{"gene":"IQCE","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2014,"finding":"IQCE forms a complex with EFCAB7 at the base of primary cilia, and this EFCAB7-IQCE module anchors the EVC-EVC2 complex in a signaling microdomain at the ciliary base; EFCAB7 depletion causes mislocalization of EVC-EVC2 within cilia and impaired activation of the transcription factor GLI2, placing IQCE as a positive regulator of the Hedgehog pathway.","method":"Co-immunoprecipitation, ciliary localization experiments, depletion (siRNA knockdown) with defined cellular phenotype (GLI2 activation assay, EVC-EVC2 mislocalization), evolutionary analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, direct localization experiments with functional consequences (GLI2 activation, EVC-EVC2 anchoring), multiple orthogonal methods in a single study; widely cited foundational paper","pmids":["24582806"],"is_preprint":false},{"year":2017,"finding":"A homozygous splice acceptor site variant (c.395-1G>A) in IQCE causes a frameshift and premature stop codon (p.Gly132Valfs*22), resulting in loss of IQCE function and postaxial polydactyly type A restricted to the lower limb, establishing IQCE's role in human limb development.","method":"Exome sequencing, Sanger sequencing validation, mini-gene splicing assay","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function variant with functional splicing assay confirmation; single family but mechanistically validated","pmids":["28488682"],"is_preprint":false},{"year":2019,"finding":"Biallelic pathogenic variants in IQCE lead to dysregulation of genes associated with the Hedgehog-signaling pathway in patient fibroblasts, and zebrafish iqce knockdown produces ciliopathy phenotypes including body curvature, kidney cysts, left-right asymmetry defects, misdirected cilia in the pronephric duct, and retinal defects, confirming IQCE's role in cilia function and Hedgehog signaling.","method":"RNA expression analysis in patient fibroblasts, zebrafish morpholino knockdown with ciliary phenotype readouts (body curvature, kidney cysts, cilia orientation), exome sequencing","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function in patient cells with Hh pathway readout plus ortholog knockdown in zebrafish with multiple ciliary phenotypes; moderate evidence from two independent methods","pmids":["31549751"],"is_preprint":false},{"year":2023,"finding":"Proteomic characterization of the endogenous EVC interactome confirmed that IQCE and EFCAB7 are main interactors of EVC; SUMO3 modification of EVC-EVC2 cytosolic tails enhances their accumulation at the EvC zone (base of cilia) possibly via increased binding to the EFCAB7-IQCE complex, and EVC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2.","method":"Endogenous co-immunoprecipitation/mass spectrometry interactome, SUMO modification assays, ciliary localization experiments, mutational mapping of EFCAB7-binding motifs","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — endogenous interactome MS confirmed known IQCE-EFCAB7-EVC interaction, with functional SUMO modification assay and mutational mapping; multiple orthogonal methods","pmids":["37576597"],"is_preprint":false},{"year":2023,"finding":"Homozygous frameshift deletions in EFCAB7 cause postaxial polydactyly, and since EFCAB7-IQCE and EVC-EVC2 form a heterotetramer (EvC complex) that positively regulates the Hedgehog pathway, depletion of either EFCAB7 or IQCE inhibits induction of GLI1 (a direct Hh target gene), further supporting IQCE's role in the complex.","method":"Exome sequencing, Sanger validation, functional annotation of IQCE-EFCAB7 complex with GLI1 induction assay","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 3 — functional data (GLI1 inhibition) cited from prior literature for IQCE, with new genetic evidence for EFCAB7; supports and extends the established mechanism","pmids":["37684519"],"is_preprint":false}],"current_model":"IQCE is a ciliary scaffold protein that forms a complex with EFCAB7 at the base of primary cilia, where the EFCAB7-IQCE module anchors the EVC-EVC2 heterodimer in a signaling microdomain (the EvC zone), thereby positively regulating Hedgehog pathway activation (GLI2/GLI1 transcription factor induction); loss of IQCE disrupts EVC-EVC2 ciliary localization, impairs Hedgehog signaling, and causes postaxial polydactyly and broader ciliopathy phenotypes in humans and zebrafish."