafficking and ciliogenesis.","method":"Fuz mutant mouse analysis, in vivo mucociliary epithelium imaging, bioinformatics, co-immunoprecipitation/interaction with Rab GTPase","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging in vivo and interaction partner identification, but focused on Fuz; Intu is cited as a co-effector in the same pathway without direct biochemical dissection","pmids":["19767740"],"is_preprint":false},{"year":2011,"finding":"The ciliogenesis-dependent neural tube patterning functions of Intu and Fuz are non-redundant; genetic removal of both genes does not produce a convergent-extension phenotype, and neither gene shows genetic interaction with the core PCP regulator Vangl2 in convergent extension. Intu and Fuz double mutants show more severe patterning defects without redundancy, positioning these effectors downstream of core PCP but upstream of cilia-dependent Hh patterning.","method":"Intu;Fuz double mutant mouse analysis, genetic epistasis with Vangl2 hypomorph, histological and molecular patterning assays","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse double mutants with defined patterning readouts; single-lab study","pmids":["21761479"],"is_preprint":false},{"year":2012,"finding":"Tissue-specific disruption of Intu in embryonic epidermis causes near-complete loss of primary cilia in epidermal and follicular keratinocytes, suppresses Hedgehog signaling, and arrests hair follicle morphogenesis due to failure of follicular keratinocyte differentiation, without affecting epidermal stratification, barrier function, or planar cell polarity—demonstrating a cell-fate-specific, cilia-dependent role for Intu in skin.","method":"Conditional knockout (Cre-lox) in mouse epidermis, immunofluorescence for cilia markers, Hh pathway reporter analysis, histological differentiation assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with clean cellular phenotype, pathway placement (Hh), multiple orthogonal readouts (cilia, differentiation, barrier), and cell-type specificity established","pmids":["22935613"],"is_preprint":false},{"year":2015,"finding":"A hypomorphic Intu allele carrying a conserved hydrophobic-to-asparagine substitution (I813N) near the C-terminus causes moderate cilia loss, skeletal defects (rib defects, delayed endochondral ossification, polydactyly), and reduced Hh signaling, while neural tube patterning and PCP appear normal. The Intu(I813N) protein exhibits compromised ability to restore ciliogenesis in Intu null cells, functionally linking this residue to ciliogenic activity.","method":"Gene-targeted hypomorphic knock-in mouse (I813N), cilia quantification, skeletal staining, qRT-PCR for Hh targets, rescue assay in Intu null cultured cells","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site/domain mutagenesis in vivo plus in vitro rescue assay; single lab but multiple orthogonal methods","pmids":["25774014"],"is_preprint":false},{"year":2017,"finding":"INTU is essential for IFT-A (intraflagellar transport A) complex assembly during ciliogenesis. In an oncogenic SmoM2-driven basal cell carcinoma model, Intu disruption prevents BCC formation by suppressing primary cilia formation and Hh signaling. In mouse embryonic fibroblasts, depleting Intu blocks Smo agonist-induced Hh pathway activation, but expression of constitutively active Gli2ΔN restores Hh signaling in Intu-deficient cells, genetically placing INTU upstream of Gli2 activation and downstream of Smo.","method":"Conditional knockout in SmoM2 BCC mouse model, shRNA knockdown, cilia quantification, IFT-A complex assembly assays, epistasis with Gli2ΔN in MEFs","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in disease model, IFT-A assembly assay, genetic epistasis with Gli2ΔN; multiple orthogonal methods placing INTU in Hh pathway","pmids":["28459465"],"is_preprint":false},{"year":2017,"finding":"RSG1 (a small GTPase) localizes to the mother centriole in a process that depends on INTU (the CPLANE protein Inturned), tau tubulin kinase 2 (TTBK2), and RSG1's own GTPase activity. Loss of RSG1 impairs axonemal microtubule elongation after ciliary vesicle docking, placing RSG1 as a downstream effector of INTU at a final maturation step of cilia initiation.","method":"Rsg1 mouse knockout, immunofluorescence for RSG1 centriolar localization, genetic epistasis with Intu and TTBK2, cilia ultrastructure analysis, Hh pathway readouts","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse, defined cellular phenotype (axoneme elongation), dependency of RSG1 localization on INTU by loss-of-function; multiple orthogonal methods","pmids":["29038301"],"is_preprint":false},{"year":2018,"finding":"INTU physically interacts with STAT1; they co-localize at the centriole/basal body. INTU promotes proteasomal degradation of STAT1. In vitro, INTU expression preserves cilia length and cell viability after stress, effects antagonized by STAT1 overexpression. Kidney-proximal-tubule-specific ablation of Intu aggravates renal ischemia-reperfusion injury and impairs post-injury ciliogenesis.