Heparan sulfate is a complex polysaccharide that plays an important role in several cellular processes, including normal fetal
development, wound healing, inflammation, cancer, neuron degeneration and cardiovascular disorders.
Defects in enzymes involved in heparan sulfate synthesis result in different abnormalities including abnormal skeletal growth.
Heparan sulfate is elongated by the alternating transfer of glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc) units.
Concomitant with elongation, the polymer is modified through a series of reactions that requires the action of several different
enzymes.
The extent of these reactions varies, giving rise to heparan sulfate chains with different structural properties. The chain
elongation reaction has been ascribed to a hetero-oligomeric complex of EXT1 and EXT2.
Mutations in either EXT1 or EXT2 have been linked to the human disorder, hereditary multiple exostoses (HME), characterized
by the formation of cartilage-capped bony outgrowths at the end of the long bones. EXT1 and EXT2 appear to act as tumor
suppressors because loss of heterozygosity of these genes has been observed in exostoses-derived chondrosarcomas and
osteosarcomas.
The individual functions of EXT1 and EXT2 in heparan sulfate chain elongation are currently unknown. EXT1 alone has the
capacity to elongate heparan sulfate chains in vitro.
Furthermore, reduced EXT1 expression levels results in the formation of heparan sulfate chains that are shorter than those
normally synthesized.
The level of EXT2 protein modifies the catalytic properties of EXT1 but the role of EXT2 in heparan sulfate chain elongation is
not clear.
Both EXT1 and EXT2 mRNA is ubiquitously expressed. A high level of expression of Ext1 and Ext2 mRNA has been found in
developing limb buds of mouse embryos and expression was demonstrated to be confined to the proliferating and
prehypertrophic chondrocytes of the growth plate.The gene products, exostosin-1 (EXT1) and exostosin-2 (EXT2), are
endoplasmic reticulum localized type II transmembrane glycoproteins which form a Golgi-localized hetero-oligomeric complex that
catalyzes heparan sulphate (HS) polymerization.Heparan sulphate proteoglycans (HSPG) are large macromolecules composed of
heparan sulphate glycosaminoglycan chains linked to a protein core.
Four HSPG families have been identified: syndecan, glypican, perlecan and isoforms of CD44. HSPGs are required for high-affinity
binding of fibroblast growth factor to its receptor.
Furthermore, an EXT1 homologue in Drosophila (tout-velu, Ttv) has been shown to be required for diffusion of an important
segment polarity protein called Hedgehog (Hh), a homologue of mammalian Indian Hedgehog (IHh). It therefore hypothesized
that EXT mutations affect FGF and IHh signalling within the normal growth plate. Indeed, diminished levels of the EXT1 and
EXT2 protein and of their putative downstream effectors (IHh/PTHrP and FGF signalling pathway) were demonstrated in both
sporadic and hereditary osteochondroma chondrocytes. Moreover, EXT mutations were described to induce cytoskeletal
abnormalities (altered actin distribution) in osteochondroma chondrocytes.
development, wound healing, inflammation, cancer, neuron degeneration and cardiovascular disorders.
Defects in enzymes involved in heparan sulfate synthesis result in different abnormalities including abnormal skeletal growth.
Heparan sulfate is elongated by the alternating transfer of glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc) units.
Concomitant with elongation, the polymer is modified through a series of reactions that requires the action of several different
enzymes.
The extent of these reactions varies, giving rise to heparan sulfate chains with different structural properties. The chain
elongation reaction has been ascribed to a hetero-oligomeric complex of EXT1 and EXT2.
Mutations in either EXT1 or EXT2 have been linked to the human disorder, hereditary multiple exostoses (HME), characterized
by the formation of cartilage-capped bony outgrowths at the end of the long bones. EXT1 and EXT2 appear to act as tumor
suppressors because loss of heterozygosity of these genes has been observed in exostoses-derived chondrosarcomas and
osteosarcomas.
The individual functions of EXT1 and EXT2 in heparan sulfate chain elongation are currently unknown. EXT1 alone has the
capacity to elongate heparan sulfate chains in vitro.
Furthermore, reduced EXT1 expression levels results in the formation of heparan sulfate chains that are shorter than those
normally synthesized.
The level of EXT2 protein modifies the catalytic properties of EXT1 but the role of EXT2 in heparan sulfate chain elongation is
not clear.
Both EXT1 and EXT2 mRNA is ubiquitously expressed. A high level of expression of Ext1 and Ext2 mRNA has been found in
developing limb buds of mouse embryos and expression was demonstrated to be confined to the proliferating and
prehypertrophic chondrocytes of the growth plate.The gene products, exostosin-1 (EXT1) and exostosin-2 (EXT2), are
endoplasmic reticulum localized type II transmembrane glycoproteins which form a Golgi-localized hetero-oligomeric complex that
catalyzes heparan sulphate (HS) polymerization.Heparan sulphate proteoglycans (HSPG) are large macromolecules composed of
heparan sulphate glycosaminoglycan chains linked to a protein core.
Four HSPG families have been identified: syndecan, glypican, perlecan and isoforms of CD44. HSPGs are required for high-affinity
binding of fibroblast growth factor to its receptor.
Furthermore, an EXT1 homologue in Drosophila (tout-velu, Ttv) has been shown to be required for diffusion of an important
segment polarity protein called Hedgehog (Hh), a homologue of mammalian Indian Hedgehog (IHh). It therefore hypothesized
that EXT mutations affect FGF and IHh signalling within the normal growth plate. Indeed, diminished levels of the EXT1 and
EXT2 protein and of their putative downstream effectors (IHh/PTHrP and FGF signalling pathway) were demonstrated in both
sporadic and hereditary osteochondroma chondrocytes. Moreover, EXT mutations were described to induce cytoskeletal
abnormalities (altered actin distribution) in osteochondroma chondrocytes.
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| EXT Gene Section |
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here to verify.# HON Conduct 282463 and is linked on the NIH National Library of Medicine, Directory of Health Organizations (SIS) website, as well as
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