{"gene":"DZIP1L","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2017,"finding":"DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2 (a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone). Loss of DZIP1L compromises ciliary-membrane translocation of polycystin-1 and polycystin-2, indicating DZIP1L is required for the diffusion barrier function at the transition zone.","method":"Co-immunoprecipitation (interaction with septin2), loss-of-function studies in mice and zebrafish, immunofluorescence localization, functional assessment of PKD protein ciliary trafficking in DZIP1L-mutant cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction data, in vivo loss-of-function in two model organisms, direct functional readout (ciliary trafficking of polycystins), replicated across cell and animal models","pmids":["28530676"],"is_preprint":false},{"year":2009,"finding":"Human DZIP1L (and its paralog DZIP1) localizes to the basal bodies of primary cilia, and together are required for primary cilia formation. In zebrafish, iguana (the ortholog) mutants have too few motile cilia in pronephric ducts and Kupffer's vesicle, causing left-right asymmetry defects, placing iguana/DZIP1L upstream of Hedgehog signaling through its role in ciliogenesis.","method":"Immunofluorescence localization to basal bodies, RNAi knockdown in planarians, zebrafish iguana mutant analysis (cilia number, left-right asymmetry phenotype), siRNA knockdown of human DZIP1 and DZIP1L","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by immunofluorescence, loss-of-function in multiple organisms (zebrafish mutant, planarian RNAi, human cell knockdown), specific cellular phenotype (cilia loss)","pmids":["19852954"],"is_preprint":false},{"year":2018,"finding":"Mouse Dzip1l is a centrosomal/basal body protein that colocalizes with basal body appendage proteins and the transition zone protein Rpgrip1l. Dzip1l interacts with Cby (a basal body appendage protein) and acts upstream of Cby in ciliogenesis. Loss of Dzip1l arrests ciliogenesis at the ciliary bud formation stage, prevents Cp110 removal from mother centrioles, and blocks Rpgrip1l recruitment to the transition zone. Dzip1l also has overlapping functions with Bromi (Tbc1d32) in ciliogenesis, cilia morphogenesis, and neural tube patterning. Dzip1l is required for Hedgehog signaling between Smoothened and Sufu.","method":"Co-immunoprecipitation (Dzip1l–Cby interaction), immunofluorescence colocalization, mouse knockout analysis (reduced ciliogenesis, dysmorphic cilia, neural tube patterning defects), epistasis analysis with Bromi double mutants, Cp110 and Rpgrip1l localization in mutant cells","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, mouse KO with defined cellular and developmental phenotypes, epistasis with Bromi, multiple orthogonal methods in single study","pmids":["29487109"],"is_preprint":false},{"year":2024,"finding":"DZIP1L modulates the architecture and function of ciliary transition fibers (TFs). In C. elegans, the sole DZIP1L homolog (C01G5.7/DZIP-1) localizes specifically to TFs. While single depletion of DZIP-1 or ANKR-26 (ortholog of ANKRD26) has subtle effects, co-depletion disrupts TF assembly and cilia gating for both soluble and membrane proteins including polycystin-2 ortholog. This synergistic role of DZIP1L and ANKRD26 in TF formation and function is conserved in mammalian cilia.","method":"C. elegans genetics (single and double depletion), immunofluorescence localization to transition fibers, cilia gating assays for soluble and membrane proteins, validation in mammalian cells","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double depletion), direct localization, functional gating assay, conserved across C. elegans and mammalian systems using multiple orthogonal methods","pmids":["38634253"],"is_preprint":false},{"year":2022,"finding":"DZIP1L missense variants in the N-terminal domain (p.Cys65Arg and p.Cys72Trp) cause mislocalization of mutant DZIP1L protein, indicating the N-terminal domain is critical for proper protein localization and function.","method":"Functional analysis of patient-derived missense variants by localization assay in cells (mislocalization of mutant DZIP1L)","journal":"Pediatric nephrology (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method (localization assay), no mechanistic follow-up beyond mislocalization observation","pmids":["35211789"],"is_preprint":false}],"current_model":"DZIP1L is an evolutionarily conserved ciliary basal body/transition zone protein that localizes to centrioles, distal basal body appendages, and transition fibers, where it interacts with septin2 and Cby to promote ciliary bud formation, maintain the periciliary diffusion barrier, and regulate selective ciliary protein entry (including polycystin-1/2); loss of DZIP1L disrupts transition fiber architecture (synergistically with ANKRD26), impairs Hedgehog signaling downstream positioning between Smoothened and Sufu, and causes ARPKD in humans."