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, conditional KO mouse (proximal tubule-specific), proteasome inhibitor assay, cell viability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-localization, co-IP, conditional KO with tissue-injury phenotype, proteasomal degradation assay; multiple orthogonal methods in one study","pmids":["29581513"],"is_preprint":false},{"year":2020,"finding":"Computational evolutionary analysis identifies INTU and FUZ as a heterodimeric complex homologous to HerMon (Hermansky-Pudlak syndrome and MON1-CCZ1) complexes, each containing triplicated Longin domains. Based on homology to known Rab effectors/GEFs, the INTU/FUZ complex is predicted to act as a GEF for Rab GTPases involved in ciliogenesis.","method":"Coevolution-based contact prediction, sequence conservation analysis (computational/bioinformatic)","journal":"Bioinformatics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only; no experimental validation of GEF activity reported in this paper","pmids":["31562761"],"is_preprint":false},{"year":2022,"finding":"CPLANE complex (composed of INTU, FUZ, and WDPCP, which interact with JBTS17 and RSG1) is required for IFT-A particle assembly and intraflagellar transport; defects in CPLANE components disrupt PCP and Hh signaling, leading to ciliopathies including orofacial-digital syndrome and Bardet-Biedl syndrome.","method":"Synthesis/review of genetic and functional studies; functional studies cited include IFT-A assembly assays and mouse genetic models","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — consolidates experimental evidence from multiple studies; IFT-A assembly role grounded in prior experimental work (PMID 28459465, 29038301)","pmids":["35740972"],"is_preprint":false},{"year":2022,"finding":"Conditional knockout of Intu in kidney tubules delays kidney repair and ameliorates renal fibrosis after ischemia-reperfusion injury. Intu KO kidneys show less senescence but higher cell proliferation and apoptosis during repair. In vitro, Intu knockdown suppresses scratch wound healing in renal tubular cells, accompanied by abnormal centrosome orientation, establishing a role for Intu in centrosome-directed tubular cell migration/repair.","method":"Conditional KO mouse (kidney tubule-specific), histological and biochemical analysis of fibrosis and senescence, scratch wound healing assay with centrosome orientation imaging","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotypes and in vitro centrosome orientation readout; single lab, multiple methods","pmids":["36586478"],"is_preprint":false},{"year":2024,"finding":"Loss of Intu severely disrupts growth and branching morphogenesis of mouse embryonic lungs, associated with greatly reduced primary cilia in epithelial and mesenchymal cells and reduced Hh target gene expression (Gli1, Ptch1). Smoothened agonist increases Hh target gene expression and tubulogenesis in wild-type but not Intu mutant lung explants. Removing both Gli2 and Intu completely abolishes lung branching morphogenesis, genetically placing Intu upstream of Gli2-dependent Hh signaling in the lung.","method":"Intu null mouse KO, lung explant culture with Smo agonist, Gli2;Intu double mutant epistasis, qRT-PCR/immunofluorescence, transcriptomics","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with organ-specific phenotype, pharmacological rescue experiment, genetic epistasis with Gli2 double mutant; multiple orthogonal methods","pmids":["39029571"],"is_preprint":false},{"year":2025,"finding":"The predicted PDZ domain unique to Inturned among TLD proteins does not interact with membranes or with Vangl2. Crystal structure of the Intu-PDZ domain reveals a unique PDZ-like fold lacking a canonical interaction site for PDZ-binding motifs. Vangl2 instead shows a phosphorylation-dependent interaction with a PDZ domain of the apical-basal polarity protein Scribble.","method":"Crystal structure determination of Intu-PDZ domain, biochemical binding assays (pulldown/binding experiments with membranes and Vangl2), structural analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus biochemical binding assays; negative result for Vangl2–Intu PDZ interaction confirmed by both structure and biochemistry; single lab","pmids":["41797376"],"is_preprint":false},{"year":2025,"finding":"Functional studies in patient-derived cells with compound heterozygous INTU variants demonstrate altered ciliogenesis and/or cilia signaling, confirming that pathogenic INTU variants cause human disease through disruption of CPLANE-dependent ciliogenesis.","method":"Patient-derived cell ciliogenesis assays (compound heterozygous INTU variants), trio whole-exome sequencing","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional ciliogenesis assay in patient-derived cells; single case report with functional follow-up, limited mechanistic depth","pmids":["40968537"],"is_preprint":false}],"current_model":"INTU (Inturned) is a core subunit of the CPLANE complex (with FUZ and WDPCP) that acts at the mother centriole/basal body to promote IFT-A complex assembly and intraflagellar transport, enabling primary cilia formation; it contains a unique PDZ-like fold (structurally incapable of canonical PDZ-ligand binding) and tripled Longin domains homologous to Rab GEF complexes, interacts with RSG1 to control the final axonemal elongation step of cilia initiation, promotes proteasomal degradation of STAT1 at the basal body, and functions genetically upstream of Gli2 activation to transduce cilia-dependent Hedgehog signaling during embryonic development, tissue homeostasis, and injury repair."