Affinage

EXT1

Exostosin-1 · UniProt Q16394

Length
746 aa
Mass
86.3 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EXT1 is a glycosyltransferase essential for the biosynthesis of cell-surface heparan sulfate (HS) glycosaminoglycans, a process that governs HS-dependent morphogen and growth-factor signaling during skeletal development (PMID:9620772, PMID:10926768). Initially identified as a type II transmembrane glycoprotein resident in the endoplasmic reticulum (PMID:9620772, PMID:9703997), EXT1 functions as part of an obligate hetero-oligomeric complex with EXT2 that accumulates in the Golgi and constitutes the biologically relevant HS polymerase; the complex exhibits far greater glycosyltransferase activity than either protein alone (PMID:10639137, PMID:10679296). EXT1 contributes both D-glucuronyltransferase and N-acetyl-D-glucosaminyltransferase activities required for HS chain elongation (PMID:11256613), and cryo-EM and substrate-bound structures show that the EXT1 GT-B domain catalyzes β1,4-GlcA transfer while EXT2 primarily provides α1,4-GlcNAc transferase activity, with active sites separated by over 90 Å, establishing a nonprocessive elongation mechanism (PMID:36402845, PMID:36593275). EXT1 is the principal driver of HS chain length: its loss or reduction yields short or absent HS chains (PMID:15161920, PMID:17761672), and complete deficiency in mouse embryos abolishes HS, blocks gastrulation, and disrupts Indian hedgehog distribution (PMID:10926768). HS produced by EXT1 both sequesters and shapes the gradients of Hedgehog, BMP, Wnt, and FGF signaling; reduced EXT1 broadens these signaling domains and perturbs chondrocyte proliferation, joint formation, and skeletal patterning (PMID:15177029, PMID:20404326, PMID:21185280, PMID:23458899). At the receptor level, EXT1-synthesized HS promotes FGF2- and PDGF-driven signaling and receptor tyrosine kinase activation (PMID:19850926, PMID:33028660). Loss of EXT1 function by mutation or epigenetic CpG-island hypermethylation reduces HS synthesis and confers a glycosyltransferase-dependent tumor suppressor activity (PMID:15385438), and EXT1-dependent HS serves as an attachment receptor exploited by filoviruses for entry (PMID:25741008).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 Medium

    Establishing where EXT1 acts and when it is expressed framed it as a developmentally regulated, membrane-resident protein, the first step toward a biochemical function.

    Evidence Epitope-tag localization and in situ hybridization in mouse embryos

    PMID:9703997

    Open questions at the time
    • No enzymatic activity demonstrated
    • ER localization later revised by EXT2 co-expression studies
  2. 1998 High

    Linking EXT1 expression to altered cell-surface HS and showing disease-causing missense mutants fail to do so connected the gene to glycosaminoglycan synthesis and to hereditary exostoses.

    Evidence Cell-based expression with GAG analysis and mutant characterization

    PMID:9620772

    Open questions at the time
    • Direct enzymatic activity of EXT1 not yet defined
    • Role of EXT2 not addressed
  3. 2000 High

    Demonstrating that EXT1 and EXT2 form a Golgi-localized heterocomplex with activity exceeding either protein alone defined the biologically relevant polymerase form and resolved why EXT2 alone is inert.

    Evidence Glycosyltransferase assays in EXT1-deficient cells, co-IP, and localization; reconstitution in yeast

    PMID:10639137 PMID:10679296 PMID:11256613

    Open questions at the time
    • Stoichiometry and how complex augments activity unresolved
    • Individual versus shared catalytic contributions not yet apportioned
  4. 2000 High

    Knockout of Ext1 in mice abolished HS synthesis and blocked gastrulation, establishing EXT1 as essential for HS biosynthesis in vivo and linking HS to Indian hedgehog localization.

    Evidence Gene-targeted knockout mouse with HPLC, glycosyltransferase assays, and immunohistochemistry

    PMID:10926768

    Open questions at the time
    • Mechanism of Ihh-HS interaction not molecularly defined
    • Tissue-specific roles obscured by early lethality
  5. 2004 High

    Hypomorphic and chain-length studies showed EXT1 controls HS chain length and that reduced HS broadens the Hedgehog signaling range, revealing a dual sequestering/gradient-shaping role for HS.

