{"gene":"IQCE","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2014,"finding":"IQCE forms a complex with EFCAB7 at the base of primary cilia that anchors the EVC-EVC2 heterodimer in a signaling microdomain (the EvC zone). EFCAB7 binds directly to a C-terminal disordered region of EVC2 that is deleted in Weyers syndrome patients. Depletion of IQCE (or EFCAB7) mislocalizes EVC-EVC2 within cilia and impairs activation of the transcription factor GLI2, placing IQCE as a positive regulator of the Hedgehog signaling pathway.","method":"Co-immunoprecipitation, protein depletion (siRNA knockdown), immunofluorescence localization in primary cilia, GLI2 activation assay, evolutionary/bioinformatic analysis","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function with defined cellular phenotype (mislocalization + GLI2 impairment), multiple orthogonal methods, independently confirmed by later studies","pmids":["24582806"],"is_preprint":false},{"year":2019,"finding":"Biallelic pathogenic variants in IQCE dysregulate hedgehog-pathway gene expression (confirmed by RNA expression analysis in patient fibroblasts). Knockdown of IQCE in zebrafish produces a full ciliopathy spectrum: body curvature, kidney cysts, left-right asymmetry defects, misdirected cilia in the pronephric duct, and retinal defects, confirming IQCE's role in cilia structure and function in vivo.","method":"RNA expression analysis in patient-derived fibroblasts; zebrafish morpholino knockdown with phenotypic analysis (body curvature, kidney cysts, laterality, cilia orientation, retinal defects)","journal":"Human Mutation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function in zebrafish with multiple ciliopathy readouts plus patient fibroblast gene-expression data, single lab but multiple orthogonal approaches","pmids":["31549751"],"is_preprint":false},{"year":2017,"finding":"A homozygous splice-acceptor variant (c.395-1G>A) in IQCE causes a -1 frameshift and premature stop codon (p.Gly132Valfs*22), demonstrated by mini-gene splicing assay, establishing that loss-of-function of IQCE underlies autosomal recessive postaxial polydactyly type A restricted to the lower limb in humans.","method":"Exome sequencing, Sanger sequencing for segregation, mini-gene splicing assay","journal":"European Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assay demonstrates molecular consequence of variant; single lab with two orthogonal methods (genetics + splicing assay)","pmids":["28488682"],"is_preprint":false},{"year":2023,"finding":"The EVC-EVC2 complex interactome confirmed IQCE and EFCAB7 as primary endogenous interactors of EVC. SUMO3 modification of EVC-EVC2 cytosolic tails enhances complex accumulation at the EvC zone, likely via increased binding to the EFCAB7-IQCE complex. A second EFCAB7-binding motif within EVC2's Weyers-deleted peptide was mapped, showing that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding sites.","method":"Endogenous EVC protein interactome by mass spectrometry in control and Evc-null cells, ubiquitination assays, SUMOylation assays, immunofluorescence localization","journal":"Frontiers in Cell and Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-confirmed endogenous interactome plus functional PTM assays in a single lab; IQCE/EFCAB7 interaction confirmed but SUMO-binding enhancement to IQCE complex is single-lab","pmids":["37576597"],"is_preprint":false},{"year":2023,"finding":"EFCAB7, the direct binding partner of IQCE, is mutated in families with autosomal recessive nonsyndromic postaxial polydactyly, further confirming that the IQCE-EFCAB7 module is required for Hedgehog pathway activity in limb development. Depletion of either EFCAB7 or IQCE inhibits induction of GLI1, a direct Hh target gene.","method":"Exome sequencing, Sanger sequencing, literature synthesis of GLI1 induction assays from prior work","journal":"European Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic evidence in multiple families corroborates mechanistic model established by Pusapati et al. (2014); GLI1 inhibition data cited from prior studies","pmids":["37684519"],"is_preprint":false},{"year":2005,"finding":"KIAA1023 (IQCE) is expressed strongly in nearly all transformed human cell lines and in a panel of 16 adult human tissues, as demonstrated by RT-PCR, indicating broad constitutive expression consistent with a general cellular role.","method":"Reverse transcription PCR in human cell lines and tissue panel","journal":"Ethnicity & Disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RT-PCR expression survey, no functional readout, single lab","pmids":["16315386"],"is_preprint":false}],"current_model":"IQCE is a ciliary scaffold protein that forms a stable complex with EFCAB7 at the base (EvC zone) of primary cilia; this IQCE-EFCAB7 module tethers the EVC-EVC2 transmembrane heterodimer to the EvC zone, and loss of IQCE mislocalizes EVC-EVC2, impairs GLI2/GLI1 activation, and disrupts Hedgehog signaling, explaining why biallelic loss-of-function variants in IQCE cause autosomal recessive postaxial polydactyly and ciliopathy phenotypes in humans and zebrafish."