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Enzyme Nomenclature
Information on EC 2.4.1.225 - N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
Word Map on EC 2.4.1.225
- 2.4.1.225
- hs
-
hereditary
- exostoses
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proteoglycans
- glycosyltransferases
- osteochondroma
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hspgs
-
hedgehog
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ext-like
- heparanase
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cartilage-capped
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metaphyseal
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wingless
- tout-velu
- medicine
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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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EC NUMBER 
COMMENTARY 
2.4.1.225
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RECOMMENDED NAME
GeneOntology No.
N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan = UDP + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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SYSTEMATIC NAME
IUBMB Comments
UDP-alpha-D-glucuronate:N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan 4-beta-glucuronosyltransferase
Involved in the biosynthesis of heparin and heparan sulfate. Some forms of the human enzyme (particularly the enzyme complex encoded by the EXT1 and EXT2 genes) act as bifunctional glycosyltransferases, which also have the glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase (EC 2.4.1.224) activity required for the synthesis of the heparan sulfate disaccharide repeats.
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CAS REGISTRY NUMBER
COMMENTARY
145539-84-0
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
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Exostosin glycosyltransferases exclusively catalyze heparan sulfate polymerization. Heparan sulfate/heparin, chondroitin sulfate, dermatan sulfate, and keratan sulfate form glycosaminoglycans, long linear polysaccharide chains consisting of repeat disaccharide units. Glycosaminoglycans are the major components of the extracellular matrix and play critical roles in regulating transport and signaling of numerous growth factors during embryonic development
physiological function
malfunction
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slight change in the number of developing B cells in B-cell Ext1-deficient mice, but alteration does not cause a change in antibody production
malfunction
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EXT1 influences fibroblast matrix interactions. Essential role of EXT1 in providing specific binding sites for growth factors and extracellular matrix proteins. Phosphorylation of ERK1/2 in response to FGF2 stimulation is markedly decreased in the Ext1 mutant fibroblasts, whereas neither PDGF-BB nor FGF10 signaling is significantly affected. Ext1 mutants display reduced ability to attach to collagen I and to contract collagen lattices. Reintroduction of Ext1 in Ext1 mutant fibroblasts rescues heparan sulfate chain length, FGF2 signaling, and the ability of the fibroblasts to contract collagen
malfunction
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Fgf targeted gene expression is reduced in ext2 mutants and the remaining expression is readily inhibited by SU5402, an FGF receptor inhibitor. In the ext2 mutants, Fgf signaling is affected during nervous system development, mechanism, overview, and reduction of Fgf ligands in the mutants affects tail development. Wnt signaling is also affected in the ext2 mutants, while Hh dependent signaling is apparently unaffected in the ext2 mutants, Hh targeted gene expression is not reduced, the Hh inhibitor cyclopamine is not more affective in the mutants and Hh-dependent cell differentiation in the retina and in the myotome are normal in ext2 mutants, ext2 mutant phenotypes, overview
malfunction
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a reduction in either Ext1 or Ext2 can cause a reduction in heparan sulfate biosynthesis, overview. Suppression of Ext1 by siRNA in FBJ-S1 cells results in the decreased expression of heparan sulfate and enhanced motility
malfunction
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ectopic cartilage forms in Ext1-deficient mouse embryo long bones, phenotype overview. perichondrium phenotype and border function regulation is deregulated in hereditary multiple exostoses. Ext1 deficiency stimulates cartilage formation
malfunction
mutations in the tumor suppressor genes EXT1 and EXT2 disturb heparan sulfate proteoglycan biosynthesis and cause multiple osteochondroma. A reduction in Rti shifts the steady-state distribution of EXTs to the trans-Golgi. These accumulated EXTs tend to be degraded and their re-entrance towards the route for polymerizing GAG chains is disengaged. Conversely, EXTs are mislocalized towards the transitional endoplasmic reticulum/cis-Golgi when Rti is overexpressed. Both loss of function and overexpression of rti result in incomplete heparan sulfate proteoglycans and perturb Hedgehog signaling; mutations in the tumor suppressor genes EXT1 and EXT2 disturb heparan sulfate proteoglycan biosynthesis and cause multiple osteochondroma. A reduction in Rti shifts the steady-state distribution of EXTs to the trans-Golgi. These accumulated EXTs tend to be degraded and their re-entrance towards the route for polymerizing GAG chains is disengaged. Conversely, EXTs are mislocalized towards the transitional endoplasmic reticulum/cis-Golgi when Rti is overexpressed. Both loss of function and overexpression of rti result in incomplete heparan sulfate proteoglycans and perturb Hedgehog signaling