    Evidence Hypomorphic and gene-trap mouse mutants with quantitative signaling and HS sizing

    PMID:15161920 PMID:15177029

    Open questions at the time
    • Quantitative relationship between chain length and signaling range not defined
    • Whether other morphogens behave identically untested at this stage
  6. 2004 High

    Identifying CpG-island hypermethylation of EXT1 in cancer with rescue of tumor phenotype by re-expression established a glycosyltransferase-dependent tumor suppressor function.

    Evidence Methylation-specific PCR, HS assay, re-expression, colony formation, and xenografts

    PMID:15385438

    Open questions at the time
    • Downstream effectors of HS loss in transformation not defined
    • Tumor types where silencing is relevant not fully mapped
  7. 2005 Medium

    Heterozygous Ext1 mice showed enhanced Ihh diffusion with altered chondrocyte proliferation and differentiation, tying HS dosage directly to endochondral bone development.

    Evidence Ext1-heterozygous mouse with immunohistochemistry and proliferation assays

    PMID:15777636

    Open questions at the time
    • Causal versus correlative link between Ihh diffusion and proliferation not isolated
  8. 2007 High

    Bidirectional manipulation showed EXT1 is the primary driver of HS chain elongation while EXT2 alone cannot elongate, refining the division of labor within the complex.

    Evidence siRNA, overexpression, and HS sizing in HEK293 cells with disease-mutant analysis

    PMID:17761672

    Open questions at the time
    • Catalytic basis for EXT1 dominance in elongation not structurally explained yet
  9. 2008 Medium

    Reciprocal effects of EXT1 and EXT2 on NDST1 expression and sulfation introduced a 'GAGosome' model in which sulfation enzymes compete for EXT2, linking chain elongation to modification.

    Evidence Overexpression, transgenic mice, immunoprecipitation, and NDST activity assays

    PMID:18337501

    Open questions at the time
    • Direct EXT1-NDST1-EXT2 complex architecture not resolved
    • Competition model partially speculative and single-lab
  10. 2009 High

    Loss-of-function plus rescue in fibroblasts connected EXT1-dependent HS to selective FGF2-ERK signaling and collagen matrix interactions, extending HS function beyond morphogen gradients.

    Evidence Gene-trap fibroblasts with growth-factor stimulation, pERK blotting, and collagen contraction assays plus rescue

    PMID:19850926

    Open questions at the time
    • Mechanism of selectivity for FGF2 over FGF10/PDGF-BB not explained
  11. 2009 High

    RNAi knockdown reducing myeloma growth and survival in vitro and in xenografts showed EXT1-dependent HS is required for tumor cell survival, expanding its cancer relevance beyond suppression.

    Evidence Inducible RNAi and xenotransplantation with apoptosis/proliferation readouts

    PMID:19965677

    Open questions at the time
    • HS-dependent survival pathway in myeloma not molecularly defined
  12. 2010 High

    Conditional Ext1 ablation and chain-length dissection in skeletal tissues established HS as essential for BMP signaling patterning and revealed an EXT2/EXTL2-dependent initiation route in EXT1's absence.

    Evidence Tissue-specific conditional knockouts (Prx1-Cre, Gdf5-Cre), micromass culture, pSmad immunostaining, and in vitro initiation assays

    PMID:20377530 PMID:20404326 PMID:21185280

    Open questions at the time
    • How HS spatially confines BMP gradients mechanistically unresolved
    • Physiological role of EXTL2-initiated short chains unclear
  13. 2013 High

    Showing that HS physically binds BMP2 and that HS disruption increases BMP responsiveness and ectopic chondrogenesis provided a direct molecular mechanism for HS-mediated BMP restraint.

    Evidence Conditional knockouts, explant/micromass cultures, pharmacological/enzymatic HS disruption, and BMP2-HS binding assays

    PMID:23458899

    Open questions at the time
    • HS sequence specificity for BMP2 binding not mapped
  14. 2015 Medium

    EXT1 knockdown reducing filovirus entry identified EXT1-synthesized HS as an attachment receptor, broadening its role to host-pathogen interactions.

    Evidence siRNA knockdown with pseudoviral and infectious EBOV/MARV entry assays and heparin competition

    PMID:25741008

    Open questions at the time
    • Specific HS structures recognized by filovirus GP not defined
  15. 2020 High

    CRISPR knockout in neural progenitors linked EXT1-dependent HS to broad RTK activation and ligand-receptor coupling, and showed HS loss sensitizes tumor cells to EGFR inhibition.