},"narrative":{"mechanistic_narrative":"IQCE is a primary cilium scaffold protein that functions as a positive regulator of Hedgehog signaling by organizing a signaling microdomain at the ciliary base [PMID:24582806]. It forms a stable complex with EFCAB7 at the base of primary cilia (the EvC zone), and this IQCE-EFCAB7 module anchors the EVC-EVC2 transmembrane heterodimer at this site; depletion of IQCE mislocalizes EVC-EVC2 within cilia and impairs activation of the GLI2/GLI1 transcription factors that execute the Hedgehog response [PMID:24582806, PMID:37684519]. Proteomic characterization of the endogenous EVC interactome confirms IQCE and EFCAB7 as primary EVC interactors and shows that EvC zone targeting depends on two separate EFCAB7-binding motifs in EVC2, with SUMO3 modification of the EVC-EVC2 tails enhancing accumulation at the EvC zone via this complex [PMID:37576597]. Loss of IQCE function disrupts cilia structure and function in vivo, producing a full ciliopathy spectrum in zebrafish including body curvature, kidney cysts, left-right asymmetry defects, and retinal defects [PMID:31549751]. Biallelic loss-of-function variants in IQCE cause autosomal recessive postaxial polydactyly type A in humans, and pathogenic variants dysregulate Hedgehog-pathway gene expression in patient fibroblasts [PMID:31549751, PMID:28488682].","teleology":[{"year":2014,"claim":"Established the core molecular function of IQCE: how the Hedgehog-promoting EVC-EVC2 heterodimer is retained in a discrete ciliary microdomain was unknown, and this work showed IQCE forms a complex with EFCAB7 that anchors EVC-EVC2 at the EvC zone and is required for GLI2 activation.","evidence":"Reciprocal Co-IP, siRNA depletion with ciliary immunofluorescence and GLI2 activation assays in cells","pmids":["24582806"],"confidence":"High","gaps":["No structural model of the IQCE-EFCAB7 interface","Direct IQCE-EFCAB7 binding determinants on IQCE not mapped","Mechanism by which the complex restricts EVC-EVC2 to the EvC zone not resolved at atomic detail"]},{"year":2017,"claim":"Connected IQCE loss-of-function to human disease by demonstrating that a homozygous splice variant produces a frameshift and premature stop, establishing IQCE as a cause of autosomal recessive postaxial polydactyly type A.","evidence":"Exome/Sanger sequencing with segregation and a mini-gene splicing assay","pmids":["28488682"],"confidence":"Medium","gaps":["Single variant in a single family; allelic spectrum not defined","Does not directly link the truncation to ciliary or Hedgehog defects in patient tissue"]},{"year":2019,"claim":"Demonstrated the in vivo requirement for IQCE in cilia, showing that knockdown produces a full ciliopathy spectrum and that patient variants dysregulate Hedgehog-pathway gene expression, extending the cell-based model to organismal phenotypes.","evidence":"Zebrafish morpholino knockdown with multiple ciliopathy readouts and RNA expression analysis in patient fibroblasts","pmids":["31549751"],"confidence":"High","gaps":["Morpholino knockdown lacks genetic mutant confirmation","Which Hedgehog target genes are most directly affected not specified","Tissue-specific basis of the polydactyly versus broader ciliopathy phenotypes unresolved"]},{"year":2023,"claim":"Refined the assembly logic of the EvC zone by confirming IQCE/EFCAB7 as the primary endogenous EVC interactors, mapping a second EFCAB7-binding motif on EVC2, and implicating SUMO3 modification in enhancing complex accumulation.","evidence":"Endogenous EVC interactome by mass spectrometry in control and Evc-null cells, plus ubiquitination/SUMOylation and immunofluorescence assays","pmids":["37576597"],"confidence":"Medium","gaps":["SUMO-dependent enhancement of binding to the IQCE complex shown in a single lab","Direct demonstration that SUMO3 increases IQCE-EFCAB7 binding not established","Role of ubiquitination in the complex not clarified"]},{"year":2023,"claim":"Reinforced the IQCE-EFCAB7 module's role in Hedgehog-dependent limb development by showing that mutations in the direct partner EFCAB7 also cause autosomal recessive postaxial polydactyly, with depletion of either protein inhibiting GLI1 induction.","evidence":"Exome/Sanger sequencing in multiple families with synthesis of prior GLI1 induction data","pmids":["37684519"],"confidence":"Medium","gaps":["GLI1 inhibition data drawn from prior studies rather than newly generated here","Does not separate the individual contributions of IQCE versus EFCAB7 to complex function"]},{"year":null,"claim":"How IQCE's IQ-motif/calmodulin-binding architecture contributes mechanistically to EVC-EVC2 anchoring and whether IQCE has Hedgehog-independent cellular roles remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical dissection of IQCE domains in the corpus","Broad constitutive expression noted but no non-ciliary function characterized","No high-resolution structure of the IQCE-EFCAB7-EVC-EVC2 assembly"]}],"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":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":["IQCE-EFCAB7 module","EVC-EVC2-EFCAB7-IQCE EvC zone complex"],"partners":["EFCAB7","EVC","EVC2"],"other_free_text":[]}},"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 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EFCAB7 binds directly to a C-terminal disordered region of EVC2 that is deleted in Weyers syndrome