},"narrative":{"mechanistic_narrative":"DZIP1L is an evolutionarily conserved ciliary basal body protein that controls the assembly and gating function of the ciliary transition zone, governing selective protein entry into the cilium and thereby Hedgehog signaling and left-right patterning [PMID:19852954, PMID:29487109, PMID:38634253]. It localizes to centrioles, the distal ends of basal bodies, and ciliary transition fibers, where it interacts with septin2 and with the basal body appendage protein Cby and colocalizes with the transition zone protein Rpgrip1l [PMID:28530676, PMID:29487109]. Functionally, DZIP1L acts at the ciliary bud formation stage of ciliogenesis: its loss prevents Cp110 removal from mother centrioles and blocks Rpgrip1l recruitment to the transition zone, and it operates upstream of Cby with functions overlapping Bromi (Tbc1d32) in ciliogenesis and neural tube patterning [PMID:29487109]. At the transition zone DZIP1L maintains the periciliary diffusion barrier required for ciliary translocation of polycystin-1 and polycystin-2, and it cooperates synergistically with ANKRD26 to build transition fiber architecture that gates both soluble and membrane cargo [PMID:28530676, PMID:38634253]. Within Hedgehog signaling DZIP1L is required at a step between Smoothened and Sufu [PMID:29487109]. Loss-of-function and N-terminal missense variants of DZIP1L cause autosomal recessive polycystic kidney disease, with the disease-associated N-terminal residues being critical for proper DZIP1L localization [PMID:28530676, PMID:35211789].","teleology":[{"year":2009,"claim":"Establishing that DZIP1L is a basal body protein required for ciliogenesis placed it upstream of Hedgehog-dependent left-right patterning, defining its cellular compartment and developmental relevance.","evidence":"Immunofluorescence localization to basal bodies, planarian RNAi, human cell knockdown, and zebrafish iguana mutant analysis of cilia number and left-right asymmetry","pmids":["19852954"],"confidence":"High","gaps":["Did not define the molecular interactions or biochemical step through which DZIP1L promotes ciliogenesis","Did not distinguish DZIP1L-specific roles from its paralog DZIP1","No link to a specific transition zone gating function"]},{"year":2017,"claim":"Linking DZIP1L to septin2 and to ciliary translocation of polycystins identified its role in the periciliary diffusion barrier and provided a mechanism for its requirement in kidney disease.","evidence":"Co-immunoprecipitation with septin2, loss-of-function in mice and zebrafish, and assays of polycystin-1/2 ciliary trafficking in mutant cells","pmids":["28530676"],"confidence":"High","gaps":["Did not resolve how DZIP1L organizes the barrier structurally","Did not identify the full set of cargo whose entry depends on DZIP1L","Mechanism of septin2 recruitment by DZIP1L not defined"]},{"year":2018,"claim":"Mapping DZIP1L to a defined ciliogenesis step clarified its order of action — upstream of Cby, controlling Cp110 removal and Rpgrip1l transition-zone recruitment — and positioned it within Hedgehog signaling between Smoothened and Sufu.","evidence":"Co-immunoprecipitation (Dzip1l-Cby), colocalization, mouse knockout with ciliary and neural tube phenotypes, Bromi double-mutant epistasis, and Cp110/Rpgrip1l localization in mutants","pmids":["29487109"],"confidence":"High","gaps":["Molecular basis of the Smoothened-to-Sufu step not resolved","Direct biochemical mechanism for Cp110 removal and Rpgrip1l recruitment unknown","Functional relationship between the Cby and septin2 interactions not integrated"]},{"year":2024,"claim":"Demonstrating synergy between DZIP1L and ANKRD26 in transition fiber assembly assigned DZIP1L a direct structural role in the gate that filters both soluble and membrane proteins, conserved from worm to mammal.","evidence":"C. elegans single and double depletion genetics, transition fiber localization, cilia gating assays, and mammalian validation","pmids":["38634253"],"confidence":"High","gaps":["How DZIP1L and ANKRD26 physically cooperate at transition fibers is not defined","The structural element of DZIP1L that builds transition fiber architecture is unknown"]},{"year":2022,"claim":"Patient-derived N-terminal missense variants showed that the DZIP1L N-terminus is required for correct localization, tying disease variants to a loss of compartment targeting.","evidence":"Localization assay of patient-derived missense variants (p.Cys65Arg, p.Cys72Trp) in