    Evidence CRISPR/Cas9 knockout with RTK phosphorylation, ligand-binding, in vivo tumor, and inhibitor-sensitivity assays

    PMID:33028660

    Open questions at the time
    • Whether HS effects are uniform across all RTKs not resolved
  16. 2022 High

    The cryo-EM structure and substrate-bound structures of the EXT1-EXT2 heterodimer assigned domain-specific catalytic roles and defined HS elongation as nonprocessive, resolving the long-standing question of activity division within the complex.

    Evidence Cryo-EM/crystal structures with substrates plus catalytic-site mutagenesis and enzymatic assays

    PMID:36402845 PMID:36593275

    Open questions at the time
    • How the dissociative mechanism is coordinated in vivo not addressed
    • Structural basis of disease mutations not fully mapped
  17. 2019 Low

    Reports tied EXT1 to ERK1/2 and WNT/β-catenin signaling in leukemia and lung cancer, implicating it in proliferation/apoptosis control via downstream pathways.

    Evidence Gain/loss-of-function with proliferation, apoptosis, proteomics, GSEA, and WNT inhibitor treatment

    PMID:31465316 PMID:33565239

    Open questions at the time
    • WNT pathway link inferred largely from GSEA without direct mechanistic validation
    • Opposing tumor-suppressor versus oncogenic roles across cancers unreconciled
    • single-lab findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EXT1-dependent HS chain length and fine structure are decoded into context-specific, sometimes opposing signaling and cellular outcomes across tissues and cancers remains unresolved.
  • No structural rules linking HS chain length to specific morphogen gradient shaping
  • Mechanistic reconciliation of EXT1's tumor-suppressor versus pro-survival roles lacking
  • In vivo dynamics of the nonprocessive elongation mechanism undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 2
Partners
EXT2EXTL2NDST1
Complex memberships
EXT1/EXT2 heparan sulfate polymerase complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 EXT1 is an ER-resident type II transmembrane glycoprotein whose expression in cells alters the synthesis and display of cell-surface heparan sulfate glycosaminoglycans (GAGs). Two EXT1 variants containing disease-causing missense mutations failed to alter cell-surface GAGs despite retaining ER localization. Cell-based expression assays, subcellular localization, cell-surface GAG analysis, missense mutant characterization Nature genetics High 9620772
2000 EXT1 and EXT2 form a hetero-oligomeric complex that accumulates in the Golgi apparatus. EXT2 alone has no significant glycosyltransferase activity; only the Golgi-localized EXT1/EXT2 complex exhibits substantially higher glycosyltransferase activity than either protein alone, representing the biologically relevant polymerase form for heparan sulfate synthesis. In vivo and in vitro glycosyltransferase assays in EXT1-deficient cell lines, co-immunoprecipitation, subcellular localization Proceedings of the National Academy of Sciences of the United States of America High 10639137
2000 EXT1 is essential for heparan sulfate biosynthesis in vivo; homozygous EXT1-deficient mouse embryos completely lack heparan sulfate synthesis (as measured by HPLC and cellular glycosyltransferase assays), fail to gastrulate, and lack organized mesoderm. Indian hedgehog (Ihh) fails to associate with cells in EXT1-deficient embryos, linking HS to Ihh distribution. Gene targeting (knockout mouse), HPLC of HS, cellular glycosyltransferase activity assays, immunohistochemistry, RT-PCR Developmental biology High 10926768
2000 EXT1 and EXT2 each individually catalyze both the D-glucuronyltransferase and N-acetyl-D-glucosaminyltransferase reactions required for heparan sulfate chain elongation. Co-expression (but not mixing of separately expressed proteins) yields hetero-oligomeric complexes with augmented glycosyltransferase activities; this stimulation does not depend on membrane-bound state. Recombinant expression in yeast (which lacks endogenous HS synthesis), in vitro glycosyltransferase assay, co-expression experiments EMBO reports High 11256613
2000 EXT1 and EXT2 associate and form homo/hetero-oligomers in vivo in the Golgi apparatus. HME-linked mutations (EXT1 R340C, EXT2 D227N) do not prevent complex formation or Golgi localization but may interfere with glycosyltransferase function. Co-immunoprecipitation, immunocytochemistry in COS-7 cells with epitope-tagged constructs, specific antibodies Biochemical and biophysical research communications Medium 10679296
