{"gene":"TTC7A","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2014,"finding":"TTC7A deficiency results in increased Rho kinase (ROCK) activity, which disrupts apicobasal polarity of intestinal epithelial cells. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity that was normalized by pharmacological inhibition of Rho kinase.","method":"Intestinal organoid cultures from patient biopsies + pharmacological ROCK inhibition rescue experiment","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived organoid model with pharmacological rescue demonstrating direct pathway link; independently consistent with multiple patient cohorts","pmids":["24292712"],"is_preprint":false},{"year":2013,"finding":"TTC7A protein is expressed in thymic epithelial cells and thymocytes, as demonstrated by immunostaining of normal thymus tissue.","method":"Immunostaining/immunohistochemistry of normal thymus","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment replicated across two independent cohort studies","pmids":["23830146","25546680"],"is_preprint":false},{"year":2014,"finding":"TTC7A protein is expressed in the cytoplasm of epithelial cells of the intestine, thymus, and pancreas, as demonstrated by immunostaining in multiple organs from control and patient samples.","method":"Immunohistochemistry/immunostaining of multiple organ biopsies and autopsies","journal":"Medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunostaining in multiple organ types, replicated across two studies","pmids":["25546680","23830146"],"is_preprint":false},{"year":2018,"finding":"PI4KIIIα forms a large heterotrimeric complex with TTC7 and FAM126, and the full-length PI4KIIIα/TTC7/FAM126 complex assembles as an overall dimer of trimers. HDX-MS revealed conformational changes in TTC7/FAM126 upon binding PI4KIIIα, including at the direct TTC7-PI4KIIIα interface and at the putative membrane-binding surface.","method":"Negative stain electron microscopy and hydrogen-deuterium exchange mass spectrometry (HDX-MS) of reconstituted complex","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural EM plus HDX-MS with reconstituted complex providing multiple orthogonal methods to define architecture and interface","pmids":["30031006"],"is_preprint":false},{"year":2019,"finding":"TTC7A-knockout (TTC7A-KO) cells have increased activity of caspases 3 and 7, reduced levels of phosphorylated AKT and XIAP, leading to increased apoptosis. Leflunomide treatment increased phosphorylated AKT and XIAP levels and reduced cleaved caspase 3, identifying PI3K/AKT as a downstream pathway regulated by TTC7A.","method":"Immunoblots in TTC7A-KO HAP1 cells and HeLa cells stably expressing mutant TTC7A; high-throughput drug screen; zebrafish ttc7a-/- model; patient-derived colonoids","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (immunoblot, KO cell line, zebrafish model, patient organoids) consistently demonstrating AKT/XIAP pathway regulation","pmids":["31743734"],"is_preprint":false},{"year":2020,"finding":"UBR5 (E3 ubiquitin ligase) co-immunoprecipitates with TTC7A, identifying UBR5 as a binding partner of TTC7A. Patient-derived UBR5 variants showed reduced interaction with TTC7A, implicating UBR5 in regulating TTC7A signaling.","method":"Co-immunoprecipitation (Co-IP) of UBR5 and TTC7A; functional interaction assay with patient variants","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment from one lab without reciprocal pulldown or orthogonal validation","pmids":["33122718"],"is_preprint":false},{"year":2019,"finding":"Ttc7a acts as an intrinsic regulator of proliferative response and self-renewal potential of murine hematopoietic stem cells (HSC) in vivo. Loss of Ttc7a enhanced competitive repopulating ability and increased proliferation in response to stress. This role is related, at least in part, to regulation of the endoplasmic reticulum stress response, as Ttc7a-deficient HSC exhibited altered transcriptomic profiles for genes controlling cellular stress response.","method":"In vivo competitive repopulation assays; serial cell transplantations; chemically-induced stress in vitro; myeloablative stress in vivo; transcriptomic profiling","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined cellular phenotype and transcriptomic pathway identification; single lab","pmids":["31004027"],"is_preprint":false},{"year":2023,"finding":"TTC7A-deficient lymphocytes exhibit altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A deficiency impairs phosphoinositide signaling, leading to downregulation of the PI3K/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamics, resulting in impaired cell motility, accumulation of DNA damage, and increased cell death under confinement.","method":"Microfabricated confinement devices for single-cell migration; actin dynamics imaging; murine and patient-derived leukocytes","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct mechanistic dissection using microfabricated devices with both murine KO and patient-derived cells, multiple orthogonal readouts (migration, actin dynamics, DNA damage, cell death)","pmids":["37390900"],"is_preprint":false},{"year":2018,"finding":"Ttc7-mutated mouse fibroblasts expressed increased transcript levels of IGF1 and antimicrobial protein Reg3γ, and in a xenograft model, Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes, identifying a cell-extrinsic role of Ttc7 in driving epithelial hyperproliferation. The severity of epithelial hyperproliferation