cells","pmids":["35211789"],"confidence":"Medium","gaps":["Single lab, single localization method with no mechanistic follow-up beyond mislocalization","Did not test whether mislocalization causally impairs gating or polycystin trafficking","Did not define the domain or interaction mediating N-terminal targeting"]},{"year":null,"claim":"The biochemical mechanism by which DZIP1L builds transition fiber/transition zone architecture and selectively gates cargo such as the polycystins remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of DZIP1L or its assembly with ANKRD26, Cby, or septin2","Direct cargo-selection mechanism for polycystin entry not established","Molecular step controlling Hedgehog signaling between Smoothened and Sufu unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["SEPT2","CBY1","RPGRIP1L","ANKRD26"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYY4","full_name":"Cilium assembly protein DZIP1L","aliases":["DAZ-interacting zinc finger protein 1-like"],"length_aa":767,"mass_kda":86.8,"function":"Involved in primary cilium formation (PubMed:19852954, PubMed:28530676). Probably acts as a transition zone protein required for localization of PKD1/PC1 and PKD2/PC2 to the ciliary membrane (PubMed:28530676)","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q8IYY4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DZIP1L","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/DZIP1L","total_profiled":1310},"omim":[{"mim_id":"617610","title":"POLYCYSTIC KIDNEY DISEASE 5; PKD5","url":"https://www.omim.org/entry/617610"},{"mim_id":"617570","title":"DAZ-INTERACTING ZINC FINGER PROTEIN 1-LIKE; DZIP1L","url":"https://www.omim.org/entry/617570"},{"mim_id":"173900","title":"POLYCYSTIC KIDNEY DISEASE 1 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE; PKD1","url":"https://www.omim.org/entry/173900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DZIP1L"},"hgnc":{"alias_symbol":["FLJ32844","DZIP2"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYY4","domains":[{"cath_id":"-","chopping":"36-161","consensus_level":"medium","plddt":90.0125,"start":36,"end":161}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYY4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYY4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYY4-F1-predicted_aligned_error_v6.png","plddt_mean":68.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DZIP1L","jax_strain_url":"https://www.jax.org/strain/search?query=DZIP1L"},"sequence":{"accession":"Q8IYY4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYY4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYY4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYY4"}},"corpus_meta":[{"pmid":"28530676","id":"PMC_28530676","title":"Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease.","date":"2017","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28530676","citation_count":156,"is_preprint":false},{"pmid":"17089004","id":"PMC_17089004","title":"Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review).","date":"2006","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17089004","citation_count":156,"is_preprint":false},{"pmid":"29479522","id":"PMC_29479522","title":"Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses.","date":"2018","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/29479522","citation_count":87,"is_preprint":false},{"pmid":"19852954","id":"PMC_19852954","title":"The Zn finger protein Iguana impacts Hedgehog signaling by promoting ciliogenesis.","date":"2009","source":"Developmental 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interacts with septin2 (a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone). Loss of DZIP1L compromises ciliary-membrane translocation of polycystin-1 and polycystin-2, indicating DZIP1L is required for the diffusion barrier function at the transition zone.\",\n      \"method\": \"Co-immunoprecipitation (interaction with septin2), loss-of-function studies in mice and zebrafish, immunofluorescence localization, functional assessment of PKD protein ciliary trafficking in DZIP1L-mutant cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction data, in vivo loss-of-function in two model organisms, direct functional readout (ciliary trafficking of polycystins), replicated across cell and animal models\",\n      \"pmids\": [\"28530676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human DZIP1L (and its paralog DZIP1) localizes to the basal bodies of primary cilia, and together are required for primary cilia formation. In zebrafish, iguana (the ortholog) mutants have too few motile cilia in pronephric ducts and Kupffer's vesicle, causing left-right asymmetry defects, placing iguana/DZIP1L upstream of Hedgehog signaling through its role in ciliogenesis.