malfunction
effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo, phenotype, overview; effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo. Silencing of microvascular endothelial cell EXT1 and EXT2 under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho-endothelial nitric oxide synthesis protein expression. Brachial artery flow-mediated dilation is significantly increased in hereditary multiple exostoses (HME) patients. In humans, heterozygous loss of function mutation in EXT1 and EXT2 are known to be involved in the development of HME syndrome, a disorder associated with bony tumor formation. In these humans, the loss-of-function mutations lead to alterations in the structure of tissue and plasma heparan sulfate composition, phenotype, overview; effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo. Silencing of microvascular endothelial cell EXT1 and EXT2 under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho-endothelial nitric oxide synthesis protein expression. Brachial artery flow-mediated dilation is significantly increased in hereditary multiple exostoses patients. In humans, heterozygous loss of function mutation in EXT1 and EXT2 are known to be involved in the development of HME syndrome, a disorder associated with bony tumor formation. In these humans, the loss-of-function mutations lead to alterations in the structure of tissue and plasma heparan sulfate composition, phenotype, overview
malfunction
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effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo, phenotype, overview
malfunction
phenotype of four patients showing clinical seizures-scoliosis-macrocephaly syndrome with seizures and macrocephaly due to decreased EXT2 expression and mutations M87R and R95C. SSM syndrome is characterised by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism and renal dysfunction. Phenotype, overview
malfunction
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deletion of Ext1 in the mesoderm induces a cardiac phenotype similar to that of a mutant with conditional deletion of UDP-glucose dehydrogenase, a key enzyme responsible for synthesis of all glycosaminoglycans. The outflow tract defect in conditional Ext1 knockout (Ext1f/f:Mesp1Cre) mice is attributable to the reduced contribution of second heart field and neural crest cells. Ext1 deletion leads to downregulation of FGF signaling in the pharyngeal mesoderm. Exogenous FGF8 ameliorates the defects in the outflow tract and pharyngeal explants. Phenotype, detailed overview
malfunction
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a reduction in either Ext1 or Ext2 can cause a reduction in heparan sulfate biosynthesis, overview. Suppression of Ext1 by siRNA in FBJ-S1 cells results in the decreased expression of heparan sulfate and enhanced motility
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physiological function
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the level of expression of EXT1 and EXT2 affects the amount of glucosaminyl N-deacetylase/N-sulfotransferase 1 (NDST1) present in the cell, which, in turn, greatly influences heparan sulfate structure. Overexpression of EXT2 in HEK 293 cells enhances NDST1 expression, increases NDST1 N-glycosylation, and results in elevated heparan sulfate sulfation, overexpression of EXT1 has opposite effects. Heart tissue from transgenic mice overexpressing EXT2 shows increased NDST activity. NDST1 interacts with EXT2, NDST1 may compete with EXT1 for binding to EXT2
physiological function
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Ext1 and Ext2 together form a copolymerase which is responsible for the polymerization process where repeating units of N-acetylglucosamine and glucuronic acid are incorporated in the growing linear polysaccharide chain, see also EC 2.4.1.224. Gene ext2 is involved in Fgf and Wnt signaling but not in Hh signaling, ext2 is a general enhancer of Fgf target gene expression, ext2 interacts genetically with Fgf signaling during tail development, specificity for gene ext2 in signaling pathways during embryonic development, overview
physiological function
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Ext1 and Ext2 are tumor suppressors. In the biosynthesis of heparan sulfate, after the attachment of a GlcNAc residue to GlcA-Gal-Gal-Xyl, Ext1 and Ext2 catalyze the subsequent elongation of glycosaminoglycans by alternately adding GlcA and GlcNAc to the end of the growing chain. Involvement of Ext1 and heparanase in migration of FBJ osteosarcoma cells, overview
physiological function
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perichondrium phenotype and border function are deranged by Ext1 and heparan sulfate in developing long bones, and in ectopic cartilage formation
physiological function
exostosin (EXT) genes encode glycosyltransferases required for glycosaminoglycan chain polymerization in the biosynthesis of heparan sulfate proteoglycans. Synthesis of heparan sulfate proteoglycans requires sequential enzymatic modifications of glycoproteins in the Golgi. Drosophila Golgi phosphoprotein 3, GOLPH3 or rotini, Rti, regulates the biosynthesis of heparan sulfate proteoglycans by modulating the retrograde trafficking of exostosins. Rti regulates the stability of EXTs. Proper function of EXTs depends not only on their enzymatic activities but also on their sub-compartmental distributions; exostosin (EXT) genes encode glycosyltransferases required for glycosaminoglycan chain polymerization in the biosynthesis of heparan sulfate proteoglycans. Synthesis of heparan sulfate proteoglycans requires sequential enzymatic modifications of glycoproteins in the Golgi. Drosophila Golgi phosphoprotein 3, GOLPH3 or rotini, Rti, regulates the biosynthesis of heparan sulfate proteoglycans by modulating the retrograde trafficking of exostosins. Rti regulates the stability of EXTs. Proper function of EXTs depends not only on their enzymatic activities but also on their sub-compartmental distributions
