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TTC7A

Tetratricopeptide repeat protein 7A · UniProt Q9ULT0

Length
858 aa
Mass
96.2 kDa
Annotated
2026-06-10
29 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 Medium

    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

    PMID:15718100

    Open questions at the time
    • No molecular mechanism connecting Ttc7 loss to iron homeostasis
    • No protein-level or pathway characterization
  2. 2014 High

    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

    PMID:24292712

    Open questions at the time
    • How TTC7A loss elevates ROCK activity at the molecular level not defined
    • Link to phosphoinositide signaling not yet established
  3. 2018 High

    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

    PMID:30031006

    Open questions at the time
    • Membrane recruitment mechanism not resolved in this study
    • Functional consequence of dimer-of-trimers assembly unclear
  4. 2018 High

    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

    PMID:29775636

    Open questions at the time
    • Molecular trigger for IGF1/Reg3γ induction in mutant fibroblasts unknown
    • Relationship to phosphoinositide pathway not addressed
  5. 2019 High

    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

    PMID:31743734

    Open questions at the time
    • Direct biochemical link between TTC7A and AKT phosphorylation not established
    • Mechanism of leflunomide rescue unclear
  6. 2019 Medium

    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

    PMID:31004027

    Open questions at the time
    • Mechanistic link between TTC7A and ER stress effectors not defined
    • Single lab
  7. 2020 Medium

    Identified UBR5 as a candidate physical partner regulating TTC7A signaling.

    Evidence Co-immunoprecipitation of UBR5 and TTC7A with patient-variant interaction assays

    PMID:33122718

    Open questions at the time
    • Single Co-IP without reciprocal pulldown or orthogonal validation
    • Functional consequence of UBR5-TTC7A interaction undefined
  8. 2021 Low

    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)

    PMID:34975848

    Open questions at the time
    • Pathway disruption inferred from single patient tissue without functional reconstitution
    • Causality of L69P not experimentally isolated
  9. 2023 High

    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

    PMID:37390900

    Open questions at the time
    • Which phosphoinositide species directly drives the migration defect not pinpointed
    • Connection to plasma-membrane PI4P generation not directly tested
  10. 2025 Medium

    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)

    PMID:bio_10.1101_2025.03.22.644724

    Open questions at the time
    • Preprint not yet peer-reviewed
    • How TTC7A partitions between PI4KIIIα and PIK3C2A complexes unknown
  11. 2025 Medium

    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)

    PMID:bio_10.1101_2025.07.28.667261

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Physiological regulation by EFR3B phosphorylation not tested in vivo
  12. 2025 Medium

    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

    PMID:39675053

    Open questions at the time
    • Genotype-phenotype rules not generalized beyond tested variants
    • Mechanistic basis for variant-specific ER stress not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified model of how TTC7A is allocated between distinct phosphoinositide complexes
  • Direct enzymatic or structural basis for chaperoning PIK3C2A not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
EFR3AEFR3BFAM126API4KAPIK3C2ARAB11AUBR5
Complex memberships
PI4KIIIα/TTC7/FAM126 complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. Intestinal organoid cultures from patient biopsies + pharmacological ROCK inhibition rescue experiment The Journal of clinical investigation High 24292712
2013 TTC7A protein is expressed in thymic epithelial cells and thymocytes, as demonstrated by immunostaining of normal thymus tissue. Immunostaining/immunohistochemistry of normal thymus The Journal of allergy and clinical immunology Medium 23830146 25546680
2014 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. Immunohistochemistry/immunostaining of multiple organ biopsies and autopsies Medicine Medium 23830146 25546680
2018 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. Negative stain electron microscopy and hydrogen-deuterium exchange mass spectrometry (HDX-MS) of reconstituted complex Journal of molecular biology High 30031006
2019 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. Immunoblots in TTC7A-KO HAP1 cells and HeLa cells stably expressing mutant TTC7A; high-throughput drug screen; zebrafish ttc7a-/- model; patient-derived colonoids Gastroenterology High 31743734
2020 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. Co-immunoprecipitation (Co-IP) of UBR5 and TTC7A; functional interaction assay with patient variants Scientific reports Medium 33122718
2019 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. In vivo competitive repopulation assays; serial cell transplantations; chemically-induced stress in vitro; myeloablative stress in vivo; transcriptomic profiling Haematologica Medium 31004027
2023 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. Microfabricated confinement devices for single-cell migration; actin dynamics imaging; murine and patient-derived leukocytes The Journal of allergy and clinical immunology High 37390900
2018 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. Bone marrow chimeras; double and triple mutant mice (Rag2-/- Ttc7fsn/fsn; Rag2-/- IL2rg-/- Ttc7fsn/fsn); xenograft model with Ttc7-mutated fibroblasts; transcriptomic analysis The Journal of allergy and clinical immunology High 29775636
2018 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. Genetic manipulation (overexpression and knockdown) in Drosophila Aβ42 model; behavioral and synaptic phenotype assays Journal of Alzheimer's disease : JAD Medium 30103315
2021 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. Whole exome sequencing; in silico structural analysis; immunostaining; pathway analysis of patient colon tissues Frontiers in immunology Low 34975848
2025 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. Patient-derived organoids; TTC7A localization imaging; PIK3C2A co-chaperone assays; Rab11a vesicle trafficking experiments; PI(3,4)P2 rescue experiments bioRxivpreprint Medium bio_10.1101_2025.03.22.644724
2025 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. Biochemical binding assays; cryo-EM; HDX-MS; yeast display nanobody isolation; lipid bilayer and cell-based PI4P production assays bioRxivpreprint Medium bio_10.1101_2025.07.28.667261
2005 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. Positional cloning; large backcross mapping; RT-PCR; sequencing of mutant alleles Genomics Medium 15718100
2025 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. TTC7A-KO Caco-2 cell reconstitution with individual variants; RNA sequencing; imaging flow cytometry for ER stress; protein abundance measurements Human molecular genetics Medium 39675053