\",\n      \"method\": \"Immunofluorescence localization to basal bodies, RNAi knockdown in planarians, zebrafish iguana mutant analysis (cilia number, left-right asymmetry phenotype), siRNA knockdown of human DZIP1 and DZIP1L\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by immunofluorescence, loss-of-function in multiple organisms (zebrafish mutant, planarian RNAi, human cell knockdown), specific cellular phenotype (cilia loss)\",\n      \"pmids\": [\"19852954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mouse Dzip1l is a centrosomal/basal body protein that colocalizes with basal body appendage proteins and the transition zone protein Rpgrip1l. Dzip1l interacts with Cby (a basal body appendage protein) and acts upstream of Cby in ciliogenesis. Loss of Dzip1l arrests ciliogenesis at the ciliary bud formation stage, prevents Cp110 removal from mother centrioles, and blocks Rpgrip1l recruitment to the transition zone. Dzip1l also has overlapping functions with Bromi (Tbc1d32) in ciliogenesis, cilia morphogenesis, and neural tube patterning. Dzip1l is required for Hedgehog signaling between Smoothened and Sufu.\",\n      \"method\": \"Co-immunoprecipitation (Dzip1l–Cby interaction), immunofluorescence colocalization, mouse knockout analysis (reduced ciliogenesis, dysmorphic cilia, neural tube patterning defects), epistasis analysis with Bromi double mutants, Cp110 and Rpgrip1l localization in mutant cells\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, mouse KO with defined cellular and developmental phenotypes, epistasis with Bromi, multiple orthogonal methods in single study\",\n      \"pmids\": [\"29487109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DZIP1L modulates the architecture and function of ciliary transition fibers (TFs). In C. elegans, the sole DZIP1L homolog (C01G5.7/DZIP-1) localizes specifically to TFs. While single depletion of DZIP-1 or ANKR-26 (ortholog of ANKRD26) has subtle effects, co-depletion disrupts TF assembly and cilia gating for both soluble and membrane proteins including polycystin-2 ortholog. This synergistic role of DZIP1L and ANKRD26 in TF formation and function is conserved in mammalian cilia.\",\n      \"method\": \"C. elegans genetics (single and double depletion), immunofluorescence localization to transition fibers, cilia gating assays for soluble and membrane proteins, validation in mammalian cells\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double depletion), direct localization, functional gating assay, conserved across C. elegans and mammalian systems using multiple orthogonal methods\",\n      \"pmids\": [\"38634253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DZIP1L missense variants in the N-terminal domain (p.Cys65Arg and p.Cys72Trp) cause mislocalization of mutant DZIP1L protein, indicating the N-terminal domain is critical for proper protein localization and function.\",\n      \"method\": \"Functional analysis of patient-derived missense variants by localization assay in cells (mislocalization of mutant DZIP1L)\",\n      \"journal\": \"Pediatric nephrology (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (localization assay), no mechanistic follow-up beyond mislocalization observation\",\n      \"pmids\": [\"35211789\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DZIP1L is an evolutionarily conserved ciliary basal body/transition zone protein that localizes to centrioles, distal basal body appendages, and transition fibers, where it interacts with septin2 and Cby to promote ciliary bud formation, maintain the periciliary diffusion barrier, and regulate selective ciliary protein entry (including polycystin-1/2); loss of DZIP1L disrupts transition fiber architecture (synergistically with ANKRD26), impairs Hedgehog signaling downstream positioning between Smoothened and Sufu, and causes ARPKD in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DZIP1L is an evolutionarily conserved ciliary basal body protein that controls the assembly and gating function of the ciliary transition zone, governing selective protein entry into the cilium and thereby Hedgehog signaling and left-right patterning [#1, #2, #3]. It localizes to centrioles, the distal ends of basal bodies, and ciliary transition fibers, where it interacts with septin2 and with the basal body appendage protein Cby and colocalizes with the transition zone protein Rpgrip1l [#0, #2]. Functionally, DZIP1L acts at the ciliary bud formation stage of ciliogenesis: its loss prevents Cp110 removal from mother centrioles and blocks Rpgrip1l recruitment to the transition zone, and it operates upstream of Cby with functions overlapping Bromi (Tbc1d32) in ciliogenesis and neural tube patterning [#2]. At the transition zone DZIP1L maintains the periciliary