{"gene":"IFT140","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2012,"finding":"IFT140 is a component of intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells; loss of IFT140 alters ciliary abundance and localization of anterograde IFT components in patient fibroblasts.","method":"Patient fibroblast immunofluorescence analysis of IFT component localization combined with human genetic identification of IFT140 mutations","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — direct cellular localization experiment in patient-derived cells showing altered anterograde IFT distribution, replicated across multiple families","pmids":["22503633"],"is_preprint":false},{"year":2014,"finding":"IFT140 is required for development and maintenance of photoreceptor outer segments; acute deletion of Ift140 causes opsin to accumulate in the plasma membrane of inner segments (not at Golgi), establishing that IFT140 functions in moving opsin through the connecting cilium after it reaches the ciliary base, downstream of IFT20-mediated Golgi-to-base transport.","method":"Conditional/inducible Ift140 knockout mouse, immunofluorescence localization of opsin, compared with Ift20 knockout","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with specific cellular phenotype and pathway placement relative to IFT20; mechanistic distinction between two IFT steps established","pmids":["24619649"],"is_preprint":false},{"year":2013,"finding":"IFT140 loss-of-function (ENU mutant Cauli allele) in mice causes Hedgehog signaling defects alongside ciliopathy phenotypes including exencephaly, digit anomalies, and craniofacial dysmorphism, placing IFT140 within the Hedgehog signaling pathway via primary cilia.","method":"ENU mutagenesis mouse model with genetic epistasis/pathway analysis of Hedgehog signaling outputs","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo mouse model with defined Hedgehog signaling phenotype, multiple orthogonal phenotypic readouts","pmids":["24009529"],"is_preprint":false},{"year":2018,"finding":"Conditional knockout of Ift140 in mouse spermatocytes/spermatids causes male infertility with sperm morphological defects (amorphous heads, short/bent flagella, swollen tail tips) and alters subcellular localization of IFT-B components IFT27 and IFT88, demonstrating IFT140 is required for sperm flagella assembly and IFT-B complex localization during spermiogenesis.","method":"Conditional Ift140 knockout mouse (spermatocyte/spermatid-specific), immunofluorescence for IFT components, transmission electron microscopy","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with multiple orthogonal methods (morphology, immunofluorescence, TEM) showing specific IFT-B mislocalization","pmids":["29236364"],"is_preprint":false},{"year":2016,"finding":"Missense mutations in IFT140 associated with nonsyndromic retinitis pigmentosa cause significantly reduced localization of IFT140 to the basal body in RPE1 cells, compared to wild-type IFT140 or a benign polymorphism.","method":"Transient plasmid transfection of hTERT-RPE1 cells with mutant vs. wild-type IFT140 constructs; immunofluorescence for basal body localization","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 3 — single-lab transfection assay with localization readout, two syndromic and two nonsyndromic mutants tested","pmids":["26968735"],"is_preprint":false},{"year":2018,"finding":"IFT140 loss-of-function (patient-derived urine renal epithelial cells and CRISPR Ift140 KO cells) causes accumulation of IFT-B protein IFT88 at the ciliary tip, consistent with impaired retrograde IFT; a patient missense variant (p.Tyr923Asp) recapitulates this tip accumulation phenotype when transfected into KO cells.","method":"Immunocytochemistry of patient urine-derived renal epithelial cells; CRISPR/Cas9 Ift140 KO rescue transfection assay","journal":"Cilia","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with rescue and specific IFT-B tip accumulation phenotype, single lab","pmids":["30479745"],"is_preprint":false},{"year":2017,"finding":"Conditional deletion of IFT140 in odontoblasts leads to abnormal primary cilia, poor odontogenic differentiation, and decreased Sonic hedgehog signaling, establishing IFT140 as required for cilia-mediated SHH signaling in dentinogenesis.","method":"Ift140flox/flox/Osx-Cre conditional knockout mice; in vitro odontoblast differentiation assay; SHH pathway marker expression","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with pathway marker analysis and in vitro phenotype, single lab","pmids":["29195058"],"is_preprint":false},{"year":2019,"finding":"Conditional deletion of IFT140 in pre-osteoblasts (Osx-Cre) causes reduced bone mass, decreased osteoblastic marker expression, and progressive bone loss with aging, establishing IFT140 as required for osteoblast-mediated bone formation.","method":"Conditional Ift140 knockout mouse (Osx-Cre), micro-CT, histomorphometry, molecular marker analysis","journal":"The journal of histochemistry and cytochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with multiple readouts (micro-CT, histology, molecular markers), single lab","pmids":["31034313"],"is_preprint":false},{"year":2022,"finding":"ARL16 GTPase is required for trafficking of IFT140 from the Golgi to cilia; Arl16 knockout in MEFs causes IFT140 accumulation at the Golgi and loss from cilia, while other IFT proteins are unaffected, indicating a specific Golgi-to-cilia export pathway for IFT140.","method":"Arl16 knockout MEFs, immunofluorescence for IFT140 and other IFT proteins at Golgi and cilia, subcellular fractionation","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with specific localization phenotype for