was accentuated by lymphocytes, but lymphocytes were not required to initiate the phenotype.","method":"Bone marrow chimeras; double and triple mutant mice (Rag2-/- Ttc7fsn/fsn; Rag2-/- IL2rg-/- Ttc7fsn/fsn); xenograft model with Ttc7-mutated fibroblasts; transcriptomic analysis","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via multiple mutant mouse lines, xenograft model, and transcriptomics with clear mechanistic conclusion about cell-extrinsic fibroblast role","pmids":["29775636"],"is_preprint":false},{"year":2018,"finding":"Genetic downregulation of Drosophila TTC7 (ortholog) reduces neuronal Aβ42 accumulation and associated synaptic and motor defects in Aβ42-expressing flies, while overexpression of TTC7 produces the opposite effect. This places TTC7 in the RBO/Efr3-PI4KIIIα/Hyccin complex that controls plasmalemmal phosphatidylinositol-4-phosphate levels.","method":"Genetic manipulation (overexpression and knockdown) in Drosophila Aβ42 model; behavioral and synaptic phenotype assays","journal":"Journal of Alzheimer's disease : JAD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain- and loss-of-function in Drosophila ortholog with multiple phenotypic readouts; single lab, non-mammalian model","pmids":["30103315"],"is_preprint":false},{"year":2021,"finding":"A homozygous TTC7A missense mutation (L69P) led to reduced TTC7A expression in lymphocytes and intestinal tissues, accompanied by impeded lymphocyte development. Colon tissue from the patient showed impairment of the PI4K-FAM126A-EFR3A pathway, experimentally linking this specific mutation to disruption of the PI4KIIIα complex.","method":"Whole exome sequencing; in silico structural analysis; immunostaining; pathway analysis of patient colon tissues","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway analysis in patient tissue, single case, limited functional follow-up","pmids":["34975848"],"is_preprint":false},{"year":2025,"finding":"TTC7A trafficking and localization to the plasma membrane is required for directionally specifying the apical membrane. TTC7A functions as a molecular chaperone for Class II phosphatidylinositol 3-kinase PIK3C2A and is trafficked in Rab11a-positive vesicles to generate phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). Defective lumen formation caused by TTC7A loss-of-function could be rescued by exogenous PI(3,4)P2 or small molecules modulating phosphoinositide homeostasis.","method":"Patient-derived organoids; TTC7A localization imaging; PIK3C2A co-chaperone assays; Rab11a vesicle trafficking experiments; PI(3,4)P2 rescue experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in patient-derived organoids with functional rescue; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.03.22.644724"],"is_preprint":true},{"year":2025,"finding":"EFR3A and EFR3B interact with TTC7A (and TTC7B) and FAM126 to recruit PI4KIIIα to the plasma membrane. Most EFR3-TTC7-FAM126 combinations show similar binding affinities. EFR3B phosphorylation markedly decreased binding to TTC7-FAM126. A TTC7B-selective nanobody that blocks EFR3 binding caused decreased membrane recruitment and decreased PM production of PI4P, validating EFR3 recruitment as the mechanism for TTC7A-complex membrane targeting.","method":"Biochemical binding assays; cryo-EM; HDX-MS; yeast display nanobody isolation; lipid bilayer and cell-based PI4P production assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM and HDX-MS with functional validation in cells; preprint not yet peer-reviewed, multiple orthogonal methods","pmids":["bio_10.1101_2025.07.28.667261"],"is_preprint":true},{"year":2005,"finding":"Positional cloning identified Ttc7 as the gene mutated in hea (hereditary erythroblastic anemia) and fsn (flaky skin) allelic anemia mouse mutants; hea mice carry a deletion in Ttc7 extending from exon 1 to exon 14, and fsn mice carry an ETn retrotransposon integration into intron 14 causing abnormal Ttc7 RNA transcript, establishing Ttc7 as required for normal iron homeostasis.","method":"Positional cloning; large backcross mapping; RT-PCR; sequencing of mutant alleles","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — positional cloning with two independent alleles validating gene identity; functional consequence established by KO-equivalent alleles","pmids":["15718100"],"is_preprint":false},{"year":2025,"finding":"Different TTC7A missense variants produce distinct molecular phenotypes in TTC7A knockout Caco-2 intestinal epithelial cells, including variant-specific alterations in RNA expression profiles, TTC7A protein abundance, and endoplasmic reticulum (ER) stress. Five of 11 variants showed molecular phenotypes; the TTC7AE71K variant displayed a unique expression profile with reduced TTC7A RNA and protein expression distinct from all other variants.","method":"TTC7A-KO Caco-2 cell reconstitution with individual variants; RNA sequencing; imaging flow cytometry for ER stress; protein abundance measurements","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic cellular reconstitution with 11 variants using multiple orthogonal assays; single lab","pmids":["39675053"],"is_preprint":false}],"current_model":"TTC7A is a scaffold/chaperone protein that forms a heterotrimeric complex with PI4KIIIα and FAM126 (recruited to the plasma membrane via EFR3A/B) to generate phosphatidylinositol-4-phosphate (PI4P) at the plasma membrane; it also acts as a molecular chaperone for PIK3C2A (Class II PI3K) in Rab11a vesicles to generate PI(3,4)P2 required for apical membrane specification, and its loss disrupts intestinal epithelial apicobasal polarity through increased ROCK activity, impairs lymphocyte migration through downregulation of the PI3K/AKT/RHOA/actin axis, and regulates hematopoietic stem cell self-renewal through the endoplasmic reticulum stress response."