},"narrative":{"teleology":[{"year":2014,"claim":"The fundamental question of how EVC-EVC2 is retained at a discrete ciliary signaling microdomain was answered by demonstrating that IQCE forms a complex with EFCAB7 at the ciliary base, and this module anchors EVC-EVC2 to positively regulate Hedgehog-dependent GLI2 activation.","evidence":"Reciprocal co-immunoprecipitation, ciliary localization imaging, siRNA depletion with GLI2 activation readout in mammalian cells","pmids":["24582806"],"confidence":"High","gaps":["Direct structural basis of IQCE-EFCAB7 interaction not determined","Whether IQCE has functions independent of the EFCAB7-EVC-EVC2 module is unknown","In vivo mammalian loss-of-function model for IQCE not yet reported"]},{"year":2017,"claim":"The clinical relevance of IQCE was established when a homozygous splice-site variant causing a frameshift and premature stop was identified as the cause of postaxial polydactyly type A, linking IQCE loss of function to a human limb patterning defect consistent with disrupted Hedgehog signaling.","evidence":"Exome sequencing in a consanguineous family, Sanger validation, mini-gene splicing assay confirming aberrant splicing","pmids":["28488682"],"confidence":"Medium","gaps":["Single family reported; additional kindreds needed to confirm genotype-phenotype spectrum","Patient-derived cell Hedgehog signaling not directly measured in this study","Whether partial IQCE loss produces milder phenotypes is unknown"]},{"year":2019,"claim":"Confirmation that IQCE loss disrupts Hedgehog signaling at the transcriptional level came from patient fibroblast RNA analysis, and zebrafish iqce knockdown expanded the phenotypic spectrum to include kidney cysts, body curvature, cilia misdirection, and left-right asymmetry defects, establishing IQCE as broadly required for ciliary function.","evidence":"RNA expression profiling in patient fibroblasts with biallelic IQCE variants; morpholino knockdown in zebrafish with multiple ciliary phenotype readouts","pmids":["31549751"],"confidence":"High","gaps":["Zebrafish data relied on morpholino knockdown rather than a stable genetic mutant","Which specific Hedgehog target genes are most sensitive to IQCE loss is not fully catalogued","Whether IQCE functions outside Hedgehog signaling (e.g., in Wnt or other ciliary pathways) is unresolved"]},{"year":2023,"claim":"Proteomic and biochemical dissection revealed that IQCE and EFCAB7 are the principal endogenous interactors of EVC, that SUMO3 modification of EVC-EVC2 enhances EvC zone accumulation likely through increased EFCAB7-IQCE binding, and that two separable EFCAB7-binding motifs in EVC2 mediate this targeting; concurrent genetic evidence from EFCAB7-mutant families confirmed heterotetramer integrity is required for Hedgehog-dependent GLI1 induction.","evidence":"Endogenous co-IP/mass spectrometry, SUMO modification assays, mutational mapping of EFCAB7-binding motifs, and exome sequencing in EFCAB7-mutant families with GLI1 induction assay","pmids":["37576597","37684519"],"confidence":"High","gaps":["Structural resolution of the IQCE-EFCAB7-EVC-EVC2 heterotetramer is lacking","Whether SUMO3-dependent regulation of EvC zone targeting is dynamic during Hedgehog signaling is unknown","A mammalian IQCE knockout model has not been reported"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of the IQCE-EFCAB7-EVC-EVC2 complex, whether IQCE participates in signaling pathways beyond Hedgehog, and whether mouse Iqce knockout recapitulates human polydactyly and broader ciliopathy phenotypes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structural data for IQCE or the EvC complex","No mammalian genetic knockout model published","Potential IQCE roles in non-Hedgehog ciliary signaling are unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4]}],"complexes":["EFCAB7-IQCE-EVC-EVC2 (EvC complex)"],"partners":["EFCAB7","EVC","EVC2"],"other_free_text":[]},"mechanistic_narrative":"IQCE is a ciliary scaffold protein that, together with EFCAB7, anchors the EVC-EVC2 signaling complex at the EvC zone at the base of primary cilia, thereby positively regulating Hedgehog pathway activation through GLI2 and GLI1 transcription factors [PMID:24582806, PMID:37576597]. Loss of IQCE disrupts EVC-EVC2 ciliary localization and impairs Hedgehog target gene induction, and biallelic loss-of-function variants in IQCE cause postaxial polydactyly in humans and ciliopathy phenotypes—including kidney cysts, body curvature, and left-right asymmetry defects—in zebrafish [PMID:28488682, PMID:31549751]. SUMO3 modification of EVC-EVC2 cytosolic tails enhances their accumulation at the EvC zone, likely by promoting binding to the EFCAB7-IQCE module, and EVC2 engages EFCAB7 through two distinct binding motifs [PMID:37576597]."