IFT140 versus other IFT proteins, single lab","pmids":["35196065"],"is_preprint":false},{"year":2025,"finding":"IFT140 physically associates with the novel conserved protein Pasovec (Psv), a core component of the IFT-A complex; this interaction is independent of Wg/Wnt-signaling activation and is required for nuclear translocation of β-catenin/Armadillo in canonical Wnt signaling in Drosophila.","method":"Co-immunoprecipitation/physical interaction assay (Psv-IFT140), Drosophila genetic epistasis, NLS mutant analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction established by co-IP, functional epistasis in Drosophila, but preprint and single lab","pmids":["bio_10.1101_2025.06.21.660855"],"is_preprint":true},{"year":2025,"finding":"Affinity purification-mass spectrometry (AP-MS) of 23 IFT140 missense mutations showed that a subset (10/23) cause domain-specific reductions in IFT140 interaction with the IFT-A complex, while knockout of IFT140 abolishes cilia; however, only mild cilia assembly effects were observed for 2 of 4 tested missense mutations, indicating the IFT-A complex is resilient to partial IFT140 dysfunction.","method":"Affinity purification coupled with mass spectrometry (AP-MS) of 23 missense mutants; IFT140 knockout ciliogenesis assay","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 1 — systematic AP-MS quantifying complex interactions for 23 mutations plus KO functional validation, multiple orthogonal methods in single rigorous study","pmids":["39880085"],"is_preprint":false},{"year":2025,"finding":"Conditional deletion of Ift140 from FOXJ1+ motile cilia-forming cells causes short motile cilia with abnormal central apparatus and accumulation of intraciliary particles; cilia beat frequency is reduced and dynein arms are present but ciliary protein localization is abnormal, demonstrating IFT140 is specifically required for motile cilia assembly and cargo delivery independent of dynein arm docking.","method":"Conditional Ift140 knockout (FOXJ1-Cre), transmission electron microscopy of cilia ultrastructure, high-speed video microscopy of cilia beat frequency, immunofluorescence of ciliary proteins","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1–2 — conditional KO with TEM ultrastructure, beat frequency measurement, and protein localization; multiple orthogonal methods","pmids":["40348912"],"is_preprint":false},{"year":2025,"finding":"In ift140-deficient zebrafish kidney epithelial cells, in addition to cilia defects, disrupted cell polarity and aberrant cytoplasmic microtubule stabilization were observed, suggesting IFT140 has a non-ciliary role in kidney epithelial cell biology that contributes to cystogenesis; mTOR and ULK1 inhibition reverses both cilia-related and non-cilia-related abnormalities.","method":"Zebrafish ift140 mutant and CRISPR crispant generation; immunostaining for polarity markers and microtubule stabilization; pharmacological mTOR/ULK1 inhibition","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo zebrafish model with multiple cellular phenotype readouts and pharmacological rescue, single lab","pmids":["40924493"],"is_preprint":false},{"year":2019,"finding":"IFT140 protein is absent from the neck and mid-piece of spermatozoa in a human patient with compound heterozygous IFT140 variants and severe oligoasthenoteratozoospermia, establishing that IFT140 is normally localized to these sperm compartments and its loss disrupts sperm morphology.","method":"Immunofluorescence staining and transmission electron microscopy of patient spermatozoa","journal":"Molecular genetics & genomic medicine","confidence":"Low","confidence_rationale":"Tier 3 — single patient immunofluorescence without functional rescue","pmids":["31397098"],"is_preprint":false}],"current_model":"IFT140 is a core structural component of the IFT-A complex that mediates retrograde intraflagellar transport in primary and motile cilia; it is required for moving ciliary cargo (including opsins) through the ciliary axoneme after delivery to the ciliary base, for proper localization of IFT-B components, for cilia-mediated Hedgehog and Wnt/β-catenin signaling, and for motile cilia assembly, with its Golgi-to-cilia trafficking specifically regulated by the ARL16 GTPase."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing IFT140 as an IFT-A subunit whose loss alters anterograde IFT component distribution in cilia provided the first direct evidence that IFT140 functions in retrograde intraflagellar transport in human cells.","evidence":"Immunofluorescence of IFT components in patient fibroblasts carrying IFT140 mutations","pmids":["22503633"],"confidence":"High","gaps":["Mechanism by which IFT140 loss alters anterograde IFT component localization not defined","Retrograde transport defect inferred from redistribution rather than live cargo tracking"]},{"year":2013,"claim":"Demonstrating that IFT140 loss-of-function in mice causes Hedgehog signaling defects placed IFT140 within the ciliary Hedgehog transduction pathway, linking retrograde IFT to developmental signaling.","evidence":"ENU mutagenesis mouse model (Cauli allele) with epistasis analysis of Hedgehog pathway outputs","pmids":["24009529"],"confidence":"High","gaps":["Whether IFT140 directly transports Hedgehog pathway effectors (Gli, Smo) or acts indirectly through cilia structure not resolved","Hedgehog pathway analysis limited to phenotypic readouts"]},{"year":2014,"claim":"Conditional Ift140 knockout in photoreceptors showed opsin accumulates at the inner segment plasma membrane rather than the Golgi, distinguishing IFT140's role in moving cargo through the connecting cilium from IFT20's role in Golgi-to-base