},"narrative":{"mechanistic_narrative":"INTU (Inturned) is an essential regulator of primary ciliogenesis and cilia-dependent Hedgehog signal transduction during embryonic development, tissue homeostasis, and injury repair [PMID:20067783, PMID:22935613]. It functions as a core subunit of the CPLANE complex together with FUZ and WDPCP, acting downstream of core planar cell polarity but upstream of cilia-dependent Hedgehog patterning [PMID:21761479, PMID:35740972]. At the mother centriole/basal body, INTU is required for assembly of the IFT-A intraflagellar transport complex, and it controls the recruitment of the small GTPase RSG1 — together with TTBK2 — to drive axonemal microtubule elongation at the final maturation step of cilia initiation [PMID:28459465, PMID:29038301]. Genetically, INTU acts downstream of Smoothened and upstream of Gli2 activation: constitutively active Gli2 restores Hedgehog signaling in INTU-deficient cells, and combined loss of Gli2 and Intu abolishes Hedgehog-dependent morphogenesis [PMID:28459465, PMID:39029571]. Loss of Intu disrupts ciliogenesis and Hedgehog output across diverse tissues, including epidermis and hair follicles, skeleton, lung branching morphogenesis, and renal tubule repair, where INTU additionally binds STAT1 at the centriole and promotes its proteasomal degradation [PMID:22935613, PMID:25774014, PMID:29581513, PMID:39029571]. Structurally, INTU contains a PDZ-like fold that lacks a canonical PDZ-ligand binding site and does not interact with membranes or Vangl2 [PMID:41797376]. Compound heterozygous INTU variants cause human disease through disruption of CPLANE-dependent ciliogenesis [PMID:40968537].","teleology":[{"year":2009,"claim":"Established that the PCP effector module to which Intu belongs operates at the interface of vesicle trafficking and ciliogenesis, before Intu itself was biochemically dissected.","evidence":"Fuz mutant mouse analysis, in vivo mucociliary imaging, and co-IP identifying a Rab-related GTPase partner","pmids":["19767740"],"confidence":"Medium","gaps":["Focused on Fuz, not direct Intu biochemistry","Did not define the molecular trafficking step controlled"]},{"year":2010,"claim":"Defined INTU as an essential ciliogenesis regulator and placed it within Hedgehog signal transduction by linking its loss to failed Gli3 processing and reduced Hh target genes.","evidence":"Intu null mouse with cilia immunofluorescence, Hh target qRT-PCR/Western, and GFP-Intu rescue in fibroblasts","pmids":["20067783"],"confidence":"High","gaps":["Molecular mechanism of how INTU promotes ciliogenesis unknown","No biochemical activity defined"]},{"year":2011,"claim":"Positioned Intu and Fuz as non-redundant effectors downstream of core PCP but upstream of cilia-dependent Hh patterning, separating their ciliogenic role from convergent-extension PCP.","evidence":"Intu;Fuz double mutant mouse epistasis and genetic tests with a Vangl2 hypomorph","pmids":["21761479"],"confidence":"Medium","gaps":["Does not establish a molecular function","Single-lab genetic study"]},{"year":2012,"claim":"Demonstrated that INTU's role is cell-fate-specific and cilia-dependent rather than tied to epidermal barrier or PCP, by restricting its requirement to follicular keratinocyte differentiation.","evidence":"Conditional epidermal Cre-lox knockout with cilia markers, Hh reporter, and differentiation/barrier assays","pmids":["22935613"],"confidence":"High","gaps":["Does not identify INTU molecular partners in skin","Mechanism of cilia loss not resolved biochemically"]},{"year":2015,"claim":"Linked a specific conserved C-terminal residue (I813) to ciliogenic activity, showing domain-level structure-function and tissue selectivity (skeletal versus neural tube).","evidence":"I813N hypomorphic knock-in mouse with cilia, skeletal, and Hh-target readouts plus rescue assay in Intu null cells","pmids":["25774014"],"confidence":"High","gaps":["Biochemical consequence of I813N not defined","Why neural tube is spared unexplained"]},{"year":2017,"claim":"Provided the molecular and epistatic placement of INTU: required for IFT-A complex assembly and acting downstream of Smo but upstream of Gli2 activation.","evidence":"Conditional KO in SmoM2 BCC model, IFT-A assembly assays, and Gli2ΔN epistasis rescue in MEFs","pmids":["28459465"],"confidence":"High","gaps":["Direct biochemical mechanism of IFT-A assembly by INTU not shown","How INTU couples to Gli2 regulation unresolved"]},{"year":2017,"claim":"Identified a downstream effector arm, showing INTU is required to recruit RSG1 to the mother centriole for axonemal elongation at a final cilia-initiation step.","evidence":"Rsg1 KO mouse, RSG1 centriolar localization dependent on Intu/TTBK2/GTPase activity, and cilia ultrastructure","pmids":["29038301"],"confidence":"High","gaps":["Whether INTU directly binds RSG1 not established","Mechanism of RSG1-driven microtubule elongation unknown"]},{"year":2018,"claim":"Revealed a non-ciliary biochemical activity: INTU binds STAT1 at the basal body and promotes its proteasomal degradation, protecting cilia length and viability under stress.","evidence":"Co-IP, reciprocal co-localization, proteasome inhibitor assay, and proximal-tubule conditional KO with ischemia-reperfusion phenotype","pmids":["29581513"],"confidence":"High","gaps":["Mechanism by which INTU targets STAT1 for degradation unknown","No identified E3 ligase or degron"]},{"year":2020,"claim":"Generated a structural hypothesis that the INTU/FUZ heterodimer carries triplicated Longin domains homologous to Rab effector/GEF complexes, predicting Rab GEF activity in ciliogenesis.","evidence":"Coevolution-based contact prediction and sequence conservation analysis (computational only)","pmids":["31562761"],"confidence":"Low","gaps":["No experimental validation of GEF activity","Predicted Rab substrate not