2004 Ext1 encodes a glycosyltransferase required for HS synthesis. Reduced HS in mice with a hypomorphic Ext1 mutation leads to an elevated range of Indian hedgehog (Ihh) signaling during chondrocyte differentiation, suggesting HS has a dual role: binding Hedgehog in the extracellular space and negatively regulating the range of Hedgehog signaling in a concentration-dependent manner. Hypomorphic mouse mutant, in vivo analysis of Ihh signaling range, chondrocyte differentiation assays Developmental cell High 15177029
2004 Embryonic fibroblasts with a gene trap mutation in Ext1 produce short heparan sulfate chains (average ~20 kDa vs ~70 kDa in wild-type), with conserved domain structure and similar disaccharide composition, demonstrating that HS chain length is a critical determinant controlled by EXT1. Gene trap mutation, metabolic labeling, immunohistochemistry, polysaccharide molecular sizing The Journal of biological chemistry High 15161920
2005 EXT1 deficiency and consequent HS reduction in heterozygous EXT1-deficient mice leads to enhanced Indian hedgehog (Ihh) diffusion, increased chondrocyte proliferation, and delayed hypertrophic differentiation during endochondral bone development. EXT1-heterozygous mouse analysis, immunohistochemistry, proliferation assays, molecular signaling analysis Bone Medium 15777636
2007 EXT1 is the primary driver of HS chain elongation: siRNA silencing of EXT1 produces shorter HS chains, whereas EXT1 overexpression increases HS chain length (further enhanced by co-expression with EXT2). EXT2 alone has no detectable effect on chain elongation; a disease-causing truncation mutant EXT2-Y419X cannot enhance HS chain length in cooperation with EXT1. siRNA knockdown, overexpression, HS chain length measurement in HEK293 cells The Journal of biological chemistry High 17761672
2008 EXT1 overexpression decreases NDST1 expression and N-glycosylation, resulting in reduced HS sulfation, while EXT2 overexpression enhances NDST1 expression and sulfation. Immunoprecipitation suggests NDST1 interacts with EXT2, and EXT1-deficient fibroblasts show increased NDST activity, supporting a model in which NDST1 competes with EXT1 for EXT2 binding within a 'GAGosome' complex. Overexpression in HEK293 cells, transgenic mice, immunoprecipitation, NDST activity assay Proceedings of the National Academy of Sciences of the United States of America Medium 18337501
2009 Ext1 mutation in embryonic fibroblasts markedly decreases FGF2-induced ERK1/2 phosphorylation (but not PDGF-BB or FGF10 signaling), and reduces fibroblast attachment to collagen I and ability to contract collagen lattices without altering collagen-binding integrin expression. Re-introduction of Ext1 rescues HS chain length, FGF2 signaling, and collagen contraction. Gene trap mutant fibroblasts, growth factor stimulation assays, western blotting for pERK1/2, collagen attachment/contraction assays, rescue with Ext1 re-expression The Journal of biological chemistry High 19850926
2009 RNAi-mediated knockdown of EXT1 in human multiple myeloma cells reduces growth and strongly increases apoptosis, similar to syndecan-1 knockdown. In vivo induction of EXT1 knockdown dramatically suppresses bone-marrow-localized myeloma growth in a xenotransplantation model, demonstrating that HS chains (via EXT1) are critical for myeloma cell survival. Inducible RNAi knockdown, xenotransplantation mouse model, apoptosis and proliferation assays Blood High 19965677
2010 Conditional ablation of Ext1 in limb bud mesenchyme causes severe limb skeletal defects. BMP signaling domains are broadened and diffuse, chondrocytes show attenuated responsiveness to exogenous BMPs, and segregation of pSmad1/5/8-expressing chondrocytes is disrupted, establishing HS as essential for BMP signaling patterning in skeletal development. Conditional knockout mice (Prx1-Cre;Ext1), micromass culture, BMP stimulation assays, immunohistochemistry for pSmad1/5/8 The Journal of biological chemistry High 20404326
2010 In EXT1-deficient cells, residual HS synthesis is short-chain and depends on EXT2 and EXTL2 but not EXTL3. Transfer of the first GlcNAc to the linkage region by EXTL2 is critically required for EXT2 to polymerize HS chains in the absence of EXT1, revealing the initiation mechanism for HS biosynthesis in EXT1-deficient conditions. siRNA knockdown, in vitro glycosyltransferase assay with synthetic substrates, metabolic labeling The Biochemical journal High 20377530
2010 Conditional deletion of Ext1 in developing joints (Gdf5-Cre) disrupts digit joint formation, causes joint fusions, impairs lubricin expression in proximal limb joints, and leads to loss of intervertebral discs. This is associated with aberrant BMP, hedgehog, and Wnt/β-catenin signaling in joint-forming cells. Conditional knockout mice (Gdf5-Cre;Ext1f/f), histology, immunostaining for signaling molecules and joint markers Developmental biology High 21185280