},"prefetch_data":{"uniprot":{"accession":"Q6IPM2","full_name":"IQ domain-containing protein E","aliases":[],"length_aa":695,"mass_kda":77.3,"function":"Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling (By similarity). Required for proper limb morphogenesis (PubMed:28488682)","subcellular_location":"Cell projection, cilium membrane","url":"https://www.uniprot.org/uniprotkb/Q6IPM2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IQCE","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IQCE","total_profiled":1310},"omim":[{"mim_id":"617642","title":"POLYDACTYLY, POSTAXIAL, TYPE A7; PAPA7","url":"https://www.omim.org/entry/617642"},{"mim_id":"617632","title":"EF-HAND CALCIUM-BINDING DOMAIN-CONTAINING PROTEIN 7; EFCAB7","url":"https://www.omim.org/entry/617632"},{"mim_id":"617631","title":"IQ DOMAIN-CONTAINING PROTEIN E; IQCE","url":"https://www.omim.org/entry/617631"},{"mim_id":"607261","title":"EVC CILIARY COMPLEX SUBUNIT 2; EVC2","url":"https://www.omim.org/entry/607261"},{"mim_id":"604831","title":"EVC CILIARY COMPLEX SUBUNIT 1; EVC","url":"https://www.omim.org/entry/604831"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IQCE"},"hgnc":{"alias_symbol":["KIAA1023"],"prev_symbol":[]},"alphafold":{"accession":"Q6IPM2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IPM2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IPM2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IPM2-F1-predicted_aligned_error_v6.png","plddt_mean":68.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IQCE","jax_strain_url":"https://www.jax.org/strain/search?query=IQCE"},"sequence":{"accession":"Q6IPM2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6IPM2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6IPM2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IPM2"}},"corpus_meta":[{"pmid":"24582806","id":"PMC_24582806","title":"EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia.","date":"2014","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/24582806","citation_count":77,"is_preprint":false},{"pmid":"28488682","id":"PMC_28488682","title":"Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/28488682","citation_count":39,"is_preprint":false},{"pmid":"30760334","id":"PMC_30760334","title":"Epigenetic findings in periodontitis in UK twins: a cross-sectional study.","date":"2019","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/30760334","citation_count":36,"is_preprint":false},{"pmid":"30982135","id":"PMC_30982135","title":"Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly.","date":"2019","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30982135","citation_count":22,"is_preprint":false},{"pmid":"29489655","id":"PMC_29489655","title":"Genome-wide association study of maternal genetic effects and parent-of-origin effects on food allergy.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29489655","citation_count":20,"is_preprint":false},{"pmid":"31115189","id":"PMC_31115189","title":"Exome sequencing revealed a novel loss-of-function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly.","date":"2019","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31115189","citation_count":19,"is_preprint":false},{"pmid":"35853630","id":"PMC_35853630","title":"Epigenome-wide DNA methylation study of whole blood in patients with sporadic amyotrophic lateral sclerosis.","date":"2022","source":"Chinese medical 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A.","date":"2020","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32147526","citation_count":9,"is_preprint":false},{"pmid":"37684519","id":"PMC_37684519","title":"Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly.","date":"2023","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/37684519","citation_count":8,"is_preprint":false},{"pmid":"34721536","id":"PMC_34721536","title":"A Novel Homozygous Missense Mutation in the Zinc Finger DNA Binding Domain of GLI1 Causes Recessive Post-Axial Polydactyly.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34721536","citation_count":8,"is_preprint":false},{"pmid":"16315386","id":"PMC_16315386","title":"Expression of IQ-motif genes in human cells and ASPM domain structure.","date":"2005","source":"Ethnicity & disease","url":"https://pubmed.ncbi.nlm.nih.gov/16315386","citation_count":7,"is_preprint":false},{"pmid":"37576597","id":"PMC_37576597","title":"EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37576597","citation_count":7,"is_preprint":false},{"pmid":"39020437","id":"PMC_39020437","title":"Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study.","date":"2024","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/39020437","citation_count":6,"is_preprint":false},{"pmid":"37323200","id":"PMC_37323200","title":"Identification of a Novel IQCE Large Deletion through Copy Number Variant Analysis from Whole-Exome Sequencing Data of a Patient with Postaxial Polydactyly Type A7.","date":"2023","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/37323200","citation_count":5,"is_preprint":false},{"pmid":"36067927","id":"PMC_36067927","title":"A novel homozygous variant in the GLI1 underlies postaxial polydactyly in a large consanguineous family with intra familial variable phenotypes.","date":"2022","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36067927","citation_count":5,"is_preprint":false},{"pmid":"38853702","id":"PMC_38853702","title":"A novel homozygous FAM92A gene (CIBAR1) variant