Abstract
Glycosaminoglycans (GAGs) including chondroitin sulfate, dermatan sulfate, and heparan sulfate are covalently attached to specific core proteins to form proteoglycans, which are distributed at the cell surface as well as in the extracellular matrix. Proteoglycans and GAGs have been demonstrated to exhibit a variety of physiological functions such as construction of the extracellular matrix, tissue development, and cell signaling through interactions with extracellular matrix components, morphogens, cytokines, and growth factors. Not only connective tissue disorders including skeletal dysplasia, chondrodysplasia, multiple exostoses, and Ehlers-Danlos syndrome, but also heart and kidney defects, immune deficiencies, and neurological abnormalities have been shown to be caused by defects in GAGs as well as core proteins of proteoglycans. These findings indicate that GAGs and proteoglycans are essential for human development in major organs. The glycobiological aspects of congenital disorders caused by defects in GAG-biosynthetic enzymes including specific glysocyltransferases, epimerases, and sulfotransferases, in addition to core proteins of proteoglycans will be comprehensively discussed based on the literature to date.
Highlights
Glycosaminoglycans (GAGs), including chondroitin sulfate (CS), dermatan sulfate (DS), and heparan sulfate (HS), are linear polysaccharides that are covalently attached to core proteins, forming proteoglycans (PGs)
The levels of HS and HS-PG, perlecan, were markedly lower in cultured fibroblasts from patients than those from normal subjects, whereas the levels of CS-PG and DS-PG, versican and decorin, respectively, in the fibroblasts of patients corresponded to the fibroblasts of normal subjects (Ritelli et al, 2014). These findings suggest that the causative mutations of spondyloepimetaphyseal dysplasia with joint laxity type 1 may affect the biosynthesis of only HS, and not CS or DS, which results in the skeletal and joint hallmarks of both disorders
The protein level of the mutant EXT2, p.Met87Arg/p.Arg95Cys, in fibroblasts from patients was lower than that from control fibroblasts (Farhan et al, 2015). These findings indicate that EXT2 and/or HS side chains of HS-PGs may contribute to normal brain development, possibly by regulating the signaling pathway of Wnt as well as fibroblast growth factor (FGF) and/or by controlling the assembly of extracellular matrix
Summary
Glycosaminoglycans (GAGs), including chondroitin sulfate (CS), dermatan sulfate (DS), and heparan sulfate (HS), are linear polysaccharides that are covalently attached to core proteins, forming proteoglycans (PGs). Homozygous or compound heterozygous mutations in CSGALNACT1 cause mild skeletal dysplasia, joint laxity, a short stature with an advanced bone age, facial dysmorphism, and mild language delay (Table 2; Vodopiutz et al, 2017; Mizumoto et al, 2020).
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