2013 Conditional Ext1 ablation in perichondrium and lateral chondrocytes causes ectopic cartilage formation preceded by ectopic BMP signaling, and disruption of HS function by genetic, pharmacological, or enzymatic means similarly triggers excess chondrogenesis. HS physically associates with BMP2, and disruption of HS reduces BMP2-HS interaction and increases cell responsiveness to BMPs. Conditional knockout mice, long bone explant cultures, micromass cultures, pharmacological/enzymatic HS disruption, BMP2-HS binding assay Developmental biology High 23458899
2015 EXT1 knockdown by siRNA impairs heparan sulfate biosynthesis and reduces filovirus (Ebola and Marburg virus) GP-mediated pseudoviral entry and infectious virus entry in tissue culture cells, demonstrating that EXT1-synthesized HS acts as an attachment receptor for filoviruses. siRNA knockdown of EXT1, pseudoviral entry assay, infectious EBOV/MARV assay, HS/heparin competition experiments Journal of virology Medium 25741008
2019 EXT1 promotes apoptosis in acute lymphoblastic leukemia (ALL) cells via deactivation of the ERK1/2 signaling pathway. miR-665 suppresses EXT1 expression, and EXT1 overexpression reduces proliferation, promotes apoptosis in vitro and in vivo, while knockdown has opposite effects. RT-PCR, western blotting, CCK-8/EdU proliferation assays, flow cytometry (apoptosis), in vivo tumorigenesis, label-free quantitative proteomics Medical science monitor Medium 31465316
2020 EXT1 knockout in neural progenitor cells eliminates cell-surface HS, decreasing proliferation, invasion, and activation of multiple receptor tyrosine kinases (RTKs) including PDGFRα. Removal of HS reduces cell-surface PDGF-BB ligand and PDGFRα phosphorylation, showing HS promotes ligand-receptor interaction. HS-deficient tumor cells show increased sensitivity to EGFR inhibition. CRISPR/Cas9 knockout of Ext1, RTK phosphorylation assays, in vivo tumor implantation, HS removal experiments, EGFR inhibitor sensitivity Molecular cancer research High 33028660
2022 Cryo-EM structure of the human EXT1-EXT2 heterodimer reveals a tightly packed complex with four glycosyltransferase domains. Mutational studies demonstrate that EXT1 can catalyze both GlcA and GlcNAc transferase reactions, whereas EXT2 primarily contributes only GlcNAc transferase activity. The two active sites are over 90 Å apart, indicating HS chain elongation is a nonprocessive (dissociative) process. Cryo-EM structure determination, in vitro glycosyltransferase assays of catalytic-site mutants, in cellulo mutational analysis Nature communications High 36402845
2023 Crystal/cryo-EM structural analysis of the EXT1-EXT2 obligate heterocomplex with bound donor and acceptor substrates reveals that the EXT1 GT-B fold domain catalyzes β1,4-GlcA transfer and the EXT2 GT-A fold domain catalyzes α1,4-GlcNAc transfer as the two major catalytic contributions. The >90 Å separation between active sites confirms a dissociative, nonprocessive HS synthesis mechanism. Cryo-EM/crystal structure with substrates, catalytic site mutagenesis, enzymatic activity assays Nature chemical biology High 36593275
2004 Epigenetic silencing of EXT1 by CpG island promoter hypermethylation in cancer cells leads to loss of heparan sulfate synthesis. Re-introduction of EXT1 into EXT1-methylated cancer cell lines reduces colony formation and tumor growth in nude mouse xenograft models, confirming a tumor suppressor function dependent on glycosyltransferase activity. Methylation-specific PCR, HS synthesis biochemical assay, EXT1 re-expression, colony formation assay, xenograft mouse model Human molecular genetics High 15385438
1997 EXT1 protein localizes to the endoplasmic reticulum, consistent with a hydrophobic N-terminal transmembrane stretch. EXT1 mRNA is expressed from gastrulation (E6.5) with high levels in developing limb buds. Epitope-tagging and subcellular localization, whole-mount in situ hybridization, Northern/RT-PCR expression analysis Biochemical and biophysical research communications Medium 9703997
2021 EXT1 methylation increases EXT1 expression in NSCLC; knockdown of EXT1 decreases proliferation and migration. EXT1 targets the WNT/β-catenin signaling pathway, and a WNT inhibitor (XAV-939) disrupts the migration-promoting effect of EXT1. siRNA knockdown, proliferation and migration assays, GSEA pathway analysis, WNT inhibitor treatment Journal of cellular and molecular medicine Low 33565239