further confirms its association with non-syndromic postaxial polydactyly type A9 (PAPA9).","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38853702","citation_count":3,"is_preprint":false},{"pmid":"41257035","id":"PMC_41257035","title":"Clinical Risk Stratification and Modifiable Risk Factors for Hepatitis B Virus-Related Follicular Lymphoma.","date":"2025","source":"ImmunoTargets and 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\"Co-immunoprecipitation, ciliary localization experiments, depletion (siRNA knockdown) with defined cellular phenotype (GLI2 activation assay, EVC-EVC2 mislocalization), evolutionary analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, direct localization experiments with functional consequences (GLI2 activation, EVC-EVC2 anchoring), multiple orthogonal methods in a single study; widely cited foundational paper\",\n      \"pmids\": [\"24582806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous splice acceptor site variant (c.395-1G>A) in IQCE causes a frameshift and premature stop codon (p.Gly132Valfs*22), resulting in loss of IQCE function and postaxial polydactyly type A restricted to the lower limb, establishing IQCE's role in human limb development.\",\n      \"method\": \"Exome sequencing, Sanger sequencing validation, mini-gene splicing assay\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function variant with functional splicing assay confirmation; single family but mechanistically validated\",\n      \"pmids\": [\"28488682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic pathogenic variants in IQCE lead to dysregulation of genes associated with the Hedgehog-signaling pathway in patient fibroblasts, and zebrafish iqce knockdown produces ciliopathy phenotypes including body curvature, kidney cysts, left-right asymmetry defects, misdirected cilia in the pronephric duct, and retinal defects, confirming IQCE's role in cilia function and Hedgehog signaling.\",\n      \"method\": \"RNA expression analysis in patient fibroblasts, zebrafish morpholino knockdown with ciliary phenotype readouts (body curvature, kidney cysts, cilia orientation), exome sequencing\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in patient cells with Hh pathway readout plus ortholog knockdown in zebrafish with multiple ciliary phenotypes; moderate evidence from two independent methods\",\n      \"pmids\": [\"31549751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proteomic characterization of the endogenous EVC interactome confirmed that IQCE and EFCAB7 are main interactors of EVC; SUMO3 modification of EVC-EVC2 cytosolic tails enhances their accumulation at the EvC zone (base of cilia) possibly via increased binding to the EFCAB7-IQCE complex, and EVC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2.\",\n      \"method\": \"Endogenous co-immunoprecipitation/mass spectrometry interactome, SUMO modification assays, ciliary localization experiments, mutational mapping of EFCAB7-binding motifs\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — endogenous interactome MS confirmed known IQCE-EFCAB7-EVC interaction, with functional SUMO modification assay and mutational mapping; multiple orthogonal methods\",\n      \"pmids\": [\"37576597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Homozygous frameshift deletions in EFCAB7 cause postaxial polydactyly, and since EFCAB7-IQCE and EVC-EVC2 form a heterotetramer (EvC complex) that positively regulates the Hedgehog pathway, depletion of either EFCAB7 or IQCE inhibits induction of GLI1 (a direct Hh target gene), further supporting IQCE's role in the complex.\",\n      \"method\": \"Exome sequencing, Sanger validation, functional annotation of IQCE-EFCAB7 complex with GLI1 induction assay\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional data (GLI1 inhibition) cited from prior literature for IQCE, with new genetic evidence for EFCAB7; supports and extends the established mechanism\",\n      \"pmids\": [\"37684519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IQCE is a ciliary scaffold protein that forms a complex with EFCAB7 at the base of primary cilia, where the EFCAB7-IQCE module anchors the EVC-EVC2 heterodimer in a signaling microdomain (the EvC zone), thereby positively regulating Hedgehog pathway activation (GLI2/GLI1 transcription factor induction); loss of IQCE disrupts EVC-EVC2 ciliary localization, impairs Hedgehog signaling, and causes postaxial polydactyly and broader ciliopathy phenotypes in humans and zebrafish.