identified"]},{"year":2022,"claim":"Consolidated INTU as a stable CPLANE subunit (with FUZ, WDPCP, JBTS17, RSG1) whose dysfunction causes ciliopathies, integrating its IFT-A and signaling roles.","evidence":"Synthesis of genetic and functional studies including IFT-A assembly and mouse models","pmids":["35740972"],"confidence":"Medium","gaps":["Review-level synthesis, not new primary data","Stoichiometry and architecture of CPLANE not resolved here"]},{"year":2022,"claim":"Extended INTU's tissue role to centrosome-directed cell migration during kidney repair, distinguishing its repair-promoting from fibrosis-modulating effects.","evidence":"Kidney-tubule conditional KO with fibrosis/senescence analysis and scratch-wound assay with centrosome orientation imaging","pmids":["36586478"],"confidence":"Medium","gaps":["Molecular basis of centrosome orientation defect unclear","Relationship to STAT1 degradation arm not tested"]},{"year":2024,"claim":"Confirmed the upstream-of-Gli2 placement in a new organ context by showing Intu is required for Hh-driven lung branching morphogenesis.","evidence":"Intu null mouse, lung explant Smo-agonist rescue, Gli2;Intu double-mutant epistasis, and transcriptomics","pmids":["39029571"],"confidence":"High","gaps":["Does not add new biochemical mechanism","Cell-type-specific contributions not fully separated"]},{"year":2025,"claim":"Resolved the structure of INTU's PDZ-like domain, overturning the assumption of canonical PDZ-ligand or Vangl2 binding and reassigning Vangl2's PDZ interaction to Scribble.","evidence":"Crystal structure of the Intu-PDZ domain plus pulldown/binding assays with membranes and Vangl2","pmids":["41797376"],"confidence":"High","gaps":["The actual binding partner(s) of the INTU PDZ-like fold remain unidentified","Functional role of this domain in ciliogenesis not defined"]},{"year":2025,"claim":"Established INTU as a human disease gene by showing pathogenic compound heterozygous variants disrupt CPLANE-dependent ciliogenesis in patient cells.","evidence":"Patient-derived cell ciliogenesis assays and trio whole-exome sequencing","pmids":["40968537"],"confidence":"Medium","gaps":["Single case with limited mechanistic depth","Genotype-phenotype correlation not generalized"]},{"year":null,"claim":"Whether the INTU/FUZ Longin-domain module possesses experimentally validated Rab GEF activity, and which Rab(s) and what binding partner of the PDZ-like fold mediate INTU's ciliogenic and IFT-A assembly functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Predicted GEF activity never tested biochemically","No identified ligand for the PDZ-like domain","Direct molecular mechanism of IFT-A assembly by INTU unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,6,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3,11]}],"complexes":["CPLANE complex"],"partners":["FUZ","WDPCP","RSG1","STAT1","TTBK2","JBTS17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULD6","full_name":"Protein inturned","aliases":["Inturned planar cell polarity effector homolog","PDZ domain-containing protein 6"],"length_aa":942,"mass_kda":105.6,"function":"Plays a key role in ciliogenesis and embryonic development. Regulator of cilia formation by controlling the organization of the apical actin cytoskeleton and the positioning of the basal bodies at the apical cell surface, which in turn is essential for the normal orientation of elongating ciliary microtubules. Plays a key role in definition of cell polarity via its role in ciliogenesis but not via conversion extension. Has an indirect effect on hedgehog signaling (By similarity). Proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies (PubMed:27158779). Required for recruitment of CPLANE2 to the mother centriole (By similarity). Binds phosphatidylinositol 3-phosphate with highest affinity, followed by phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate (By similarity)","subcellular_location":"Cytoplasm; Cell surface; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q9ULD6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INTU","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INTU","total_profiled":1310},"omim":[{"mim_id":"621180","title":"CRANIOECTODERMAL DYSPLASIA 5; CED5","url":"https://www.omim.org/entry/621180"},{"mim_id":"620566","title":"CLAUDIN 22; CLDN22","url":"https://www.omim.org/entry/620566"},{"mim_id":"620487","title":"CILIOGENESIS AND PLANAR POLARITY EFFECTOR COMPLEX, SUBUNIT 2; CPLANE2","url":"https://www.omim.org/entry/620487"},{"mim_id":"617926","title":"OROFACIODIGITAL SYNDROME XVII; OFD17","url":"https://www.omim.org/entry/617926"},{"mim_id":"617925","title":"SHORT-RIB THORACIC DYSPLASIA 20 WITH POLYDACTYLY; SRTD20","url":"https://www.omim.org/entry/617925"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Basal body","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":12.2}],"url":"https://www.proteinatlas.org/search/INTU"},"hgnc":{"alias_symbol":["KIAA1284","CPLANE4"],"prev_symbol":["PDZK6","PDZD6"]},"alphafold":{"accession":"Q9ULD6","domains":[{"cath_id":"-","chopping":"56-78_284-303_472-572_585-649","consensus_level":"medium","plddt":84.0971,"start":56,"end":649},{"cath_id":"2.30.42.10","chopping":"159-172_179-192_207-263","consensus_level":"high","plddt":83.0041,"start":159,"end":263},{"cath_id":"3.30.450.70","chopping":"307-456","consensus_level":"high","plddt":87.263,"start":307,"end":456},{"cath_id":"-","chopping":"650-661_770-857_875-942","consensus_level":"medium","plddt":75.2898,"start":650,"end":942}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULD6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULD6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULD6-F1-predicted_aligned_error_v6.png","plddt_mean":66.