diffusion barrier required for ciliary translocation of polycystin-1 and polycystin-2, and it cooperates synergistically with ANKRD26 to build transition fiber architecture that gates both soluble and membrane cargo [#0, #3]. Within Hedgehog signaling DZIP1L is required at a step between Smoothened and Sufu [#2]. Loss-of-function and N-terminal missense variants of DZIP1L cause autosomal recessive polycystic kidney disease, with the disease-associated N-terminal residues being critical for proper DZIP1L localization [#0, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that DZIP1L is a basal body protein required for ciliogenesis placed it upstream of Hedgehog-dependent left-right patterning, defining its cellular compartment and developmental relevance.\",\n      \"evidence\": \"Immunofluorescence localization to basal bodies, planarian RNAi, human cell knockdown, and zebrafish iguana mutant analysis of cilia number and left-right asymmetry\",\n      \"pmids\": [\"19852954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not define the molecular interactions or biochemical step through which DZIP1L promotes ciliogenesis\",\n        \"Did not distinguish DZIP1L-specific roles from its paralog DZIP1\",\n        \"No link to a specific transition zone gating function\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking DZIP1L to septin2 and to ciliary translocation of polycystins identified its role in the periciliary diffusion barrier and provided a mechanism for its requirement in kidney disease.\",\n      \"evidence\": \"Co-immunoprecipitation with septin2, loss-of-function in mice and zebrafish, and assays of polycystin-1/2 ciliary trafficking in mutant cells\",\n      \"pmids\": [\"28530676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve how DZIP1L organizes the barrier structurally\",\n        \"Did not identify the full set of cargo whose entry depends on DZIP1L\",\n        \"Mechanism of septin2 recruitment by DZIP1L not defined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapping DZIP1L to a defined ciliogenesis step clarified its order of action — upstream of Cby, controlling Cp110 removal and Rpgrip1l transition-zone recruitment — and positioned it within Hedgehog signaling between Smoothened and Sufu.\",\n      \"evidence\": \"Co-immunoprecipitation (Dzip1l-Cby), colocalization, mouse knockout with ciliary and neural tube phenotypes, Bromi double-mutant epistasis, and Cp110/Rpgrip1l localization in mutants\",\n      \"pmids\": [\"29487109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of the Smoothened-to-Sufu step not resolved\",\n        \"Direct biochemical mechanism for Cp110 removal and Rpgrip1l recruitment unknown\",\n        \"Functional relationship between the Cby and septin2 interactions not integrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating synergy between DZIP1L and ANKRD26 in transition fiber assembly assigned DZIP1L a direct structural role in the gate that filters both soluble and membrane proteins, conserved from worm to mammal.\",\n      \"evidence\": \"C. elegans single and double depletion genetics, transition fiber localization, cilia gating assays, and mammalian validation\",\n      \"pmids\": [\"38634253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How DZIP1L and ANKRD26 physically cooperate at transition fibers is not defined\",\n        \"The structural element of DZIP1L that builds transition fiber architecture is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Patient-derived N-terminal missense variants showed that the DZIP1L N-terminus is required for correct localization, tying disease variants to a loss of compartment targeting.\",\n      \"evidence\": \"Localization assay of patient-derived missense variants (p.Cys65Arg, p.Cys72Trp) in cells\",\n      \"pmids\": [\"35211789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single localization method with no mechanistic follow-up beyond mislocalization\",\n        \"Did not test whether mislocalization causally impairs gating or polycystin trafficking\",\n        \"Did not define the domain or interaction mediating N-terminal targeting\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which DZIP1L builds transition fiber/transition zone architecture and selectively gates cargo such as the polycystins remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of DZIP1L or its assembly with ANKRD26, Cby, or septin2\",\n        \"Direct cargo-selection mechanism for polycystin entry not established\",\n        \"Molecular step controlling Hedgehog signaling between Smoothened and Sufu unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEPT2\", \"CBY1\", \"RPGRIP1L\", \"ANKRD26\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}