transport.","evidence":"Conditional/inducible Ift140 KO mouse compared with Ift20 KO; opsin immunofluorescence","pmids":["24619649"],"confidence":"High","gaps":["Direct binding of IFT140 to opsin cargo not demonstrated","Whether all photoreceptor cargo depends on IFT140 remains untested"]},{"year":2016,"claim":"Pathogenic IFT140 missense mutations associated with retinitis pigmentosa were shown to reduce IFT140 localization to the basal body, linking disease variants to a specific subcellular trafficking defect.","evidence":"Transfection of mutant vs. wild-type IFT140 constructs in RPE1 cells; basal body immunofluorescence","pmids":["26968735"],"confidence":"Medium","gaps":["Overexpression system may not recapitulate endogenous protein behavior","Impact on retrograde IFT dynamics not measured"]},{"year":2017,"claim":"Conditional deletion of IFT140 in odontoblasts extended the requirement for IFT140 in Hedgehog signaling to dentinogenesis, reinforcing its broad role in cilia-dependent SHH transduction.","evidence":"Ift140flox/Osx-Cre conditional KO mice; SHH pathway marker expression and odontoblast differentiation assay","pmids":["29195058"],"confidence":"Medium","gaps":["Whether IFT140 requirement reflects general cilia loss or specific cargo transport in odontoblasts not distinguished"]},{"year":2018,"claim":"IFT140 was shown to be essential for sperm flagella assembly and proper IFT-B component localization during spermiogenesis, extending its function from primary cilia to motile flagella.","evidence":"Conditional Ift140 KO in mouse spermatocytes/spermatids; TEM, immunofluorescence for IFT27/IFT88","pmids":["29236364"],"confidence":"High","gaps":["Whether IFT140 participates in flagellar dynein arm transport not addressed","Mechanism of IFT-B mislocalization upon IFT140 loss not defined"]},{"year":2018,"claim":"Demonstration that IFT140 loss causes IFT88 accumulation at the ciliary tip in both patient-derived renal cells and CRISPR KO cells, with a patient missense variant recapitulating the defect, provided direct cellular evidence for impaired retrograde IFT as the primary consequence of IFT140 dysfunction.","evidence":"Patient urine-derived renal epithelial cells and CRISPR Ift140 KO with rescue transfection; immunocytochemistry","pmids":["30479745"],"confidence":"Medium","gaps":["Cargo identity beyond IFT88 not systematically profiled","Rescue only tested with single mutant allele"]},{"year":2019,"claim":"Conditional deletion of IFT140 in pre-osteoblasts demonstrated its requirement for bone formation, broadening the tissue repertoire of IFT140-dependent cilia functions.","evidence":"Ift140 conditional KO mouse (Osx-Cre); micro-CT, histomorphometry, molecular marker analysis","pmids":["31034313"],"confidence":"Medium","gaps":["Whether the bone phenotype is cilia-dependent or reflects a non-ciliary IFT140 function not tested"]},{"year":2022,"claim":"Identification of ARL16 as specifically required for Golgi-to-cilia trafficking of IFT140, while other IFT proteins were unaffected, revealed a dedicated export pathway for IFT140.","evidence":"Arl16 KO MEFs; immunofluorescence and subcellular fractionation of IFT140 vs. other IFT proteins","pmids":["35196065"],"confidence":"Medium","gaps":["Whether ARL16 directly binds IFT140 or acts through an adaptor not determined","Mechanism of specificity for IFT140 over other IFT-A subunits unknown"]},{"year":2025,"claim":"Systematic AP-MS of 23 IFT140 missense mutations revealed domain-specific disruptions of IFT-A complex assembly, while functional assays showed the complex is resilient to partial IFT140 dysfunction, providing a genotype–interaction map for disease variants.","evidence":"AP-MS of 23 missense mutants; IFT140 KO ciliogenesis assay in mammalian cells","pmids":["39880085"],"confidence":"High","gaps":["Retrograde transport dynamics not measured for individual mutants","Structural basis for domain-specific disruption not resolved"]},{"year":2025,"claim":"Conditional deletion of IFT140 from FOXJ1+ motile cilia-forming cells demonstrated that IFT140 is specifically required for motile cilia assembly and intraciliary cargo delivery independent of dynein arm docking.","evidence":"FOXJ1-Cre conditional KO; TEM ultrastructure, high-speed video microscopy, immunofluorescence","pmids":["40348912"],"confidence":"High","gaps":["Whether IFT140 transports central apparatus precursors directly not shown","Which specific cargo proteins are IFT140-dependent in motile cilia remains undefined"]},{"year":2025,"claim":"Discovery of disrupted cell polarity and aberrant cytoplasmic microtubule stabilization in ift140-deficient zebrafish kidney cells, reversible by mTOR/ULK1 inhibition, suggested a non-ciliary role for IFT140 in kidney epithelial biology.","evidence":"Zebrafish ift140 mutant; immunostaining for polarity and microtubule markers; pharmacological rescue","pmids":["40924493"],"confidence":"Medium","gaps":["Non-ciliary function not yet separated from indirect consequences of cilia loss","Molecular target of IFT140 in microtubule regulation unknown","Pharmacological rescue does not establish direct mechanism"]},{"year":null,"claim":"The direct cargo repertoire of IFT140 within the retrograde IFT pathway, the structural basis for its domain-specific interactions with the IFT-A complex, and whether its non-ciliary functions in cell polarity and microtubule regulation are physiologically independent of cilia remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No systematic identification of direct IFT140-transported ciliary cargoes","No high-resolution structure of IFT140 within the IFT-A complex","Non-ciliary vs. ciliary-dependent functions not mechanistically separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,10]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,3,5,8,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,3,5,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[1,4]}],"complexes":["IFT-A complex"],"partners":["IFT88","IFT27","ARL16","IFT20"],"other_free_text":[]},"mechanistic_narrative":"IFT140 is a core subunit of the intraflagellar transport complex A (IFT-A) that mediates retrograde transport within both primary and motile cilia, functioning in ciliary cargo delivery, signaling, and ciliogenesis across diverse cell types. Loss of IFT140 causes accumulation of IFT-B components (IFT88, IFT27) at the ciliary tip, consistent with defective retrograde transport, and disrupts the ciliary delivery of opsins through the connecting cilium of photoreceptors — acting downstream of IFT20-mediated Golgi-to-base trafficking [PMID:22503633, PMID:24619649, PMID:30479745]. IFT140 is required for cilia-dependent Hedgehog signaling in multiple developmental contexts and for motile cilia assembly where its loss produces short cilia with abnormal central apparatus and reduced beat frequency [PMID:24009529, PMID:29195058, PMID:40348912]. Trafficking of IFT140 from the Golgi to cilia depends specifically on the ARL16 GTPase, and systematic AP-MS analysis of 23 disease-associated missense mutations reveals domain-specific disruptions of IFT-A complex assembly, although the complex shows resilience to partial IFT140 dysfunction [PMID:35196065, PMID:39880085]."},"prefetch_data":{"uniprot":{"accession":"Q96RY7","full_name":"Intraflagellar transport protein 140 homolog","aliases":["WD and tetratricopeptide repeats protein 2"],"length_aa":1462,"mass_kda":165.2,"function":"Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs) (PubMed:20889716, PubMed:22503633). Plays a pivotal role in proper development and function of ciliated cells through its role in ciliogenesis and/or cilium maintenance (PubMed:22503633). Required for the development and maintenance of the outer segments of rod and cone photoreceptor cells. Plays a role in maintenance and the delivery of opsin to the outer segment of photoreceptor cells (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q96RY7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFT140","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFT140","total_profiled":1310},"omim":[{"mim_id":"621180","title":"CRANIOECTODERMAL DYSPLASIA 5; CED5","url":"https://www.omim.org/entry/621180"},{"mim_id":"621164","title":"POLYCYSTIC KIDNEY DISEASE 9, SUSCEPTIBILITY TO; PKD9","url":"https://www.omim.org/entry/621164"},{"mim_id":"617781","title":"RETINITIS PIGMENTOSA 80; RP80","url":"https://www.omim.org/entry/617781"},{"mim_id":"614620","title":"INTRAFLAGELLAR TRANSPORT 140; IFT140","url":"https://www.omim.org/entry/614620"},{"mim_id":"608671","title":"DAZ-INTERACTING ZINC FINGER PROTEIN 1; DZIP1","url":"https://www.omim.org/entry/608671"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Basal body","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFT140"},"hgnc":{"alias_symbol":["gs114","KIAA0590"],"prev_symbol":["WDTC2"]},"alphafold":{"accession":"Q96RY7","domains":[{"cath_id":"-","chopping":"801-871","consensus_level":"medium","plddt":82.149,"start":801,"end":871},{"cath_id":"-","chopping":"872-942","consensus_level":"medium","plddt":88.4313,"start":872,"end":942},{"cath_id":"4.10.810","chopping":"762-796","consensus_level":"medium","plddt":76.9554,"start":762,"end":796},{"cath_id":"1.25.40","chopping":"1047-1115","consensus_level":"medium","plddt":77.7523,"start":1047,"end":1115},{"cath_id":"1.25.40","chopping":"1340-1428","consensus_level":"medium","plddt":80.3445,"start":1340,"end":1428}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RY7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RY7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RY7-F1-predicted_aligned_error_v6.png","plddt_mean":80.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFT140","jax_strain_url":"https://www.jax.org/strain/search?query=IFT140"},"sequence":{"accession":"Q96RY7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96RY7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96RY7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RY7"}},"corpus_meta":[{"pmid":"22503633","id":"PMC_22503633","title":"Mainzer-Saldino 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infant with Mainzer-Saldino syndrome presenting with retinal dystrophy.","date":"2022","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/36393898","citation_count":6,"is_preprint":false},{"pmid":"39291187","id":"PMC_39291187","title":"Importance of IFT140 in Patients with Polycystic Kidney Disease Without a Family History.","date":"2024","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/39291187","citation_count":6,"is_preprint":false},{"pmid":"39015124","id":"PMC_39015124","title":"The First Pediatric Case of an IFT140 Heterozygous Deletion Causing Autosomal Dominant Polycystic Kidney Disease: Case Report.","date":"2024","source":"Case reports in nephrology and dialysis","url":"https://pubmed.ncbi.nlm.nih.gov/39015124","citation_count":4,"is_preprint":false},{"pmid":"37628605","id":"PMC_37628605","title":"Rare IFT140-Associated Phenotype of Cranioectodermal Dysplasia and Features of Diagnostic Journey in Patients with Suspected Ciliopathies.