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTU","jax_strain_url":"https://www.jax.org/strain/search?query=INTU"},"sequence":{"accession":"Q9ULD6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULD6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULD6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULD6"}},"corpus_meta":[{"pmid":"19767740","id":"PMC_19767740","title":"The 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A cytoplasmic GFP-Intu fusion protein efficiently rescues ciliogenic defects in Intu mutant cells.\",\n      \"method\": \"Gene-targeted null mutation in mice, immunofluorescence for cilia, qRT-PCR and Western blot for Hh pathway components, rescue with GFP-Intu in cultured fibroblasts\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype (ciliogenesis), pathway placement (Hh/Gli3 processing), and genetic rescue experiment; replicated across multiple readouts in one study\",\n      \"pmids\": [\"20067783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fuz (a PCP effector functionally linked to Intu in the same pathway) is essential for trafficking of cargo to basal bodies and to apical cilia tips, and for exocytosis in secretory cells; a Rab-related small GTPase was identified as a Fuz interaction partner also required for ciliogenesis and secretion, placing the PCP effector module at the interface of vesicle trafficking and ciliogenesis.\",\n      \"method\": \"Fuz mutant mouse analysis, in vivo mucociliary epithelium imaging, bioinformatics, co-immunoprecipitation/interaction with Rab GTPase\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging in vivo and interaction partner identification, but focused on Fuz; Intu is cited as a co-effector in the same pathway without direct biochemical dissection\",\n      \"pmids\": [\"19767740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The ciliogenesis-dependent neural tube patterning functions of Intu and Fuz are non-redundant; genetic removal of both genes does not produce a convergent-extension phenotype, and neither gene shows genetic interaction with the core PCP regulator Vangl2 in convergent extension. Intu and Fuz double mutants show more severe patterning defects without redundancy, positioning these effectors downstream of core PCP but upstream of cilia-dependent Hh patterning.\",\n      \"method\": \"Intu;Fuz double mutant mouse analysis, genetic epistasis with Vangl2 hypomorph, histological and molecular patterning assays\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse double mutants with defined patterning readouts; single-lab study\",\n      \"pmids\": [\"21761479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tissue-specific disruption of Intu in embryonic epidermis causes near-complete loss of primary cilia in epidermal and follicular keratinocytes, suppresses Hedgehog signaling, and arrests hair follicle morphogenesis due to failure of follicular keratinocyte differentiation, without affecting epidermal stratification, barrier function, or planar cell polarity—demonstrating a cell-fate-specific, cilia-dependent role for Intu in skin.\",\n      \"method\": \"Conditional knockout (Cre-lox) in mouse epidermis, immunofluorescence for cilia markers, Hh pathway reporter analysis, histological differentiation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with clean cellular phenotype, pathway placement (Hh), multiple orthogonal readouts (cilia, differentiation, barrier), and cell-type specificity established\",\n      \"pmids\": [\"22935613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A hypomorphic Intu allele carrying a conserved hydrophobic-to-asparagine substitution (I813N) near the C-terminus causes moderate cilia loss, skeletal defects (rib defects, delayed endochondral ossification, polydactyly), and reduced Hh signaling, while neural tube patterning and PCP appear normal. The Intu(I813N) protein exhibits compromised ability to restore ciliogenesis in Intu null cells, functionally linking this residue to ciliogenic activity.\",\n      \"method\": \"Gene-targeted hypomorphic knock-in mouse (I813N), cilia quantification, skeletal staining, qRT-PCR for Hh targets, rescue assay in Intu null cultured cells\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site/domain mutagenesis in vivo plus in vitro rescue assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25774014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"INTU is essential for IFT-A (intraflagellar transport A) complex assembly during ciliogenesis. In an oncogenic SmoM2-driven basal cell carcinoma model, Intu disruption prevents BCC formation by suppressing primary cilia formation and Hh signaling. In mouse embryonic fibroblasts, depleting Intu blocks Smo agonist-induced Hh pathway activation, but expression of constitutively active Gli2ΔN restores Hh signaling in Intu-deficient cells, genetically placing INTU upstream of Gli2 activation and downstream of Smo.