Abstract
Musculocontractural Ehlers-Danlos syndrome (MC-EDS) is a rare recessive disorder that is characterized by connective tissue fragility, distinct craniofacial features and congenital malformations. MC-EDS patients have defects in the enzymes dermatan sulfate epimerase-1 and dermatan 4-O-sulfotransferase-1, which are involved in the biosynthesis of iduronic acid in the chondroitin sulfate/dermatan sulfate (CS/DS) chains of proteoglycans (PGs). While the connective tissue defect is a result of disturbed collagen fibril assembly based on a decreased iduronic acid content of interacting CS/DS-PGs, the cause of the developmental malformations in MC-EDS is not well understood. This review focuses on a new role of CS/DS-PGs in the development of multipotent and highly migratory neural crest (NC) cells in the Xenopus embryo model of MC-EDS. Single iduronic acid residues in CS/DS-PGs are involved in the formation of NC-derived craniofacial structures by facilitating the migration and adhesion of NC cells to fibronectin. Our results suggest a defect in NC development as cause of the craniofacial and other congenital anomalies in MC-EDS patients, which might contribute to an improved diagnosis and etiology-based therapy. (Less)
Highlights
Chondroitin sulfate/dermatan sulfate proteoglycans (CS/ DS-PGs) are abundant components on the cell surface and in the extracellular matrix (ECM) of connective tissues
Avian and mouse embryos revealed that the CS-PGs aggrecan and versicans V0 and V1 act in the ECM as guidance cues for neural crest (NC) cell migration[19,20,21]
In Xenopus, versicans are expressed in tissues surrounding the migratory cranial neural crest (CNC) and enhance directional migration by confining the pathway of NC cells[22,23]
Summary
Chondroitin sulfate/dermatan sulfate proteoglycans (CS/ DS-PGs) are abundant components on the cell surface and in the extracellular matrix (ECM) of connective tissues. In patients with the very rare progeroid form of EDS9 and a pleiotropic EDS-like disorder[10,11], hypomorphic homozygous mutations in galactosyltransferase 1 and galactosyltransferase 2, respectively, reduce the ability to synthesize the tetrasaccharide linker sequences and the whole GAGs. MC-EDS is the first human disorder that affects the CS/DS biosynthesis[2].
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