patients. Depletion of IQCE (or EFCAB7) mislocalizes EVC-EVC2 within cilia and impairs activation of the transcription factor GLI2, placing IQCE as a positive regulator of the Hedgehog signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, protein depletion (siRNA knockdown), immunofluorescence localization in primary cilia, GLI2 activation assay, evolutionary/bioinformatic analysis\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function with defined cellular phenotype (mislocalization + GLI2 impairment), multiple orthogonal methods, independently confirmed by later studies\",\n      \"pmids\": [\"24582806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic pathogenic variants in IQCE dysregulate hedgehog-pathway gene expression (confirmed by RNA expression analysis in patient fibroblasts). Knockdown of IQCE in zebrafish produces a full ciliopathy spectrum: body curvature, kidney cysts, left-right asymmetry defects, misdirected cilia in the pronephric duct, and retinal defects, confirming IQCE's role in cilia structure and function in vivo.\",\n      \"method\": \"RNA expression analysis in patient-derived fibroblasts; zebrafish morpholino knockdown with phenotypic analysis (body curvature, kidney cysts, laterality, cilia orientation, retinal defects)\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function in zebrafish with multiple ciliopathy readouts plus patient fibroblast gene-expression data, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"31549751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous splice-acceptor variant (c.395-1G>A) in IQCE causes a -1 frameshift and premature stop codon (p.Gly132Valfs*22), demonstrated by mini-gene splicing assay, establishing that loss-of-function of IQCE underlies autosomal recessive postaxial polydactyly type A restricted to the lower limb in humans.\",\n      \"method\": \"Exome sequencing, Sanger sequencing for segregation, mini-gene splicing assay\",\n      \"journal\": \"European Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assay demonstrates molecular consequence of variant; single lab with two orthogonal methods (genetics + splicing assay)\",\n      \"pmids\": [\"28488682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The EVC-EVC2 complex interactome confirmed IQCE and EFCAB7 as primary endogenous interactors of EVC. SUMO3 modification of EVC-EVC2 cytosolic tails enhances complex accumulation at the EvC zone, likely via increased binding to the EFCAB7-IQCE complex. A second EFCAB7-binding motif within EVC2's Weyers-deleted peptide was mapped, showing that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding sites.\",\n      \"method\": \"Endogenous EVC protein interactome by mass spectrometry in control and Evc-null cells, ubiquitination assays, SUMOylation assays, immunofluorescence localization\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-confirmed endogenous interactome plus functional PTM assays in a single lab; IQCE/EFCAB7 interaction confirmed but SUMO-binding enhancement to IQCE complex is single-lab\",\n      \"pmids\": [\"37576597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EFCAB7, the direct binding partner of IQCE, is mutated in families with autosomal recessive nonsyndromic postaxial polydactyly, further confirming that the IQCE-EFCAB7 module is required for Hedgehog pathway activity in limb development. Depletion of either EFCAB7 or IQCE inhibits induction of GLI1, a direct Hh target gene.\",\n      \"method\": \"Exome sequencing, Sanger sequencing, literature synthesis of GLI1 induction assays from prior work\",\n      \"journal\": \"European Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic evidence in multiple families corroborates mechanistic model established by Pusapati et al. (2014); GLI1 inhibition data cited from prior studies\",\n      \"pmids\": [\"37684519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KIAA1023 (IQCE) is expressed strongly in nearly all transformed human cell lines and in a panel of 16 adult human tissues, as demonstrated by RT-PCR, indicating broad constitutive expression consistent with a general cellular role.\",\n      \"method\": \"Reverse transcription PCR in human cell lines and tissue panel\",\n      \"journal\": \"Ethnicity & Disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RT-PCR expression survey, no functional readout, single lab\",\n      \"pmids\": [\"16315386\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IQCE is a ciliary scaffold protein that forms a stable complex with EFCAB7 at the base (EvC zone) of primary cilia; this IQCE-EFCAB7 module tethers the EVC-EVC2 transmembrane heterodimer to the EvC zone, and loss of IQCE mislocalizes EVC-EVC2, impairs GLI2/GLI1 activation, and disrupts Hedgehog signaling, explaining why biallelic loss-of-function variants in IQCE cause autosomal recessive postaxial polydactyly and ciliopathy phenotypes in humans and zebrafish.