physiological function
heparan sulfate elongation genes EXT1 and EXT2 are involved in heparan sulfate elongation and in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability; heparan sulfate elongation genes EXT1 and EXT2 are involved in heparan sulfate elongation and in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability; heparan sulfate elongation genes EXT1 and EXT2 are involved in heparan sulfate elongation and in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability
physiological function
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heparan sulfate elongation genes EXT1 and EXT2 are involved in heparan sulfate elongation and in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability
physiological function
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Ext1 is a glycosyltransferase responsible for heparan sulfate synthesis. Function of Ext1 in heart development, overview. Ext1 expression in second heart field and neural crest cells is required for outflow tract remodeling. Ext1 is crucial for outflow tract formation in distinct progenitor cells, and heparan sulfate modulates FGF signaling during early heart development. Proper expression of Ext1 is required for cardiogenesis, heparan sulfate is required for heart development
physiological function
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Ext1 and Ext2 are tumor suppressors. In the biosynthesis of heparan sulfate, after the attachment of a GlcNAc residue to GlcA-Gal-Gal-Xyl, Ext1 and Ext2 catalyze the subsequent elongation of glycosaminoglycans by alternately adding GlcA and GlcNAc to the end of the growing chain. Involvement of Ext1 and heparanase in migration of FBJ osteosarcoma cells, overview
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP-N-acetyl-D-glucosamine + alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
UDP + alpha-N-acetyl-D-glucosaminyl-alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
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-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
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-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
UDP + alpha-N-acetyl-D-glucosaminyl-alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
UDP + alpha-N-acetyl-D-glucosaminyl-alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
-
-
-
-
?
additional information
?
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formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 alone
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-
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additional information
?
-
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EXT1 has both GlcNAc transferase activity of EC 2.4.1.224 and GlcA transferase activity of EC 2.4.1.225, EXT2 only has low activity of EC 2.4.1.225, coexpression of EXT1 and EXT2 yields high activity of EC 2.4.1.225 and low activity of EC 2.4.1.224
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-
-
additional information
?
-
-
formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 has alone
-
-
-
additional information
?
-
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
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-
-
additional information
?
-
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
-
-
-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
O77783
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
-
-
-
-
?
additional information
?
-
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
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-
-
additional information
?
-
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
-
-
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial chondrocytes’ ability to differentiate normally and to survive in a differentiated state in vitro
additional information
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FBJ, highly metastatic mouse osteosarcoma FBJ-LL cells and the poorly metastatic FBJ-S1 cells are produced from a FBJ virus-induced osteosarcoma
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FBJ, highly metastatic mouse osteosarcoma FBJ-LL cells and the poorly metastatic FBJ-S1 cells are produced from a FBJ virus-induced osteosarcoma
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additional information
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zebrafish ext2 gene is ubiquitously expressed during zebrafish development
additional information
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kidney extract is devoid of EXT2 in EXT2-overexpressing mice
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
Ext1 and Ext2 are type II transmembrane glycoproteins
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Ext1 and Ext2 are type II transmembrane glycoproteins
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EXT isozymes are localized mainly in the cis- and middle-Golgi stacks. Rotini, Rti, mediates the retrograde transport of EXT enzymes within the Golgi complex. Rotini regulates the sub-compartmental distribution of EXTs in the Golgi; EXT isozymes are localized mainly in the cis- and middle-Golgi stacks. Rotini, Rti, mediates the retrograde transport of EXT enzymes within the Golgi complex. Rotini regulates the sub-compartmental distribution of EXTs in the Golgi
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
-
2 * 80000, EXT1, calculated, 1 * 80000 + 1 * 80000, EXT1/EXT2 heterodimer, calculated
monomer
additional information
additional information