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proceedings of the National Academy of Sciences of the United States of America 357 10639137
2000 Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Developmental biology 341 10926768
1998 Detection of a novel DNA virus (TTV) in blood donors and blood products. Lancet (London, England) 336 9683208
1998 The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nature genetics 317 9620772
1998 Fecal excretion of a nonenveloped DNA virus (TTV) associated with posttransfusion non-A-G hepatitis. Journal of medical virology 303 9746068
2004 Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Developmental cell 221 15177029
2007 Contribution of EXT1, EXT2, and EXTL3 to heparan sulfate chain elongation. The Journal of biological chemistry 158 17761672
1998 Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. American journal of human genetics 156 9463333
2000 Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Human mutation 149 10679937
2007 Torque teno virus (TTV): current status. Reviews in medical virology 142 17146841
2008 Heparan sulfate biosynthesis enzymes EXT1 and EXT2 affect NDST1 expression and heparan sulfate sulfation. Proceedings of the National Academy of Sciences of the United States of America 138 18337501
2009 Classification of TTV and related viruses (anelloviruses). Current topics in microbiology and immunology 135 19230555
2000 The EXT1/EXT2 tumor suppressors: catalytic activities and role in heparan sulfate biosynthesis. EMBO reports 134 11256613
2005 Rolling-circle amplification of Torque teno virus (TTV) complete genomes from human and swine sera and identification of a novel swine TTV genogroup. The Journal of general virology 118 15831945
1998 Infection with an unenveloped DNA virus (TTV) associated with posttransfusion non-A to G hepatitis in hepatitis patients and healthy blood donors in Thailand. Journal of medical virology 116 9783691
1997 Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. American journal of human genetics 116 8981950
2001 TT virus (TTV) loads associated with different peripheral blood cell types and evidence for TTV replication in activated mononuclear cells. Journal of medical virology 101 11360252
1997 Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. American journal of human genetics 99 9326317
2002 TTV, a new human virus with single stranded circular DNA genome. Reviews in medical virology 90 11987140
2000 Comparison of fluorescent single-strand conformation polymorphism analysis and denaturing high-performance liquid chromatography for detection of EXT1 and EXT2 mutations in hereditary multiple exostoses. European journal of human genetics : EJHG 87 10713884
2001 Genomic and evolutionary characterization of TT virus (TTV) in tupaias and comparison with species-specific TTVs in humans and non-human primates. The Journal of general virology 86 11514713
2007 The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. Journal of the National Cancer Institute 76 17341731
2014 TTV DNA plasma load and its association with age, gender, and HCMV IgG serostatus in healthy adults. Age (Dordrecht, Netherlands) 75 25284090
2009 Torque Teno Virus (TTV) distribution in healthy Russian population. Virology journal 73 19735552
2004 Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells. Human molecular genetics 70 15385438
2005 EXT1 regulates chondrocyte proliferation and differentiation during endochondral bone development. Bone 61 15777636
1998 Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Human mutation 58 9521425
2000 Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus. Biochemical and biophysical research communications 57 10679296
2015 Role of EXT1 and Glycosaminoglycans in the Early Stage of Filovirus Entry. Journal of virology 55 25741008
2010 Conditional ablation of the heparan sulfate-synthesizing enzyme Ext1 leads to dysregulation of bone morphogenic protein signaling and severe skeletal defects. The Journal of biological chemistry 55 20404326
2013 Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses. Developmental biology 53 23458899
1999 TT viruses (TTV) of non-human primates and their relationship to the human TTV genotypes. The Journal of general virology 53 10501506
2011 Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones. Bone 52 21310272
2004 Embryonic fibroblasts with a gene trap mutation in Ext1 produce short heparan sulfate chains. The Journal of biological chemistry 49 15161920
2016 Prevalence of anelloviruses (TTV, TTMDV, and TTMV) in healthy blood donors and in patients infected with HBV or HCV in Qatar. Virology journal 48 28031027
