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.
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.
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By the Health On the Net Foundation. Click 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 the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
The MHE Research Foundation is proud to be working with the EuroBoNeT consortium, a European Commission
granted Network of Excellence for studying the pathology and genetics of bone tumors.
granted Network of Excellence for studying the pathology and genetics of bone tumors.