-
formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 alone
additional information
-
formation of heterooligomers of ttv and sotv, co-immunoprecipitation experiments
additional information
-
formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 has alone
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in HEK-293 cells
EXT1 and EXT2 cDNA, alone or in combination, cloned into the pBudCE4.1 vector, which contains two multiple cloning sites for simultaneous expression of two proteins. EXT1 cloned into the multiple cloning sites with the cytomegalovirus (CMV) immediate-early promotor and EXT2 into the multiple cloning sites with the human elongation factor 1alpha promotor. Constructs transfected into HEK-293 cells stably expressing NDST1 from the pCDNA3 vector. Mutated EXT2 cDNA cloned into the pBudCE4.1 vector and transfected into HEK-93 cells overexpressing NDST1. EXT2 cDNA inserted into the pCAGGS expression vector under the control of the CMV immediate-early enhancer and the chicken beta-actin promoter (CAG) for constitutively high tissue expression from fertilized eggs and early embryonic stage through adulthood. The cDNA construct cloned into the unique EcoR1 site between the CAG promoter and the rabbit beta-globin sequence. Vector linearized with BamH1 and SalI and injected into mice B6CBAF1 oocytes
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full-length Ext1 cDNA cloned into the pBudCE4.1 vector and transfected into Ext1Gt/Gt fibroblasts
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gene EXT1, creation of loxP-modified Ext1 allele and establishment of the Ext1 floxed mouse line (Ext1flox/flox), expression of the enzyme in Gdf-5-Cre transgenic mice, semiquantitative real-time PCR enzyme expression analysis
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gene EXT1, recombinant expression of Myc-DKK-tagged enzyme in S2 cells, interaction analysis with GOLPH3 via yeast two-hybrid assay; gene EXT2, recombinant expression of Myc-DKK-tagged enzyme in S2 cells, interaction analysis with GOLPH3 via yeast two-hybrid assay
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C333R
naturally occuring mutation in hereditary multiple exostoses syndrome
L462W
naturally occuring mutation in hereditary multiple exostoses syndrome
L46F
naturally occuring mutation in hereditary multiple exostoses syndrome
M87R
naturally occuring mutation from a patient with clinical seizures-scoliosis-macrocephaly syndrome
medicine
-
the mutation status of patients with multiple osteochondromas correlates with decreased EXT1 or EXT2 expression, loss of EXT expression disrupts the function of the EXT1/2 complex in heparan sulfate proteoglycan biosynthesis, resulting in the intracellular accumulation of heparan sulfate proteoglycan core proteins in tumo tissues; the mutation status of patients with multiple osteochondromas correlates with decreased EXT1 or EXT2 expression, loss of EXT expression disrupts the function of the EXT1/2 complex in heparan sulfate proteoglycan biosynthesis, resulting in the intracellular accumulation of heparan sulfate proteoglycan core proteins in tumo tissues
N288K
naturally occuring mutation in hereditary multiple exostoses syndrome
R227D
naturally occuring mutation in hereditary multiple exostoses syndrome
R340H
naturally occuring mutation in hereditary multiple exostoses syndrome
R95C
naturally occuring mutation from a patient with clinical seizures-scoliosis-macrocephaly syndrome
S344F
naturally occuring mutation in hereditary multiple exostoses syndrome
S478L
naturally occuring mutation in hereditary multiple exostoses syndrome
V68G
naturally occuring mutation in hereditary multiple exostoses syndrome
additional information
additional information
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enzyme null mutants, defects in Hedgehog and Decapentaplegic signalling, abnormal distribution of Wingless morphogen
additional information
-
enzyme null mutant, dramatically reduced levels of heparan sulfate, impaired Hedgehog, Wingless and Decapentaplegic signalling, alterations in chondroitin sulfate composition and levels
additional information
generation of Ext2+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext2+/- mice compared to wild-type littermates; in vitro EXT1 silencing, suppressed with siRNA, in microvascular endothelial cells under laminar flow; in vitro EXT2 silencing, suppressed with siRNA, in microvascular endothelial cells under laminar flow
additional information
generation of Ext2+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext2+/- mice compared to wild-type littermates; in vitro EXT1 silencing, suppressed with siRNA, in microvascular endothelial cells under laminar flow; in vitro EXT2 silencing, suppressed with siRNA, in microvascular endothelial cells under laminar flow
additional information
generation of Ext2+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext2+/- mice compared to wild-type littermates; in vitro EXT1 silencing, suppressed with siRNA, in microvascular endothelial cells under laminar flow; in vitro EXT2 silencing, suppressed with siRNA, in microvascular endothelial cells under laminar flow
additional information
-
generation of Ext1+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext1+/- mice compared to wild-type littermates
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
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analysis of enzyme mutations in patients with hereditary multiple exostoses, mutation spectrum
medicine
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there is deficiency of heparan sulfate and perlecan, together with accumulation of collagens in the matrix of EXT1-associated osteosarcomas
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