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37628605","citation_count":3,"is_preprint":false},{"pmid":"39594267","id":"PMC_39594267","title":"Compound Heterozygous Variants in the IFT140 Gene Associated with Skeletal Ciliopathies.","date":"2024","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39594267","citation_count":2,"is_preprint":false},{"pmid":"38465144","id":"PMC_38465144","title":"IFT140 Mutation and End-Stage Renal Disease in Mainzer-Saldino Syndrome: A Case Report.","date":"2024","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38465144","citation_count":2,"is_preprint":false},{"pmid":"39880085","id":"PMC_39880085","title":"Ciliopathy-Associated Missense Mutations in IFT140 are Tolerated by the Inherent Resilience of the IFT Machinery.","date":"2025","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/39880085","citation_count":1,"is_preprint":false},{"pmid":"40924493","id":"PMC_40924493","title":"ift140 -Deficient Zebrafish as a Model for Kidney Cystogenesis and an F0-Based Screen for Genetic Modifiers of Kidney Cysts.","date":"2025","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/40924493","citation_count":1,"is_preprint":false},{"pmid":"40370963","id":"PMC_40370963","title":"Novel Pathogenic Variants in IFT140 and IFT172 Genes in Three Patients with Similar Retinal Dystrophy Phenotypes.","date":"2025","source":"Case reports in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/40370963","citation_count":1,"is_preprint":false},{"pmid":"40348912","id":"PMC_40348912","title":"Role of intraflagellar transport protein IFT140 in the formation and function of motile cilia in mammals.","date":"2025","source":"Cellular and molecular life sciences : 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Modifiers of Kidney Cysts.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39803421","citation_count":0,"is_preprint":false},{"pmid":"42021201","id":"PMC_42021201","title":"A novel mutation of IFT140 in a preschool child with Mainzer-Saldino syndrome accompanied by rare tumor blastic plasmacytoid dendritic cell neoplasm: a case report.","date":"2026","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/42021201","citation_count":0,"is_preprint":false},{"pmid":"39927556","id":"PMC_39927556","title":"Pathogenic variants in the IFT140 gene and an intriguing clinical presentation in two pediatric patients. Cases report and review of literature.","date":"2025","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39927556","citation_count":0,"is_preprint":false},{"pmid":"40972705","id":"PMC_40972705","title":"Monoallelic IFT140 Variants Causing Childhood-Onset Autosomal Dominant Polycystic Kidney Disease.","date":"2025","source":"American journal of kidney diseases : the official journal of the National Kidney Foundation","url":"https://pubmed.ncbi.nlm.nih.gov/40972705","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.21.660855","title":"A novel conserved protein associates with the IFT-A complex to mediate nuclear translocation of β-catenin in Wg/Wnt-signaling","date":"2025-06-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.21.660855","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.02.631132","title":"The <i>ift140</i>-Deficient Zebrafish: A Model for Renal Cystogenesis and an F0-Based Screen to Identify Genetic Modifiers of Kidney Cysts","date":"2025-01-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.02.631132","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24052,"output_tokens":3411,"usd":0.061661},"stage2":{"model":"claude-opus-4-6","input_tokens":6800,"output_tokens":2991,"usd":0.163162},"total_usd":0.224823,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"IFT140 is a component of intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells; loss of IFT140 alters ciliary abundance and localization of anterograde IFT components in patient fibroblasts.\",\n      \"method\": \"Patient fibroblast immunofluorescence analysis of IFT component localization combined with human genetic identification of IFT140 mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct cellular localization experiment in patient-derived cells showing altered anterograde IFT distribution, replicated across multiple families\",\n      \"pmids\": [\"22503633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IFT140 is required for development and maintenance of photoreceptor outer segments; acute deletion of Ift140 causes opsin to accumulate in the plasma membrane of inner segments (not at Golgi), establishing that IFT140 functions in moving opsin through the connecting cilium after it reaches the ciliary base, downstream of IFT20-mediated Golgi-to-base transport.\",\n      \"method\": \"Conditional/inducible Ift140 knockout mouse, immunofluorescence localization of opsin, compared with Ift20 knockout\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with specific cellular phenotype and pathway placement relative to IFT20; mechanistic distinction between two IFT steps established\",\n      \"pmids\": [\"24619649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFT140 loss-of-function (ENU mutant Cauli allele) in mice causes Hedgehog signaling defects alongside ciliopathy phenotypes including exencephaly, digit anomalies, and craniofacial dysmorphism, placing IFT140 within the Hedgehog signaling pathway via primary cilia.\",\n      \"method\": \"ENU mutagenesis mouse model with genetic epistasis/pathway analysis of Hedgehog signaling outputs\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with defined Hedgehog signaling phenotype, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"24009529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional knockout of Ift140 in mouse spermatocytes/spermatids causes male infertility with sperm morphological defects (amorphous heads, short/bent flagella, swollen tail tips) and alters subcellular localization of IFT-B components IFT27 and IFT88, demonstrating IFT140 is required for sperm flagella assembly and IFT-B complex localization during spermiogenesis.