},"narrative":{"mechanistic_narrative":"TTC7A is a cytoplasmic scaffold/chaperone that controls phosphoinositide signaling and epithelial polarity across the intestine, thymus, and hematopoietic system [PMID:25546680, PMID:23830146, PMID:31743734]. It assembles into a heterotrimeric complex with PI4KIIIα and FAM126 that dimerizes into a dimer-of-trimers, with TTC7 contacting both PI4KIIIα and a putative membrane-binding surface [PMID:30031006]; this complex is recruited to the plasma membrane through interaction with EFR3A/EFR3B, where it generates plasma-membrane PI4P, a step that can be blocked by a nanobody disrupting EFR3 binding [PMID:bio_10.1101_2025.07.28.667261]. Beyond the PI4KIIIα complex, TTC7A acts as a molecular chaperone for the Class II PI3K PIK3C2A and traffics in Rab11a-positive vesicles to generate PI(3,4)P2 required for apical membrane specification, and TTC7A loss-of-function lumen defects are rescued by exogenous PI(3,4)P2 [PMID:bio_10.1101_2025.03.22.644724]. Through these phosphoinositide functions, TTC7A maintains intestinal epithelial apicobasal polarity by restraining ROCK activity [PMID:24292712], sustains the PI3K/AKT/XIAP survival pathway to limit caspase-mediated apoptosis [PMID:31743734], and supports lymphocyte migration via the PI3K/AKT/RHOA/actin axis [PMID:37390900]. TTC7A additionally restrains hematopoietic stem cell proliferation and self-renewal in part through regulation of the ER stress response [PMID:31004027], and exerts a cell-extrinsic role in which mutant fibroblasts drive epithelial hyperproliferation [PMID:29775636]. Human TTC7A mutations disrupt the PI4K-FAM126A-EFR3A pathway and produce variant-specific molecular phenotypes including altered TTC7A abundance and ER stress [PMID:34975848, PMID:39675053].","teleology":[{"year":2005,"claim":"Established Ttc7 as a genetically defined locus with an organismal phenotype, providing the first link between the gene and a defined biological process.","evidence":"Positional cloning of two allelic anemia mouse mutants (hea and fsn) with deletion and retrotransposon-disrupting alleles","pmids":["15718100"],"confidence":"Medium","gaps":["No molecular mechanism connecting Ttc7 loss to iron homeostasis","No protein-level or pathway characterization"]},{"year":2014,"claim":"Connected TTC7A deficiency to a specific cellular defect by showing it controls intestinal epithelial apicobasal polarity, and identified ROCK as the actionable downstream effector.","evidence":"Patient-derived intestinal organoids with pharmacological ROCK inhibition rescue","pmids":["24292712"],"confidence":"High","gaps":["How TTC7A loss elevates ROCK activity at the molecular level not defined","Link to phosphoinositide signaling not yet established"]},{"year":2018,"claim":"Resolved the molecular architecture of the TTC7-containing complex, showing how TTC7 engages PI4KIIIα and FAM126 and undergoes conformational change at the membrane-binding surface.","evidence":"Negative-stain EM and HDX-MS of reconstituted PI4KIIIα/TTC7/FAM126 complex","pmids":["30031006"],"confidence":"High","gaps":["Membrane recruitment mechanism not resolved in this study","Functional consequence of dimer-of-trimers assembly unclear"]},{"year":2018,"claim":"Demonstrated a cell-extrinsic mechanism whereby Ttc7-mutant fibroblasts drive epithelial hyperproliferation independent of lymphocytes, expanding TTC7 function beyond the epithelium itself.","evidence":"Bone marrow chimeras, compound mutant mice, fibroblast xenografts, and transcriptomics","pmids":["29775636"],"confidence":"High","gaps":["Molecular trigger for IGF1/Reg3γ induction in mutant fibroblasts unknown","Relationship to phosphoinositide pathway not addressed"]},{"year":2019,"claim":"Identified the PI3K/AKT/XIAP survival pathway as downstream of TTC7A and revealed a druggable apoptosis phenotype.","evidence":"Immunoblots in TTC7A-KO HAP1 and mutant HeLa cells, drug screen, zebrafish model, and patient colonoids","pmids":["31743734"],"confidence":"High","gaps":["Direct biochemical link between TTC7A and AKT phosphorylation not established","Mechanism of leflunomide rescue unclear"]},{"year":2019,"claim":"Extended TTC7A function to hematopoietic stem cell self-renewal, implicating the ER stress response as a regulatory node.","evidence":"In vivo competitive repopulation and serial transplantation of Ttc7a-deficient murine HSCs with transcriptomic profiling","pmids":["31004027"],"confidence":"Medium","gaps":["Mechanistic link between TTC7A and ER stress effectors not defined","Single lab"]},{"year":2020,"claim":"Identified UBR5 as a candidate physical partner regulating TTC7A signaling.","evidence":"Co-immunoprecipitation of UBR5 and TTC7A with patient-variant interaction assays","pmids":["33122718"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal pulldown or orthogonal validation","Functional consequence of UBR5-TTC7A interaction undefined"]},{"year":2021,"claim":"Linked a specific human missense mutation to disruption of the PI4K-FAM126A-EFR3A pathway in patient tissue.","evidence":"Whole exome sequencing, structural modeling, and pathway analysis of