\",\n      \"method\": \"Conditional knockout in SmoM2 BCC mouse model, shRNA knockdown, cilia quantification, IFT-A complex assembly assays, epistasis with Gli2ΔN in MEFs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in disease model, IFT-A assembly assay, genetic epistasis with Gli2ΔN; multiple orthogonal methods placing INTU in Hh pathway\",\n      \"pmids\": [\"28459465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RSG1 (a small GTPase) localizes to the mother centriole in a process that depends on INTU (the CPLANE protein Inturned), tau tubulin kinase 2 (TTBK2), and RSG1's own GTPase activity. Loss of RSG1 impairs axonemal microtubule elongation after ciliary vesicle docking, placing RSG1 as a downstream effector of INTU at a final maturation step of cilia initiation.\",\n      \"method\": \"Rsg1 mouse knockout, immunofluorescence for RSG1 centriolar localization, genetic epistasis with Intu and TTBK2, cilia ultrastructure analysis, Hh pathway readouts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse, defined cellular phenotype (axoneme elongation), dependency of RSG1 localization on INTU by loss-of-function; multiple orthogonal methods\",\n      \"pmids\": [\"29038301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"INTU physically interacts with STAT1; they co-localize at the centriole/basal body. INTU promotes proteasomal degradation of STAT1. In vitro, INTU expression preserves cilia length and cell viability after stress, effects antagonized by STAT1 overexpression. Kidney-proximal-tubule-specific ablation of Intu aggravates renal ischemia-reperfusion injury and impairs post-injury ciliogenesis.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, conditional KO mouse (proximal tubule-specific), proteasome inhibitor assay, cell viability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-localization, co-IP, conditional KO with tissue-injury phenotype, proteasomal degradation assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"29581513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Computational evolutionary analysis identifies INTU and FUZ as a heterodimeric complex homologous to HerMon (Hermansky-Pudlak syndrome and MON1-CCZ1) complexes, each containing triplicated Longin domains. Based on homology to known Rab effectors/GEFs, the INTU/FUZ complex is predicted to act as a GEF for Rab GTPases involved in ciliogenesis.\",\n      \"method\": \"Coevolution-based contact prediction, sequence conservation analysis (computational/bioinformatic)\",\n      \"journal\": \"Bioinformatics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only; no experimental validation of GEF activity reported in this paper\",\n      \"pmids\": [\"31562761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPLANE complex (composed of INTU, FUZ, and WDPCP, which interact with JBTS17 and RSG1) is required for IFT-A particle assembly and intraflagellar transport; defects in CPLANE components disrupt PCP and Hh signaling, leading to ciliopathies including orofacial-digital syndrome and Bardet-Biedl syndrome.\",\n      \"method\": \"Synthesis/review of genetic and functional studies; functional studies cited include IFT-A assembly assays and mouse genetic models\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — consolidates experimental evidence from multiple studies; IFT-A assembly role grounded in prior experimental work (PMID 28459465, 29038301)\",\n      \"pmids\": [\"35740972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional knockout of Intu in kidney tubules delays kidney repair and ameliorates renal fibrosis after ischemia-reperfusion injury. Intu KO kidneys show less senescence but higher cell proliferation and apoptosis during repair. In vitro, Intu knockdown suppresses scratch wound healing in renal tubular cells, accompanied by abnormal centrosome orientation, establishing a role for Intu in centrosome-directed tubular cell migration/repair.\",\n      \"method\": \"Conditional KO mouse (kidney tubule-specific), histological and biochemical analysis of fibrosis and senescence, scratch wound healing assay with centrosome orientation imaging\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotypes and in vitro centrosome orientation readout; single lab, multiple methods\",\n      \"pmids\": [\"36586478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Intu severely disrupts growth and branching morphogenesis of mouse embryonic lungs, associated with greatly reduced primary cilia in epithelial and mesenchymal cells and reduced Hh target gene expression (Gli1, Ptch1). Smoothened agonist increases Hh target gene expression and tubulogenesis in wild-type but not Intu mutant lung explants. Removing both Gli2 and Intu completely abolishes lung branching morphogenesis, genetically placing Intu upstream of Gli2-dependent Hh signaling in the lung.\",\n      \"method\": \"Intu null mouse KO, lung explant culture with Smo agonist, Gli2;Intu double mutant epistasis, qRT-PCR/immunofluorescence, transcriptomics\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with organ-specific phenotype, pharmacological rescue experiment, genetic epistasis with Gli2 double mutant; multiple orthogonal methods\",\n      \"pmids\": [\"39029571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The predicted PDZ domain unique to Inturned among TLD proteins does not interact with membranes or with Vangl2. Crystal structure of the Intu-PDZ domain reveals a unique PDZ-like fold lacking a canonical interaction site for PDZ-binding motifs. Vangl2 instead shows a phosphorylation-dependent interaction with a PDZ domain of the apical-basal polarity protein Scribble.