\",\n      \"method\": \"Conditional Ift140 knockout mouse (spermatocyte/spermatid-specific), immunofluorescence for IFT components, transmission electron microscopy\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple orthogonal methods (morphology, immunofluorescence, TEM) showing specific IFT-B mislocalization\",\n      \"pmids\": [\"29236364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Missense mutations in IFT140 associated with nonsyndromic retinitis pigmentosa cause significantly reduced localization of IFT140 to the basal body in RPE1 cells, compared to wild-type IFT140 or a benign polymorphism.\",\n      \"method\": \"Transient plasmid transfection of hTERT-RPE1 cells with mutant vs. wild-type IFT140 constructs; immunofluorescence for basal body localization\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single-lab transfection assay with localization readout, two syndromic and two nonsyndromic mutants tested\",\n      \"pmids\": [\"26968735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFT140 loss-of-function (patient-derived urine renal epithelial cells and CRISPR Ift140 KO cells) causes accumulation of IFT-B protein IFT88 at the ciliary tip, consistent with impaired retrograde IFT; a patient missense variant (p.Tyr923Asp) recapitulates this tip accumulation phenotype when transfected into KO cells.\",\n      \"method\": \"Immunocytochemistry of patient urine-derived renal epithelial cells; CRISPR/Cas9 Ift140 KO rescue transfection assay\",\n      \"journal\": \"Cilia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with rescue and specific IFT-B tip accumulation phenotype, single lab\",\n      \"pmids\": [\"30479745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional deletion of IFT140 in odontoblasts leads to abnormal primary cilia, poor odontogenic differentiation, and decreased Sonic hedgehog signaling, establishing IFT140 as required for cilia-mediated SHH signaling in dentinogenesis.\",\n      \"method\": \"Ift140flox/flox/Osx-Cre conditional knockout mice; in vitro odontoblast differentiation assay; SHH pathway marker expression\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with pathway marker analysis and in vitro phenotype, single lab\",\n      \"pmids\": [\"29195058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional deletion of IFT140 in pre-osteoblasts (Osx-Cre) causes reduced bone mass, decreased osteoblastic marker expression, and progressive bone loss with aging, establishing IFT140 as required for osteoblast-mediated bone formation.\",\n      \"method\": \"Conditional Ift140 knockout mouse (Osx-Cre), micro-CT, histomorphometry, molecular marker analysis\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple readouts (micro-CT, histology, molecular markers), single lab\",\n      \"pmids\": [\"31034313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARL16 GTPase is required for trafficking of IFT140 from the Golgi to cilia; Arl16 knockout in MEFs causes IFT140 accumulation at the Golgi and loss from cilia, while other IFT proteins are unaffected, indicating a specific Golgi-to-cilia export pathway for IFT140.\",\n      \"method\": \"Arl16 knockout MEFs, immunofluorescence for IFT140 and other IFT proteins at Golgi and cilia, subcellular fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific localization phenotype for IFT140 versus other IFT proteins, single lab\",\n      \"pmids\": [\"35196065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFT140 physically associates with the novel conserved protein Pasovec (Psv), a core component of the IFT-A complex; this interaction is independent of Wg/Wnt-signaling activation and is required for nuclear translocation of β-catenin/Armadillo in canonical Wnt signaling in Drosophila.\",\n      \"method\": \"Co-immunoprecipitation/physical interaction assay (Psv-IFT140), Drosophila genetic epistasis, NLS mutant analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction established by co-IP, functional epistasis in Drosophila, but preprint and single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.21.660855\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Affinity purification-mass spectrometry (AP-MS) of 23 IFT140 missense mutations showed that a subset (10/23) cause domain-specific reductions in IFT140 interaction with the IFT-A complex, while knockout of IFT140 abolishes cilia; however, only mild cilia assembly effects were observed for 2 of 4 tested missense mutations, indicating the IFT-A complex is resilient to partial IFT140 dysfunction.\",\n      \"method\": \"Affinity purification coupled with mass spectrometry (AP-MS) of 23 missense mutants; IFT140 knockout ciliogenesis assay\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic AP-MS quantifying complex interactions for 23 mutations plus KO functional validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39880085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional deletion of Ift140 from FOXJ1+ motile cilia-forming cells causes short motile cilia with abnormal central apparatus and accumulation of intraciliary particles; cilia beat frequency is reduced and dynein arms are present but ciliary protein localization is abnormal, demonstrating IFT140 is specifically required for motile cilia assembly and cargo delivery independent of dynein arm docking.