patient colon and lymphocytes (L69P)","pmids":["34975848"],"confidence":"Low","gaps":["Pathway disruption inferred from single patient tissue without functional reconstitution","Causality of L69P not experimentally isolated"]},{"year":2023,"claim":"Dissected how TTC7A loss impairs immune cell function by linking phosphoinositide signaling to the PI3K/AKT/RHOA/actin axis governing confined migration.","evidence":"Microfabricated confinement devices, actin imaging, and DNA-damage/death readouts in murine KO and patient leukocytes","pmids":["37390900"],"confidence":"High","gaps":["Which phosphoinositide species directly drives the migration defect not pinpointed","Connection to plasma-membrane PI4P generation not directly tested"]},{"year":2025,"claim":"Revealed a second phosphoinositide function of TTC7A as a chaperone for PIK3C2A generating PI(3,4)P2 in Rab11a vesicles to specify the apical membrane, with rescue by exogenous PI(3,4)P2.","evidence":"Patient-derived organoids, PIK3C2A co-chaperone assays, Rab11a trafficking, and PI(3,4)P2 rescue (preprint)","pmids":["bio_10.1101_2025.03.22.644724"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How TTC7A partitions between PI4KIIIα and PIK3C2A complexes unknown"]},{"year":2025,"claim":"Established EFR3A/EFR3B as the membrane-recruitment mechanism for the TTC7-FAM126 module and validated it functionally with a binding-blocking nanobody.","evidence":"Biochemical binding assays, cryo-EM, HDX-MS, nanobody isolation, and lipid/cell PI4P production assays (preprint)","pmids":["bio_10.1101_2025.07.28.667261"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Physiological regulation by EFR3B phosphorylation not tested in vivo"]},{"year":2025,"claim":"Systematically resolved that distinct TTC7A missense variants produce divergent molecular phenotypes, including variant-specific ER stress and protein abundance changes.","evidence":"Reconstitution of 11 variants in TTC7A-KO Caco-2 cells with RNA-seq, ER stress imaging, and protein abundance measurements","pmids":["39675053"],"confidence":"Medium","gaps":["Genotype-phenotype rules not generalized beyond tested variants","Mechanistic basis for variant-specific ER stress not resolved"]},{"year":null,"claim":"How TTC7A coordinates its dual roles in the PI4KIIIα/FAM126 plasma-membrane complex versus the PIK3C2A/Rab11a apical-specification pathway, and how these integrate to produce tissue-specific phenotypes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of how TTC7A is allocated between distinct phosphoinositide complexes","Direct enzymatic or structural basis for chaperoning PIK3C2A not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,11]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,14]}],"complexes":["PI4KIIIα/TTC7/FAM126 complex"],"partners":["PI4KA","FAM126A","EFR3A","EFR3B","PIK3C2A","RAB11A","UBR5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULT0","full_name":"Tetratricopeptide repeat protein 7A","aliases":[],"length_aa":858,"mass_kda":96.2,"function":"Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:23229899, PubMed:24417819). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (Probable). In the complex, plays a central role in bridging PI4KA to EFR3B and HYCC1, via direct interactions (By similarity)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULT0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TTC7A","classification":"Not Classified","n_dependent_lines":150,"n_total_lines":1208,"dependency_fraction":0.12417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PI4KA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TTC7A","total_profiled":1310},"omim":[{"mim_id":"619708","title":"GASTROINTESTINAL DEFECTS AND IMMUNODEFICIENCY SYNDROME 2; GIDID2","url":"https://www.omim.org/entry/619708"},{"mim_id":"609332","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 7A; TTC7A","url":"https://www.omim.org/entry/609332"},{"mim_id":"600286","title":"PHOSPHATIDYLINOSITOL 4-KINASE, ALPHA; PI4KA","url":"https://www.omim.org/entry/600286"},{"mim_id":"243150","title":"GASTROINTESTINAL DEFECTS AND IMMUNODEFICIENCY SYNDROME 1; GIDID1","url":"https://www.omim.org/entry/243150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":38.0}],"url":"https://www.proteinatlas.org/search/TTC7A"},"hgnc":{"alias_symbol":["KIAA1140"],"prev_symbol":["TTC7"]},"alphafold":{"accession":"Q9ULT0","domains":[{"cath_id":"1.25.40.10","chopping":"704-854","consensus_level":"medium","plddt":93.8596,"start":704,"end":854}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULT0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULT0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULT0-F1-predicted_aligned_error_v6.png","plddt_mean":84.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TTC7A","jax_strain_url":"https://www.jax.org/strain/search?query=TTC7A"},"sequence":{"accession":"Q9ULT0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULT0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULT0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULT0"}},"corpus_meta":[{"pmid":"24292712","id":"PMC_24292712","title":"TTC7A mutations disrupt intestinal epithelial apicobasal polarity.