2009 Swine torque teno virus (TTV) infection and excretion dynamics in conventional pig farms. Veterinary microbiology 48 19559548
1998 Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer 48 9576285
2007 Mutation screening of EXT1 and EXT2 by denaturing high-performance liquid chromatography, direct sequencing analysis, fluorescence in situ hybridization, and a new multiplex ligation-dependent probe amplification probe set in patients with multiple osteochondromas. The Journal of molecular diagnostics : JMD 47 18165274
2005 Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations. European journal of human genetics : EJHG 47 15586175
2001 Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Cell motility and the cytoskeleton 47 11169766
1999 Prevalence and persistence of a novel DNA TT virus (TTV) infection in Japanese haemophiliacs. British journal of haematology 47 10086806
2013 Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas. Scientific reports 45 23439489
2008 Expression of all six human Torque teno virus (TTV) proteins in bacteria and in insect cells, and analysis of their IgG responses. Virology 45 18947848
2010 Synovial joint formation requires local Ext1 expression and heparan sulfate production in developing mouse embryo limbs and spine. Developmental biology 43 21185280
2009 Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma. Blood 43 19965677
2006 Determination of the mutation spectrum of the EXT1/EXT2 genes in British Caucasian patients with multiple osteochondromas, and exclusion of six candidate genes in EXT negative cases. Human mutation 43 17041877
2001 Existence of TT virus DNA and TTV-like mini virus DNA in infant cord blood: mother-to-neonatal transmission. Hepatology research : the official journal of the Japan Society of Hepatology 42 11673113
2018 Torquetenovirus (TTV) load is associated with mortality in Italian elderly subjects. Experimental gerontology 41 30223047
2010 Biosynthesis of heparan sulfate in EXT1-deficient cells. The Biochemical journal 40 20377530
2001 High prevalence of TT virus (TTV) and TTV-like minivirus in cervical swabs. Journal of clinical microbiology 40 11326040
2001 Molecular epidemiology of TT virus (TTV) and characterization of two novel TTV genotypes in Indonesia. Archives of virology 40 11556704
1997 Genomic organization and promoter structure of the human EXT1 gene. Genomics 40 9119404
2010 Roles of heparan sulfate in mammalian brain development current views based on the findings from Ext1 conditional knockout studies. Progress in molecular biology and translational science 38 20807644
2015 Detection and genotyping of torque teno virus (TTV) in healthy blood donors and patients infected with HBV or HCV in Qatar. Journal of medical virology 36 25676255
1997 Identification of novel mutations in the human EXT1 tumor suppressor gene. Human genetics 36 9150727
1999 Detection of a novel DNA virus (TTV) sequence in peripheral blood mononuclear cells. Journal of medical virology 35 10335866
2003 Distribution of TT virus (TTV), TTV-like minivirus, and related viruses in humans and nonhuman primates. Virology 33 12642105
1998 Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene. Biochemical and biophysical research communications 33 9703997
2022 Structure of the human heparan sulfate polymerase complex EXT1-EXT2. Nature communications 32 36402845
2017 Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation. International journal of molecular sciences 32 29104277
2009 Mutation in the heparan sulfate biosynthesis enzyme EXT1 influences growth factor signaling and fibroblast interactions with the extracellular matrix. The Journal of biological chemistry 32 19850926
2016 Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas. BMC genetics 31 26961984
2005 Novel EXT1 and EXT2 mutations identified by DHPLC in Italian patients with multiple osteochondromas. Human mutation 31 16088908
2015 Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency. The Journal of pathology 30 25644707
2001 Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses. American journal of medical genetics 29 11170095
2021 Herpes DNAemia and TTV Viraemia in Intensive Care Unit Critically Ill Patients: A Single-Centre Prospective Longitudinal Study. Frontiers in immunology 28 34795661
2000 High prevalence of TT virus (TTV) in naive chimpanzees and in hepatitis C virus-infected humans: frequent mixed infections and identification of new TTV genotypes in chimpanzees. The Journal of general virology 28 10725426
2023 Structural basis for heparan sulfate co-polymerase action by the EXT1-2 complex. Nature chemical biology 27 36593275