\",\n      \"method\": \"Crystal structure determination of Intu-PDZ domain, biochemical binding assays (pulldown/binding experiments with membranes and Vangl2), structural analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus biochemical binding assays; negative result for Vangl2–Intu PDZ interaction confirmed by both structure and biochemistry; single lab\",\n      \"pmids\": [\"41797376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Functional studies in patient-derived cells with compound heterozygous INTU variants demonstrate altered ciliogenesis and/or cilia signaling, confirming that pathogenic INTU variants cause human disease through disruption of CPLANE-dependent ciliogenesis.\",\n      \"method\": \"Patient-derived cell ciliogenesis assays (compound heterozygous INTU variants), trio whole-exome sequencing\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional ciliogenesis assay in patient-derived cells; single case report with functional follow-up, limited mechanistic depth\",\n      \"pmids\": [\"40968537\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTU (Inturned) is a core subunit of the CPLANE complex (with FUZ and WDPCP) that acts at the mother centriole/basal body to promote IFT-A complex assembly and intraflagellar transport, enabling primary cilia formation; it contains a unique PDZ-like fold (structurally incapable of canonical PDZ-ligand binding) and tripled Longin domains homologous to Rab GEF complexes, interacts with RSG1 to control the final axonemal elongation step of cilia initiation, promotes proteasomal degradation of STAT1 at the basal body, and functions genetically upstream of Gli2 activation to transduce cilia-dependent Hedgehog signaling during embryonic development, tissue homeostasis, and injury repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INTU (Inturned) is an essential regulator of primary ciliogenesis and cilia-dependent Hedgehog signal transduction during embryonic development, tissue homeostasis, and injury repair [#0, #3]. It functions as a core subunit of the CPLANE complex together with FUZ and WDPCP, acting downstream of core planar cell polarity but upstream of cilia-dependent Hedgehog patterning [#2, #9]. At the mother centriole/basal body, INTU is required for assembly of the IFT-A intraflagellar transport complex, and it controls the recruitment of the small GTPase RSG1 — together with TTBK2 — to drive axonemal microtubule elongation at the final maturation step of cilia initiation [#5, #6]. Genetically, INTU acts downstream of Smoothened and upstream of Gli2 activation: constitutively active Gli2 restores Hedgehog signaling in INTU-deficient cells, and combined loss of Gli2 and Intu abolishes Hedgehog-dependent morphogenesis [#5, #11]. Loss of Intu disrupts ciliogenesis and Hedgehog output across diverse tissues, including epidermis and hair follicles, skeleton, lung branching morphogenesis, and renal tubule repair, where INTU additionally binds STAT1 at the centriole and promotes its proteasomal degradation [#3, #4, #7, #11]. Structurally, INTU contains a PDZ-like fold that lacks a canonical PDZ-ligand binding site and does not interact with membranes or Vangl2 [#12]. Compound heterozygous INTU variants cause human disease through disruption of CPLANE-dependent ciliogenesis [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that the PCP effector module to which Intu belongs operates at the interface of vesicle trafficking and ciliogenesis, before Intu itself was biochemically dissected.\",\n      \"evidence\": \"Fuz mutant mouse analysis, in vivo mucociliary imaging, and co-IP identifying a Rab-related GTPase partner\",\n      \"pmids\": [\"19767740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Focused on Fuz, not direct Intu biochemistry\", \"Did not define the molecular trafficking step controlled\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined INTU as an essential ciliogenesis regulator and placed it within Hedgehog signal transduction by linking its loss to failed Gli3 processing and reduced Hh target genes.\",\n      \"evidence\": \"Intu null mouse with cilia immunofluorescence, Hh target qRT-PCR/Western, and GFP-Intu rescue in fibroblasts\",\n      \"pmids\": [\"20067783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of how INTU promotes ciliogenesis unknown\", \"No biochemical activity defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Positioned Intu and Fuz as non-redundant effectors downstream of core PCP but upstream of cilia-dependent Hh patterning, separating their ciliogenic role from convergent-extension PCP.\",\n      \"evidence\": \"Intu;Fuz double mutant mouse epistasis and genetic tests with a Vangl2 hypomorph\",\n      \"pmids\": [\"21761479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish a molecular function\", \"Single-lab genetic study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that INTU's role is cell-fate-specific and cilia-dependent rather than tied to epidermal barrier or PCP, by restricting its requirement to follicular keratinocyte differentiation.\",\n      \"evidence\": \"Conditional epidermal Cre-lox knockout with cilia markers, Hh reporter, and differentiation/barrier assays\",\n      \"pmids\": [\"22935613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify INTU molecular partners in skin\", \"Mechanism of cilia loss not resolved biochemically\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked a specific conserved C-terminal residue (I813) to ciliogenic activity, showing domain-level structure-function and tissue selectivity (skeletal versus neural tube).