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24292712","citation_count":151,"is_preprint":false},{"pmid":"23830146","id":"PMC_23830146","title":"Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.","date":"2013","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23830146","citation_count":119,"is_preprint":false},{"pmid":"23423984","id":"PMC_23423984","title":"Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia.","date":"2013","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23423984","citation_count":94,"is_preprint":false},{"pmid":"31743734","id":"PMC_31743734","title":"Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency.","date":"2019","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31743734","citation_count":52,"is_preprint":false},{"pmid":"30031006","id":"PMC_30031006","title":"Probing the Architecture, Dynamics, and Inhibition of the PI4KIIIα/TTC7/FAM126 Complex.","date":"2018","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30031006","citation_count":38,"is_preprint":false},{"pmid":"25546680","id":"PMC_25546680","title":"Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort.","date":"2014","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25546680","citation_count":36,"is_preprint":false},{"pmid":"24931897","id":"PMC_24931897","title":"Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined 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with early inflammatory bowel disease: Two new case reports and a literature review.","date":"2018","source":"Archives de pediatrie : organe officiel de la Societe francaise de pediatrie","url":"https://pubmed.ncbi.nlm.nih.gov/29921470","citation_count":11,"is_preprint":false},{"pmid":"33122718","id":"PMC_33122718","title":"The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33122718","citation_count":9,"is_preprint":false},{"pmid":"37390900","id":"PMC_37390900","title":"Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement.","date":"2023","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37390900","citation_count":8,"is_preprint":false},{"pmid":"29775636","id":"PMC_29775636","title":"Epithelial proliferation in inflammatory skin disease is 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Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity that was normalized by pharmacological inhibition of Rho kinase.\",\n      \"method\": \"Intestinal organoid cultures from patient biopsies + pharmacological ROCK inhibition rescue experiment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived organoid model with pharmacological rescue demonstrating direct pathway link; independently consistent with multiple patient cohorts\",\n      \"pmids\": [\"24292712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TTC7A protein is expressed in thymic epithelial cells and thymocytes, as demonstrated by immunostaining of normal thymus tissue.\",\n      \"method\": \"Immunostaining/immunohistochemistry of normal thymus\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment replicated across two independent cohort studies\",\n      \"pmids\": [\"23830146\", \"25546680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TTC7A protein is expressed in the cytoplasm of epithelial cells of the intestine, thymus, and pancreas, as demonstrated by immunostaining in multiple organs from control and patient samples.\",\n      \"method\": \"Immunohistochemistry/immunostaining of multiple organ biopsies and autopsies\",\n      \"journal\": \"Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunostaining in multiple organ types, replicated across two studies\",\n      \"pmids\": [\"25546680\", \"23830146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PI4KIIIα forms a large heterotrimeric complex with TTC7 and FAM126, and the full-length PI4KIIIα/TTC7/FAM126 complex assembles as an overall dimer of trimers. HDX-MS revealed conformational changes in TTC7/FAM126 upon binding PI4KIIIα, including at the direct TTC7-PI4KIIIα interface and at the putative membrane-binding surface.\",\n      \"method\": \"Negative stain electron microscopy and hydrogen-deuterium exchange mass spectrometry (HDX-MS) of reconstituted complex\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural EM plus HDX-MS with reconstituted complex providing multiple orthogonal methods to define architecture and interface\",\n      \"pmids\": [\"30031006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TTC7A-knockout (TTC7A-KO) cells have increased activity of caspases 3 and 7, reduced levels of phosphorylated AKT and XIAP, leading to increased apoptosis. Leflunomide treatment increased phosphorylated AKT and XIAP levels and reduced cleaved caspase 3, identifying PI3K/AKT as a downstream pathway regulated by TTC7A.\",\n      \"method\": \"Immunoblots in TTC7A-KO HAP1 cells and HeLa cells stably expressing mutant TTC7A; high-throughput drug screen; zebrafish ttc7a-/- model; patient-derived colonoids\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (immunoblot, KO cell line, zebrafish model, patient organoids) consistently demonstrating AKT/XIAP pathway regulation\",\n      \"pmids\": [\"31743734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBR5 (E3 ubiquitin ligase) co-immunoprecipitates with TTC7A, identifying UBR5 as a binding partner of TTC7A. Patient-derived UBR5 variants showed reduced interaction with TTC7A, implicating UBR5 in regulating TTC7A signaling.