\",\n      \"method\": \"Conditional Ift140 knockout (FOXJ1-Cre), transmission electron microscopy of cilia ultrastructure, high-speed video microscopy of cilia beat frequency, immunofluorescence of ciliary proteins\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — conditional KO with TEM ultrastructure, beat frequency measurement, and protein localization; multiple orthogonal methods\",\n      \"pmids\": [\"40348912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ift140-deficient zebrafish kidney epithelial cells, in addition to cilia defects, disrupted cell polarity and aberrant cytoplasmic microtubule stabilization were observed, suggesting IFT140 has a non-ciliary role in kidney epithelial cell biology that contributes to cystogenesis; mTOR and ULK1 inhibition reverses both cilia-related and non-cilia-related abnormalities.\",\n      \"method\": \"Zebrafish ift140 mutant and CRISPR crispant generation; immunostaining for polarity markers and microtubule stabilization; pharmacological mTOR/ULK1 inhibition\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo zebrafish model with multiple cellular phenotype readouts and pharmacological rescue, single lab\",\n      \"pmids\": [\"40924493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFT140 protein is absent from the neck and mid-piece of spermatozoa in a human patient with compound heterozygous IFT140 variants and severe oligoasthenoteratozoospermia, establishing that IFT140 is normally localized to these sperm compartments and its loss disrupts sperm morphology.\",\n      \"method\": \"Immunofluorescence staining and transmission electron microscopy of patient spermatozoa\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single patient immunofluorescence without functional rescue\",\n      \"pmids\": [\"31397098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFT140 is a core structural component of the IFT-A complex that mediates retrograde intraflagellar transport in primary and motile cilia; it is required for moving ciliary cargo (including opsins) through the ciliary axoneme after delivery to the ciliary base, for proper localization of IFT-B components, for cilia-mediated Hedgehog and Wnt/β-catenin signaling, and for motile cilia assembly, with its Golgi-to-cilia trafficking specifically regulated by the ARL16 GTPase.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IFT140 is a core subunit of the intraflagellar transport complex A (IFT-A) that mediates retrograde transport within both primary and motile cilia, functioning in ciliary cargo delivery, signaling, and ciliogenesis across diverse cell types. Loss of IFT140 causes accumulation of IFT-B components (IFT88, IFT27) at the ciliary tip, consistent with defective retrograde transport, and disrupts the ciliary delivery of opsins through the connecting cilium of photoreceptors — acting downstream of IFT20-mediated Golgi-to-base trafficking [PMID:22503633, PMID:24619649, PMID:30479745]. IFT140 is required for cilia-dependent Hedgehog signaling in multiple developmental contexts and for motile cilia assembly where its loss produces short cilia with abnormal central apparatus and reduced beat frequency [PMID:24009529, PMID:29195058, PMID:40348912]. Trafficking of IFT140 from the Golgi to cilia depends specifically on the ARL16 GTPase, and systematic AP-MS analysis of 23 disease-associated missense mutations reveals domain-specific disruptions of IFT-A complex assembly, although the complex shows resilience to partial IFT140 dysfunction [PMID:35196065, PMID:39880085].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing IFT140 as an IFT-A subunit whose loss alters anterograde IFT component distribution in cilia provided the first direct evidence that IFT140 functions in retrograde intraflagellar transport in human cells.\",\n      \"evidence\": \"Immunofluorescence of IFT components in patient fibroblasts carrying IFT140 mutations\",\n      \"pmids\": [\"22503633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IFT140 loss alters anterograde IFT component localization not defined\", \"Retrograde transport defect inferred from redistribution rather than live cargo tracking\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that IFT140 loss-of-function in mice causes Hedgehog signaling defects placed IFT140 within the ciliary Hedgehog transduction pathway, linking retrograde IFT to developmental signaling.\",\n      \"evidence\": \"ENU mutagenesis mouse model (Cauli allele) with epistasis analysis of Hedgehog pathway outputs\",\n      \"pmids\": [\"24009529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFT140 directly transports Hedgehog pathway effectors (Gli, Smo) or acts indirectly through cilia structure not resolved\", \"Hedgehog pathway analysis limited to phenotypic readouts\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Conditional Ift140 knockout in photoreceptors showed opsin accumulates at the inner segment plasma membrane rather than the Golgi, distinguishing IFT140's role in moving cargo through the connecting cilium from IFT20's role in Golgi-to-base transport.\",\n      \"evidence\": \"Conditional/inducible Ift140 KO mouse compared with Ift20 KO; opsin immunofluorescence\",\n      \"pmids\": [\"24619649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding of IFT140 to opsin cargo not demonstrated\", \"Whether all photoreceptor cargo depends on IFT140 remains untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pathogenic IFT140 missense mutations associated with retinitis pigmentosa were shown to reduce IFT140 localization to the basal body, linking disease variants to a specific subcellular trafficking defect.\",\n      \"evidence\": \"Transfection of mutant vs. wild-type IFT140 constructs in RPE1 cells; basal body immunofluorescence\",\n      \"pmids\": [\"26968735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system may not recapitulate endogenous protein behavior\", \"Impact on retrograde IFT dynamics not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional deletion of IFT140 in odontoblasts extended the requirement for IFT140 in Hedgehog signaling to dentinogenesis, reinforcing its broad role in cilia-dependent SHH transduction.