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IQCE is a ciliary scaffold protein that, together with EFCAB7, anchors the EVC-EVC2 signaling complex at the EvC zone at the base of primary cilia, thereby positively regulating Hedgehog pathway activation through GLI2 and GLI1 transcription factors [PMID:24582806, PMID:37576597]. Loss of IQCE disrupts EVC-EVC2 ciliary localization and impairs Hedgehog target gene induction, and biallelic loss-of-function variants in IQCE cause postaxial polydactyly in humans and ciliopathy phenotypes—including kidney cysts, body curvature, and left-right asymmetry defects—in zebrafish [PMID:28488682, PMID:31549751]. SUMO3 modification of EVC-EVC2 cytosolic tails enhances their accumulation at the EvC zone, likely by promoting binding to the EFCAB7-IQCE module, and EVC2 engages EFCAB7 through two distinct binding motifs [PMID:37576597].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"The fundamental question of how EVC-EVC2 is retained at a discrete ciliary signaling microdomain was answered by demonstrating that IQCE forms a complex with EFCAB7 at the ciliary base, and this module anchors EVC-EVC2 to positively regulate Hedgehog-dependent GLI2 activation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ciliary localization imaging, siRNA depletion with GLI2 activation readout in mammalian cells\",\n      \"pmids\": [\"24582806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct structural basis of IQCE-EFCAB7 interaction not determined\",\n        \"Whether IQCE has functions independent of the EFCAB7-EVC-EVC2 module is unknown\",\n        \"In vivo mammalian loss-of-function model for IQCE not yet reported\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The clinical relevance of IQCE was established when a homozygous splice-site variant causing a frameshift and premature stop was identified as the cause of postaxial polydactyly type A, linking IQCE loss of function to a human limb patterning defect consistent with disrupted Hedgehog signaling.\",\n      \"evidence\": \"Exome sequencing in a consanguineous family, Sanger validation, mini-gene splicing assay confirming aberrant splicing\",\n      \"pmids\": [\"28488682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single family reported; additional kindreds needed to confirm genotype-phenotype spectrum\",\n        \"Patient-derived cell Hedgehog signaling not directly measured in this study\",\n        \"Whether partial IQCE loss produces milder phenotypes is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmation that IQCE loss disrupts Hedgehog signaling at the transcriptional level came from patient fibroblast RNA analysis, and zebrafish iqce knockdown expanded the phenotypic spectrum to include kidney cysts, body curvature, cilia misdirection, and left-right asymmetry defects, establishing IQCE as broadly required for ciliary function.\",\n      \"evidence\": \"RNA expression profiling in patient fibroblasts with biallelic IQCE variants; morpholino knockdown in zebrafish with multiple ciliary phenotype readouts\",\n      \"pmids\": [\"31549751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Zebrafish data relied on morpholino knockdown rather than a stable genetic mutant\",\n        \"Which specific Hedgehog target genes are most sensitive to IQCE loss is not fully catalogued\",\n        \"Whether IQCE functions outside Hedgehog signaling (e.g., in Wnt or other ciliary pathways) is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proteomic and biochemical dissection revealed that IQCE and EFCAB7 are the principal endogenous interactors of EVC, that SUMO3 modification of EVC-EVC2 enhances EvC zone accumulation likely through increased EFCAB7-IQCE binding, and that two separable EFCAB7-binding motifs in EVC2 mediate this targeting; concurrent genetic evidence from EFCAB7-mutant families confirmed heterotetramer integrity is required for Hedgehog-dependent GLI1 induction.\",\n      \"evidence\": \"Endogenous co-IP/mass spectrometry, SUMO modification assays, mutational mapping of EFCAB7-binding motifs, and exome sequencing in EFCAB7-mutant families with GLI1 induction assay\",\n      \"pmids\": [\"37576597\", \"37684519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural resolution of the IQCE-EFCAB7-EVC-EVC2 heterotetramer is lacking\",\n        \"Whether SUMO3-dependent regulation of EvC zone targeting is dynamic during Hedgehog signaling is unknown\",\n        \"A mammalian IQCE knockout model has not been reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of the IQCE-EFCAB7-EVC-EVC2 complex, whether IQCE participates in signaling pathways beyond Hedgehog, and whether mouse Iqce knockout recapitulates human polydactyly and broader ciliopathy phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structural data for IQCE or the EvC complex\",\n        \"No mammalian genetic knockout model published\",\n        \"Potential IQCE roles in non-Hedgehog ciliary signaling are unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"complexes\": [\n      \"EFCAB7-IQCE-EVC-EVC2 (EvC complex)\"\n    ],\n    \"partners\": [\n      \"EFCAB7\",\n      \"EVC\",\n      \"EVC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}