Abstract
The indispensable roles of dermatan sulfate-proteoglycans (DS-PGs) have been demonstrated in various biological events including construction of the extracellular matrix and cell signaling through interactions with collagen and transforming growth factor-β, respectively. Defects in the core proteins of DS-PGs such as decorin and biglycan cause congenital stromal dystrophy of the cornea, spondyloepimetaphyseal dysplasia, and Meester-Loeys syndrome. Furthermore, mutations in human genes encoding the glycosyltransferases, epimerases, and sulfotransferases responsible for the biosynthesis of DS chains cause connective tissue disorders including Ehlers-Danlos syndrome and spondyloepimetaphyseal dysplasia with joint laxity characterized by skin hyperextensibility, joint hypermobility, and tissue fragility, and by severe skeletal disorders such as kyphoscoliosis, short trunk, dislocation, and joint laxity. Glycobiological approaches revealed that mutations in DS-biosynthetic enzymes cause reductions in enzymatic activities and in the amount of synthesized DS and also disrupt the formation of collagen bundles. This review focused on the growing number of glycobiological studies on recently reported genetic diseases caused by defects in the biosynthesis of DS and DS-PGs.
Highlights
Dermatan sulfate (DS) is a linear polysaccharide that has been classified as a sulfated glycosaminoglycan, which is covalently attached to the core proteins of proteoglycans (PGs) [1,2,3,4]
DS chains are modified by sulfation at the C-2 and C-4 positions on IdoUA and GalNAc residues, respectively, which is a structural fundament to a wide range of biological events involving DS such as the assembly of extracellular matrices, signal transduction through binding to growth factors, wound healing, and anti-coagulation [2,3]
Recent advances in genetic and glycobiological studies on connective tissue disorders have clarified the biological significance of DS side chains and the core proteins of dermatan sulfate-proteoglycans (DS-PGs)
Summary
Dermatan sulfate (DS) is a linear polysaccharide that has been classified as a sulfated glycosaminoglycan, which is covalently attached to the core proteins of proteoglycans (PGs) [1,2,3,4]. Compound heterozygous or homozygous mutations (p.Met1?, p.Ser65Gly, p.Pro67Leu, p.Asp156Asn, p.Arg232Cys, and p.Cys300Ser) in B3GALT6 cause an autosomal-recessive disorder, spondyloepimetaphyseal dysplasia with joint laxity type 1, which is characterized by kyphoscoliosis, clubfeet, hip dislocation, elbow contracture, platyspondyly, and craniofacial dysmorphisms including a small mandible with a cleft palate, prominent eyes, and a long upper lip (Table 1, MIM#271640) [38,39,40]. Alazami et al detected a homozygous missense mutations (p.Phe186Lue and p.Arg179_Arg180dup) in patients with profound joint laxity, severe kyphoscoliosis, spondyloepimetaphyseal dysplasia, arthrogryposis, and joint dislocation [41] These findings indicate that partial defects in DS, CS, and heparan sulfate due to mutations in B3GALT6 affect the development of the skeleton, and the skin with different or a wide range of symptoms in each patient. Hypertelorism, proptosis, downslanting palpebral fissures, frontal bossing, malar hypoplasia, pectus deformities, joint hypermobility or contracture, skin striae, a bifid uvula, cervical spine instability, ventricular dilation, hip dislocation, platyspondyly, phalangeal dysplasia, and dysplastic epiphyses of the long bones
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