heparitin-sulfate and Craniofacial-Abnormalities

Glycosaminoglycans, including chondroitin, dermatan, and heparan sulfate, have various roles in a wide range of biological events such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Their polysaccharides covalently attach to the serine residues on specific core proteins through the common linker region tetrasaccharide, -xylose-galactose-galactose-glucuronic acid, which is produced through the stepwise addition of respective monosaccharides by four distinct glycosyltransferases. Mutations in the human genes encoding the glycosyltransferases responsible for the biosynthesis of the linker region tetrasaccharide cause a number of genetic disorders, called glycosaminoglycan linkeropathies, including Desbuquois dysplasia type 2, spondyloepimetaphyseal dysplasia, Ehlers-Danlos syndrome, and Larsen syndrome. This review focused on recent studies on genetic diseases caused by defects in the biosynthesis of the common linker region tetrasaccharide.

Topics: Cell Proliferation; Chondroitin; Craniofacial Abnormalities; Dermatan Sulfate; Dwarfism; Ehlers-Danlos Syndrome; Glycosyltransferases; Heparitin Sulfate; Humans; Joint Instability; Morphogenesis; Mutation; Ossification, Heterotopic; Osteochondrodysplasias; Polydactyly

Mutant mice bearing a targeted disruption of the heparan sulfate (HS) modifying enzyme GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) exhibit severe developmental defects of the forebrain and forebrain-derived structures, including cerebral hypoplasia, lack of olfactory bulbs, eye defects and axon guidance errors. Neural crest-derived facial structures are also severely affected. We show that properly synthesized heparan sulfate is required for the normal development of the brain and face, and that Ndst1 is a modifier of heparan sulfate-dependent growth factor/morphogen signalling in those tissues. Among the multiple heparan sulfate-binding factors potentially affected in Ndst1 mutant embryos, the facial phenotypes are consistent with impaired sonic hedgehog (Shh) and fibroblast growth factor (Fgf) interaction with mutant heparan sulfate. Most importantly, the data suggest the possibility that defects in heparan sulfate synthesis could give rise to or contribute to a number of developmental brain and facial defects in humans.

Topics: Animals; Apoptosis; Brain; Cell Proliferation; Craniofacial Abnormalities; Embryo, Mammalian; Fibroblast Growth Factors; Gene Targeting; Hedgehog Proteins; Heparitin Sulfate; Humans; In Situ Hybridization; Mice; Mice, Knockout; Morphogenesis; Phenotype; Signal Transduction; Sulfotransferases; Trans-Activators