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) of UBR5 and TTC7A; functional interaction assay with patient variants\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment from one lab without reciprocal pulldown or orthogonal validation\",\n      \"pmids\": [\"33122718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ttc7a acts as an intrinsic regulator of proliferative response and self-renewal potential of murine hematopoietic stem cells (HSC) in vivo. Loss of Ttc7a enhanced competitive repopulating ability and increased proliferation in response to stress. This role is related, at least in part, to regulation of the endoplasmic reticulum stress response, as Ttc7a-deficient HSC exhibited altered transcriptomic profiles for genes controlling cellular stress response.\",\n      \"method\": \"In vivo competitive repopulation assays; serial cell transplantations; chemically-induced stress in vitro; myeloablative stress in vivo; transcriptomic profiling\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined cellular phenotype and transcriptomic pathway identification; single lab\",\n      \"pmids\": [\"31004027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TTC7A-deficient lymphocytes exhibit altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A deficiency impairs phosphoinositide signaling, leading to downregulation of the PI3K/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamics, resulting in impaired cell motility, accumulation of DNA damage, and increased cell death under confinement.\",\n      \"method\": \"Microfabricated confinement devices for single-cell migration; actin dynamics imaging; murine and patient-derived leukocytes\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct mechanistic dissection using microfabricated devices with both murine KO and patient-derived cells, multiple orthogonal readouts (migration, actin dynamics, DNA damage, cell death)\",\n      \"pmids\": [\"37390900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ttc7-mutated mouse fibroblasts expressed increased transcript levels of IGF1 and antimicrobial protein Reg3γ, and in a xenograft model, Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes, identifying a cell-extrinsic role of Ttc7 in driving epithelial hyperproliferation. The severity of epithelial hyperproliferation was accentuated by lymphocytes, but lymphocytes were not required to initiate the phenotype.\",\n      \"method\": \"Bone marrow chimeras; double and triple mutant mice (Rag2-/- Ttc7fsn/fsn; Rag2-/- IL2rg-/- Ttc7fsn/fsn); xenograft model with Ttc7-mutated fibroblasts; transcriptomic analysis\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via multiple mutant mouse lines, xenograft model, and transcriptomics with clear mechanistic conclusion about cell-extrinsic fibroblast role\",\n      \"pmids\": [\"29775636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Genetic downregulation of Drosophila TTC7 (ortholog) reduces neuronal Aβ42 accumulation and associated synaptic and motor defects in Aβ42-expressing flies, while overexpression of TTC7 produces the opposite effect. This places TTC7 in the RBO/Efr3-PI4KIIIα/Hyccin complex that controls plasmalemmal phosphatidylinositol-4-phosphate levels.\",\n      \"method\": \"Genetic manipulation (overexpression and knockdown) in Drosophila Aβ42 model; behavioral and synaptic phenotype assays\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain- and loss-of-function in Drosophila ortholog with multiple phenotypic readouts; single lab, non-mammalian model\",\n      \"pmids\": [\"30103315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A homozygous TTC7A missense mutation (L69P) led to reduced TTC7A expression in lymphocytes and intestinal tissues, accompanied by impeded lymphocyte development. Colon tissue from the patient showed impairment of the PI4K-FAM126A-EFR3A pathway, experimentally linking this specific mutation to disruption of the PI4KIIIα complex.\",\n      \"method\": \"Whole exome sequencing; in silico structural analysis; immunostaining; pathway analysis of patient colon tissues\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway analysis in patient tissue, single case, limited functional follow-up\",\n      \"pmids\": [\"34975848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TTC7A trafficking and localization to the plasma membrane is required for directionally specifying the apical membrane. TTC7A functions as a molecular chaperone for Class II phosphatidylinositol 3-kinase PIK3C2A and is trafficked in Rab11a-positive vesicles to generate phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). Defective lumen formation caused by TTC7A loss-of-function could be rescued by exogenous PI(3,4)P2 or small molecules modulating phosphoinositide homeostasis.\",\n      \"method\": \"Patient-derived organoids; TTC7A localization imaging; PIK3C2A co-chaperone assays; Rab11a vesicle trafficking experiments; PI(3,4)P2 rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in patient-derived organoids with functional rescue; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.22.644724\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EFR3A and EFR3B interact with TTC7A (and TTC7B) and FAM126 to recruit PI4KIIIα to the plasma membrane. Most EFR3-TTC7-FAM126 combinations show similar binding affinities. EFR3B phosphorylation markedly decreased binding to TTC7-FAM126. A TTC7B-selective nanobody that blocks EFR3 binding caused decreased membrane recruitment and decreased PM production of PI4P, validating EFR3 recruitment as the mechanism for TTC7A-complex membrane targeting.