\",\n      \"evidence\": \"I813N hypomorphic knock-in mouse with cilia, skeletal, and Hh-target readouts plus rescue assay in Intu null cells\",\n      \"pmids\": [\"25774014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical consequence of I813N not defined\", \"Why neural tube is spared unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the molecular and epistatic placement of INTU: required for IFT-A complex assembly and acting downstream of Smo but upstream of Gli2 activation.\",\n      \"evidence\": \"Conditional KO in SmoM2 BCC model, IFT-A assembly assays, and Gli2ΔN epistasis rescue in MEFs\",\n      \"pmids\": [\"28459465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of IFT-A assembly by INTU not shown\", \"How INTU couples to Gli2 regulation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a downstream effector arm, showing INTU is required to recruit RSG1 to the mother centriole for axonemal elongation at a final cilia-initiation step.\",\n      \"evidence\": \"Rsg1 KO mouse, RSG1 centriolar localization dependent on Intu/TTBK2/GTPase activity, and cilia ultrastructure\",\n      \"pmids\": [\"29038301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether INTU directly binds RSG1 not established\", \"Mechanism of RSG1-driven microtubule elongation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a non-ciliary biochemical activity: INTU binds STAT1 at the basal body and promotes its proteasomal degradation, protecting cilia length and viability under stress.\",\n      \"evidence\": \"Co-IP, reciprocal co-localization, proteasome inhibitor assay, and proximal-tubule conditional KO with ischemia-reperfusion phenotype\",\n      \"pmids\": [\"29581513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which INTU targets STAT1 for degradation unknown\", \"No identified E3 ligase or degron\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generated a structural hypothesis that the INTU/FUZ heterodimer carries triplicated Longin domains homologous to Rab effector/GEF complexes, predicting Rab GEF activity in ciliogenesis.\",\n      \"evidence\": \"Coevolution-based contact prediction and sequence conservation analysis (computational only)\",\n      \"pmids\": [\"31562761\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental validation of GEF activity\", \"Predicted Rab substrate not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Consolidated INTU as a stable CPLANE subunit (with FUZ, WDPCP, JBTS17, RSG1) whose dysfunction causes ciliopathies, integrating its IFT-A and signaling roles.\",\n      \"evidence\": \"Synthesis of genetic and functional studies including IFT-A assembly and mouse models\",\n      \"pmids\": [\"35740972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis, not new primary data\", \"Stoichiometry and architecture of CPLANE not resolved here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended INTU's tissue role to centrosome-directed cell migration during kidney repair, distinguishing its repair-promoting from fibrosis-modulating effects.\",\n      \"evidence\": \"Kidney-tubule conditional KO with fibrosis/senescence analysis and scratch-wound assay with centrosome orientation imaging\",\n      \"pmids\": [\"36586478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of centrosome orientation defect unclear\", \"Relationship to STAT1 degradation arm not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed the upstream-of-Gli2 placement in a new organ context by showing Intu is required for Hh-driven lung branching morphogenesis.\",\n      \"evidence\": \"Intu null mouse, lung explant Smo-agonist rescue, Gli2;Intu double-mutant epistasis, and transcriptomics\",\n      \"pmids\": [\"39029571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not add new biochemical mechanism\", \"Cell-type-specific contributions not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structure of INTU's PDZ-like domain, overturning the assumption of canonical PDZ-ligand or Vangl2 binding and reassigning Vangl2's PDZ interaction to Scribble.\",\n      \"evidence\": \"Crystal structure of the Intu-PDZ domain plus pulldown/binding assays with membranes and Vangl2\",\n      \"pmids\": [\"41797376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The actual binding partner(s) of the INTU PDZ-like fold remain unidentified\", \"Functional role of this domain in ciliogenesis not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established INTU as a human disease gene by showing pathogenic compound heterozygous variants disrupt CPLANE-dependent ciliogenesis in patient cells.\",\n      \"evidence\": \"Patient-derived cell ciliogenesis assays and trio whole-exome sequencing\",\n      \"pmids\": [\"40968537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case with limited mechanistic depth\", \"Genotype-phenotype correlation not generalized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the INTU/FUZ Longin-domain module possesses experimentally validated Rab GEF activity, and which Rab(s) and what binding partner of the PDZ-like fold mediate INTU's ciliogenic and IFT-A assembly functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Predicted GEF activity never tested biochemically\", \"No identified ligand for the PDZ-like domain\", \"Direct molecular mechanism of IFT-A assembly by INTU unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 6, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 11]}\n    ],\n    \"complexes\": [\"CPLANE complex\"],\n    \"partners\": [\"FUZ\", \"WDPCP\", \"RSG1\", \"STAT1\", \"TTBK2\", \"JBTS17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}