2008 Familial nephropathy and multiple exostoses with exostosin-1 (EXT1) gene mutation. Journal of the American Society of Nephrology : JASN 27 18216313
2004 TTV infection in children born to mothers infected with TTV but not with HBV, HCV, or HIV. Journal of medical virology 27 15368510
2015 Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans. Journal of lipid research 25 25568062
2023 TTV and other anelloviruses: The astonishingly wide spread of a viral infection. Aspects of molecular medicine 24 37398508
2019 EXT1, Regulated by MiR-665, Promotes Cell Apoptosis via ERK1/2 Signaling Pathway in Acute Lymphoblastic Leukemia. Medical science monitor : international medical journal of experimental and clinical research 24 31465316
2014 Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function. Journal of the American Heart Association 24 25468659
2013 Torque teno virus (TTV) in multiple sclerosis patients with different patterns of disease. Journal of medical virology 24 23960011
2012 Fibroblast EXT1-levels influence tumor cell proliferation and migration in composite spheroids. PloS one 24 22848466
2009 New mutations of EXT1 and EXT2 genes in German patients with Multiple Osteochondromas. Annals of human genetics 24 19344451
2018 Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas. Molecular genetics & genomic medicine 22 29529714
2012 20 novel point mutations and one large deletion in EXT1 and EXT2 genes: report of diagnostic screening in a large Italian cohort of patients affected by hereditary multiple exostosis. Gene 21 23262345
2005 HEV, TTV and GBV-C/HGV markers in patients with acute viral hepatitis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 21 15917959
2005 A novel EXT1 splice site mutation in a kindred with hereditary multiple exostosis and osteoporosis. The Journal of clinical endocrinology and metabolism 18 15985493
2000 Prevalence of TTV DNA among children with a history of transfusion or liver disease. Journal of medical virology 18 10596017
2000 TTV - a virus searching for a disease. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 18 10814932
2023 Prediction of humoral and cellular immune response to COVID-19 mRNA vaccination by TTV load in kidney transplant recipients and hemodialysis patients. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 17 36989730
2020 Heparan Sulfate Synthesized by Ext1 Regulates Receptor Tyrosine Kinase Signaling and Promotes Resistance to EGFR Inhibitors in GBM. Molecular cancer research : MCR 17 33028660
2016 Investigation on torquetenovirus (TTV) microRNA transcriptome in vivo. Virus research 17 26959653
2023 EXT1 and NCAM1-associated membranous lupus nephritis in a cohort of patients undergoing repeat kidney biopsies. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 16 35278072
2021 EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway. Journal of cellular and molecular medicine 16 33565239
2010 Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively--coincidence within one family. BMC medical genetics 16 20618940
2001 Prevalence of TTV DNA and GBV-C RNA in patients with systemic sclerosis, rheumatoid arthritis, and osteoarthritis does not differ from that in healthy blood donors. Annals of the rheumatic diseases 16 11454648
2019 RNA-Seq detects a SAMD12-EXT1 fusion transcript and leads to the discovery of an EXT1 deletion in a child with multiple osteochondromas. Molecular genetics & genomic medicine 15 30632316
2014 A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG. Scientific reports 15 25230886
2013 Intronic deletion and duplication proximal of the EXT1 gene: a novel causative mechanism for multiple osteochondromas. Genes, chromosomes & cancer 15 23341036
2011 Identification and functional characterization of the human EXT1 promoter region. Gene 14 22037484
2001 Transfusion transmissible virus TTV and its putative role in the etiology of liver disease. Hepato-gastroenterology 14 11268979
1999 Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses. Journal of human genetics 14 10429361
1999 The prevalence of TT virus (TTV) infection and its relationship to hepatitis in children. Medical microbiology and immunology 14 10753060
2014 Cloning and expression of N22 region of Torque Teno virus (TTV) genome and use of peptide in developing immunoassay for TTV antibodies. Virology journal 13 24884576
2021 Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses. Orphanet journal of rare diseases 12 33632255
2005 Methylation status of EXT1 and EXT2 promoters and two mutations of EXT2 in chondrosarcoma. Cancer genetics and cytogenetics 12 15796962

Missed literature

Know a paper Affinage missed for EXT1? Flag it for the maintainers and the community.

No submissions yet.