\",\n      \"method\": \"Biochemical binding assays; cryo-EM; HDX-MS; yeast display nanobody isolation; lipid bilayer and cell-based PI4P production assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM and HDX-MS with functional validation in cells; preprint not yet peer-reviewed, multiple orthogonal methods\",\n      \"pmids\": [\"bio_10.1101_2025.07.28.667261\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Positional cloning identified Ttc7 as the gene mutated in hea (hereditary erythroblastic anemia) and fsn (flaky skin) allelic anemia mouse mutants; hea mice carry a deletion in Ttc7 extending from exon 1 to exon 14, and fsn mice carry an ETn retrotransposon integration into intron 14 causing abnormal Ttc7 RNA transcript, establishing Ttc7 as required for normal iron homeostasis.\",\n      \"method\": \"Positional cloning; large backcross mapping; RT-PCR; sequencing of mutant alleles\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — positional cloning with two independent alleles validating gene identity; functional consequence established by KO-equivalent alleles\",\n      \"pmids\": [\"15718100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Different TTC7A missense variants produce distinct molecular phenotypes in TTC7A knockout Caco-2 intestinal epithelial cells, including variant-specific alterations in RNA expression profiles, TTC7A protein abundance, and endoplasmic reticulum (ER) stress. Five of 11 variants showed molecular phenotypes; the TTC7AE71K variant displayed a unique expression profile with reduced TTC7A RNA and protein expression distinct from all other variants.\",\n      \"method\": \"TTC7A-KO Caco-2 cell reconstitution with individual variants; RNA sequencing; imaging flow cytometry for ER stress; protein abundance measurements\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic cellular reconstitution with 11 variants using multiple orthogonal assays; single lab\",\n      \"pmids\": [\"39675053\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TTC7A is a scaffold/chaperone protein that forms a heterotrimeric complex with PI4KIIIα and FAM126 (recruited to the plasma membrane via EFR3A/B) to generate phosphatidylinositol-4-phosphate (PI4P) at the plasma membrane; it also acts as a molecular chaperone for PIK3C2A (Class II PI3K) in Rab11a vesicles to generate PI(3,4)P2 required for apical membrane specification, and its loss disrupts intestinal epithelial apicobasal polarity through increased ROCK activity, impairs lymphocyte migration through downregulation of the PI3K/AKT/RHOA/actin axis, and regulates hematopoietic stem cell self-renewal through the endoplasmic reticulum stress response.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TTC7A is a cytoplasmic scaffold/chaperone that controls phosphoinositide signaling and epithelial polarity across the intestine, thymus, and hematopoietic system [#2, #4]. It assembles into a heterotrimeric complex with PI4KIIIα and FAM126 that dimerizes into a dimer-of-trimers, with TTC7 contacting both PI4KIIIα and a putative membrane-binding surface [#3]; this complex is recruited to the plasma membrane through interaction with EFR3A/EFR3B, where it generates plasma-membrane PI4P, a step that can be blocked by a nanobody disrupting EFR3 binding [#12]. Beyond the PI4KIIIα complex, TTC7A acts as a molecular chaperone for the Class II PI3K PIK3C2A and traffics in Rab11a-positive vesicles to generate PI(3,4)P2 required for apical membrane specification, and TTC7A loss-of-function lumen defects are rescued by exogenous PI(3,4)P2 [#11]. Through these phosphoinositide functions, TTC7A maintains intestinal epithelial apicobasal polarity by restraining ROCK activity [#0], sustains the PI3K/AKT/XIAP survival pathway to limit caspase-mediated apoptosis [#4], and supports lymphocyte migration via the PI3K/AKT/RHOA/actin axis [#7]. TTC7A additionally restrains hematopoietic stem cell proliferation and self-renewal in part through regulation of the ER stress response [#6], and exerts a cell-extrinsic role in which mutant fibroblasts drive epithelial hyperproliferation [#8]. Human TTC7A mutations disrupt the PI4K-FAM126A-EFR3A pathway and produce variant-specific molecular phenotypes including altered TTC7A abundance and ER stress [#10, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established Ttc7 as a genetically defined locus with an organismal phenotype, providing the first link between the gene and a defined biological process.\",\n      \"evidence\": \"Positional cloning of two allelic anemia mouse mutants (hea and fsn) with deletion and retrotransposon-disrupting alleles\",\n      \"pmids\": [\"15718100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism connecting Ttc7 loss to iron homeostasis\", \"No protein-level or pathway characterization\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected TTC7A deficiency to a specific cellular defect by showing it controls intestinal epithelial apicobasal polarity, and identified ROCK as the actionable downstream effector.\",\n      \"evidence\": \"Patient-derived intestinal organoids with pharmacological ROCK inhibition rescue\",\n      \"pmids\": [\"24292712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TTC7A loss elevates ROCK activity at the molecular level not defined\", \"Link to phosphoinositide signaling not yet established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the molecular architecture of the TTC7-containing complex, showing how TTC7 engages PI4KIIIα and FAM126 and undergoes conformational change at the membrane-binding surface.