\",\n      \"evidence\": \"Ift140flox/Osx-Cre conditional KO mice; SHH pathway marker expression and odontoblast differentiation assay\",\n      \"pmids\": [\"29195058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFT140 requirement reflects general cilia loss or specific cargo transport in odontoblasts not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"IFT140 was shown to be essential for sperm flagella assembly and proper IFT-B component localization during spermiogenesis, extending its function from primary cilia to motile flagella.\",\n      \"evidence\": \"Conditional Ift140 KO in mouse spermatocytes/spermatids; TEM, immunofluorescence for IFT27/IFT88\",\n      \"pmids\": [\"29236364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFT140 participates in flagellar dynein arm transport not addressed\", \"Mechanism of IFT-B mislocalization upon IFT140 loss not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that IFT140 loss causes IFT88 accumulation at the ciliary tip in both patient-derived renal cells and CRISPR KO cells, with a patient missense variant recapitulating the defect, provided direct cellular evidence for impaired retrograde IFT as the primary consequence of IFT140 dysfunction.\",\n      \"evidence\": \"Patient urine-derived renal epithelial cells and CRISPR Ift140 KO with rescue transfection; immunocytochemistry\",\n      \"pmids\": [\"30479745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo identity beyond IFT88 not systematically profiled\", \"Rescue only tested with single mutant allele\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional deletion of IFT140 in pre-osteoblasts demonstrated its requirement for bone formation, broadening the tissue repertoire of IFT140-dependent cilia functions.\",\n      \"evidence\": \"Ift140 conditional KO mouse (Osx-Cre); micro-CT, histomorphometry, molecular marker analysis\",\n      \"pmids\": [\"31034313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the bone phenotype is cilia-dependent or reflects a non-ciliary IFT140 function not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of ARL16 as specifically required for Golgi-to-cilia trafficking of IFT140, while other IFT proteins were unaffected, revealed a dedicated export pathway for IFT140.\",\n      \"evidence\": \"Arl16 KO MEFs; immunofluorescence and subcellular fractionation of IFT140 vs. other IFT proteins\",\n      \"pmids\": [\"35196065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ARL16 directly binds IFT140 or acts through an adaptor not determined\", \"Mechanism of specificity for IFT140 over other IFT-A subunits unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Systematic AP-MS of 23 IFT140 missense mutations revealed domain-specific disruptions of IFT-A complex assembly, while functional assays showed the complex is resilient to partial IFT140 dysfunction, providing a genotype–interaction map for disease variants.\",\n      \"evidence\": \"AP-MS of 23 missense mutants; IFT140 KO ciliogenesis assay in mammalian cells\",\n      \"pmids\": [\"39880085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Retrograde transport dynamics not measured for individual mutants\", \"Structural basis for domain-specific disruption not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional deletion of IFT140 from FOXJ1+ motile cilia-forming cells demonstrated that IFT140 is specifically required for motile cilia assembly and intraciliary cargo delivery independent of dynein arm docking.\",\n      \"evidence\": \"FOXJ1-Cre conditional KO; TEM ultrastructure, high-speed video microscopy, immunofluorescence\",\n      \"pmids\": [\"40348912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFT140 transports central apparatus precursors directly not shown\", \"Which specific cargo proteins are IFT140-dependent in motile cilia remains undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery of disrupted cell polarity and aberrant cytoplasmic microtubule stabilization in ift140-deficient zebrafish kidney cells, reversible by mTOR/ULK1 inhibition, suggested a non-ciliary role for IFT140 in kidney epithelial biology.\",\n      \"evidence\": \"Zebrafish ift140 mutant; immunostaining for polarity and microtubule markers; pharmacological rescue\",\n      \"pmids\": [\"40924493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-ciliary function not yet separated from indirect consequences of cilia loss\", \"Molecular target of IFT140 in microtubule regulation unknown\", \"Pharmacological rescue does not establish direct mechanism\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct cargo repertoire of IFT140 within the retrograde IFT pathway, the structural basis for its domain-specific interactions with the IFT-A complex, and whether its non-ciliary functions in cell polarity and microtubule regulation are physiologically independent of cilia remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No systematic identification of direct IFT140-transported ciliary cargoes\", \"No high-resolution structure of IFT140 within the IFT-A complex\", \"Non-ciliary vs. ciliary-dependent functions not mechanistically separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 3, 5, 8, 11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 3, 5, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\n      \"IFT-A complex\"\n    ],\n    \"partners\": [\n      \"IFT88\",\n      \"IFT27\",\n      \"ARL16\",\n      \"IFT20\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}