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IQCE is a primary cilium scaffold protein that functions as a positive regulator of Hedgehog signaling by organizing a signaling microdomain at the ciliary base [#0]. It forms a stable complex with EFCAB7 at the base of primary cilia (the EvC zone), and this IQCE-EFCAB7 module anchors the EVC-EVC2 transmembrane heterodimer at this site; depletion of IQCE mislocalizes EVC-EVC2 within cilia and impairs activation of the GLI2/GLI1 transcription factors that execute the Hedgehog response [#0, #4]. Proteomic characterization of the endogenous EVC interactome confirms IQCE and EFCAB7 as primary EVC interactors and shows that EvC zone targeting depends on two separate EFCAB7-binding motifs in EVC2, with SUMO3 modification of the EVC-EVC2 tails enhancing accumulation at the EvC zone via this complex [#3]. Loss of IQCE function disrupts cilia structure and function in vivo, producing a full ciliopathy spectrum in zebrafish including body curvature, kidney cysts, left-right asymmetry defects, and retinal defects [#1]. Biallelic loss-of-function variants in IQCE cause autosomal recessive postaxial polydactyly type A in humans, and pathogenic variants dysregulate Hedgehog-pathway gene expression in patient fibroblasts [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the core molecular function of IQCE: how the Hedgehog-promoting EVC-EVC2 heterodimer is retained in a discrete ciliary microdomain was unknown, and this work showed IQCE forms a complex with EFCAB7 that anchors EVC-EVC2 at the EvC zone and is required for GLI2 activation.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA depletion with ciliary immunofluorescence and GLI2 activation assays in cells\",\n      \"pmids\": [\"24582806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the IQCE-EFCAB7 interface\",\n        \"Direct IQCE-EFCAB7 binding determinants on IQCE not mapped\",\n        \"Mechanism by which the complex restricts EVC-EVC2 to the EvC zone not resolved at atomic detail\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected IQCE loss-of-function to human disease by demonstrating that a homozygous splice variant produces a frameshift and premature stop, establishing IQCE as a cause of autosomal recessive postaxial polydactyly type A.\",\n      \"evidence\": \"Exome/Sanger sequencing with segregation and a mini-gene splicing assay\",\n      \"pmids\": [\"28488682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single variant in a single family; allelic spectrum not defined\",\n        \"Does not directly link the truncation to ciliary or Hedgehog defects in patient tissue\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated the in vivo requirement for IQCE in cilia, showing that knockdown produces a full ciliopathy spectrum and that patient variants dysregulate Hedgehog-pathway gene expression, extending the cell-based model to organismal phenotypes.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with multiple ciliopathy readouts and RNA expression analysis in patient fibroblasts\",\n      \"pmids\": [\"31549751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Morpholino knockdown lacks genetic mutant confirmation\",\n        \"Which Hedgehog target genes are most directly affected not specified\",\n        \"Tissue-specific basis of the polydactyly versus broader ciliopathy phenotypes unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined the assembly logic of the EvC zone by confirming IQCE/EFCAB7 as the primary endogenous EVC interactors, mapping a second EFCAB7-binding motif on EVC2, and implicating SUMO3 modification in enhancing complex accumulation.\",\n      \"evidence\": \"Endogenous EVC interactome by mass spectrometry in control and Evc-null cells, plus ubiquitination/SUMOylation and immunofluorescence assays\",\n      \"pmids\": [\"37576597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"SUMO-dependent enhancement of binding to the IQCE complex shown in a single lab\",\n        \"Direct demonstration that SUMO3 increases IQCE-EFCAB7 binding not established\",\n        \"Role of ubiquitination in the complex not clarified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reinforced the IQCE-EFCAB7 module's role in Hedgehog-dependent limb development by showing that mutations in the direct partner EFCAB7 also cause autosomal recessive postaxial polydactyly, with depletion of either protein inhibiting GLI1 induction.\",\n      \"evidence\": \"Exome/Sanger sequencing in multiple families with synthesis of prior GLI1 induction data\",\n      \"pmids\": [\"37684519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"GLI1 inhibition data drawn from prior studies rather than newly generated here\",\n        \"Does not separate the individual contributions of IQCE versus EFCAB7 to complex function\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IQCE's IQ-motif/calmodulin-binding architecture contributes mechanistically to EVC-EVC2 anchoring and whether IQCE has Hedgehog-independent cellular roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical dissection of IQCE domains in the corpus\",\n        \"Broad constitutive expression noted but no non-ciliary function characterized\",\n        \"No high-resolution structure of the IQCE-EFCAB7-EVC-EVC2 assembly\"\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, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"IQCE-EFCAB7 module\", \"EVC-EVC2-EFCAB7-IQCE EvC zone complex\"],\n    \"partners\": [\"EFCAB7\", \"EVC\", \"EVC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}