\",\n      \"evidence\": \"Negative-stain EM and HDX-MS of reconstituted PI4KIIIα/TTC7/FAM126 complex\",\n      \"pmids\": [\"30031006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane recruitment mechanism not resolved in this study\", \"Functional consequence of dimer-of-trimers assembly unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a cell-extrinsic mechanism whereby Ttc7-mutant fibroblasts drive epithelial hyperproliferation independent of lymphocytes, expanding TTC7 function beyond the epithelium itself.\",\n      \"evidence\": \"Bone marrow chimeras, compound mutant mice, fibroblast xenografts, and transcriptomics\",\n      \"pmids\": [\"29775636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger for IGF1/Reg3γ induction in mutant fibroblasts unknown\", \"Relationship to phosphoinositide pathway not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the PI3K/AKT/XIAP survival pathway as downstream of TTC7A and revealed a druggable apoptosis phenotype.\",\n      \"evidence\": \"Immunoblots in TTC7A-KO HAP1 and mutant HeLa cells, drug screen, zebrafish model, and patient colonoids\",\n      \"pmids\": [\"31743734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between TTC7A and AKT phosphorylation not established\", \"Mechanism of leflunomide rescue unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TTC7A function to hematopoietic stem cell self-renewal, implicating the ER stress response as a regulatory node.\",\n      \"evidence\": \"In vivo competitive repopulation and serial transplantation of Ttc7a-deficient murine HSCs with transcriptomic profiling\",\n      \"pmids\": [\"31004027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between TTC7A and ER stress effectors not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified UBR5 as a candidate physical partner regulating TTC7A signaling.\",\n      \"evidence\": \"Co-immunoprecipitation of UBR5 and TTC7A with patient-variant interaction assays\",\n      \"pmids\": [\"33122718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal pulldown or orthogonal validation\", \"Functional consequence of UBR5-TTC7A interaction undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked a specific human missense mutation to disruption of the PI4K-FAM126A-EFR3A pathway in patient tissue.\",\n      \"evidence\": \"Whole exome sequencing, structural modeling, and pathway analysis of patient colon and lymphocytes (L69P)\",\n      \"pmids\": [\"34975848\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway disruption inferred from single patient tissue without functional reconstitution\", \"Causality of L69P not experimentally isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Dissected how TTC7A loss impairs immune cell function by linking phosphoinositide signaling to the PI3K/AKT/RHOA/actin axis governing confined migration.\",\n      \"evidence\": \"Microfabricated confinement devices, actin imaging, and DNA-damage/death readouts in murine KO and patient leukocytes\",\n      \"pmids\": [\"37390900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which phosphoinositide species directly drives the migration defect not pinpointed\", \"Connection to plasma-membrane PI4P generation not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a second phosphoinositide function of TTC7A as a chaperone for PIK3C2A generating PI(3,4)P2 in Rab11a vesicles to specify the apical membrane, with rescue by exogenous PI(3,4)P2.\",\n      \"evidence\": \"Patient-derived organoids, PIK3C2A co-chaperone assays, Rab11a trafficking, and PI(3,4)P2 rescue (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.22.644724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How TTC7A partitions between PI4KIIIα and PIK3C2A complexes unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established EFR3A/EFR3B as the membrane-recruitment mechanism for the TTC7-FAM126 module and validated it functionally with a binding-blocking nanobody.\",\n      \"evidence\": \"Biochemical binding assays, cryo-EM, HDX-MS, nanobody isolation, and lipid/cell PI4P production assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.28.667261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Physiological regulation by EFR3B phosphorylation not tested in vivo\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Systematically resolved that distinct TTC7A missense variants produce divergent molecular phenotypes, including variant-specific ER stress and protein abundance changes.\",\n      \"evidence\": \"Reconstitution of 11 variants in TTC7A-KO Caco-2 cells with RNA-seq, ER stress imaging, and protein abundance measurements\",\n      \"pmids\": [\"39675053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype rules not generalized beyond tested variants\", \"Mechanistic basis for variant-specific ER stress not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TTC7A coordinates its dual roles in the PI4KIIIα/FAM126 plasma-membrane complex versus the PIK3C2A/Rab11a apical-specification pathway, and how these integrate to produce tissue-specific phenotypes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of how TTC7A is allocated between distinct phosphoinositide complexes\", \"Direct enzymatic or structural basis for chaperoning PIK3C2A not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 14]}\n    ],\n    \"complexes\": [\n      \"PI4KIIIα/TTC7/FAM126 complex\"\n    ],\n    \"partners\": [\n      \"PI4KA\",\n      \"FAM126A\",\n      \"EFR3A\",\n      \"EFR3B\",\n      \"PIK3C2A\",\n      \"RAB11A\",\n      \"UBR5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}