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 TTC7A mutations disrupt intestinal epithelial apicobasal polarity. The Journal of clinical investigation 151 24292712
2013 Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. The Journal of allergy and clinical immunology 119 23830146
2013 Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. Journal of medical genetics 94 23423984
2019 Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency. Gastroenterology 52 31743734
2018 Probing the Architecture, Dynamics, and Inhibition of the PI4KIIIα/TTC7/FAM126 Complex. Journal of molecular biology 38 30031006
2014 Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort. Medicine 36 25546680
2014 Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency. Journal of clinical immunology 31 24931897
2005 Positional cloning of the Ttc7 gene required for normal iron homeostasis and mutated in hea and fsn anemia mice. Genomics 30 15718100
2015 Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency. Clinical genetics 29 25534311
2017 Missense mutation of TTC7A mimicking tricho-hepato-enteric (SD/THE) syndrome in a patient with very-early onset inflammatory bowel disease. European journal of medical genetics 19 29174094
2021 A Novel Homozygous TTC7A Missense Mutation Results in Familial Multiple Intestinal Atresia and Combined Immunodeficiency. Frontiers in immunology 16 34975848
2022 Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations: A Rare Condition Leading to Multiple Intestinal Atresias, Severe Combined Immunodeficiency, and Congenital Enteropathy. The American journal of surgical pathology 11 34985046
2018 TTC7A mutation must be considered in patients with repeated intestinal atresia associated with early inflammatory bowel disease: Two new case reports and a literature review. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 11 29921470
2020 The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease. Scientific reports 9 33122718
2023 Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement. The Journal of allergy and clinical immunology 8 37390900
2022 Prominent Follicular Keratosis in Multiple Intestinal Atresia with Combined Immune Deficiency Caused by a TTC7A Homozygous Mutation. Genes 6 35627206
2022 Clinical Characteristics, In Silico Analysis, and Intervention of Neonatal-Onset Inflammatory Bowel Disease With Combined Immunodeficiency Caused by Novel TTC7A Variants. Frontiers in genetics 6 35783276
2018 Epithelial proliferation in inflammatory skin disease is regulated by tetratricopeptide repeat domain 7 (Ttc7) in fibroblasts and lymphocytes. The Journal of allergy and clinical immunology 6 29775636
2019 Combined Immunodeficiency With Inflammatory Bowel Disease in a Patient With TTC7A Deficiency. ACG case reports journal 5 31616743
2019 Ttc7a regulates hematopoietic stem cell functions while controlling the stress-induced response. Haematologica 4 31004027
2025 TTC7A missense variants in intestinal disease can be classified by molecular and cellular phenotypes. Human molecular genetics 3 39675053
2025 TTC7A-ALK, a novel ALK fusion variant identified in a patient with metastatic lung adenocarcinoma, exhibits excellent response to crizotinib. Translational oncology 2 40054123
2024 Meconium peritonitis in multiple intestinal atresia with combined immune deficiency caused by a TTC7A mutation: A case report. SAGE open medical case reports 2 38292879
2024 Systematic review of phenotypes and genotypes of patients with gastrointestinal defects and immunodeficiency syndrome-1 (GIDID1) (related to TTC7A). Intractable & rare diseases research 2 38836179
2024 Hereditary Multiple Intestinal Atresia With a Novel TTC7A Pathogenic Variant: Gastrointestinal Manifestations in Two Cases. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 1 39444084
2018 TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila. Journal of Alzheimer's disease : JAD 1 30103315
2026 Rare variants in TTC7A, ROCK2 and LIMK2 suggest a role for the ROCK-signaling pathway in isolated intestinal malrotation. Pediatric surgery international 0 42185554
2025 Genotype-Phenotype Correlation in TTC7A -Associated Gastrointestinal Defects and Immunodeficiency Syndrome 1. American journal of medical genetics. Part A 0 40685546
2025 Case Report: Prenatal diagnosis of gastrointestinal defects and immunodeficiency syndrome caused by compound heterozygous mutations in TTC7A gene. Frontiers in immunology 0 40901475

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