Chondroitin sulfate (CS) dermatan sulfate (DS), and CS/DS hybrid chains are biologically active like heparan sulfate, and structurally the most complex species of the glycosaminoglycan family along with heparan sulfate. They exist at the cell surface and extracellular matrix in the form of proteoglycans. They function as regulators of functional proteins such as growth factors, cytokines, chemokines, adhesion molecules, and lipoproteins through interactions with the ligands of these proteins via specific saccharide domains. Structural alterations have been often implicated in pathological conditions, such as cancer and atherosclerosis. Recent microsequencing of CS/DS oligosaccharides that bind growth factors, such as pleiotrophin, and various monoclonal antibodies against CS/DS, have revealed a considerable number of unique oligosaccharide sequences. This review focuses on recent advances in the study of the structure-function relation of CS, DS and their hybrid chains in physiological and pathological conditions.

Ehlers‐Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4‐O‐sulfotransferase 1 (D4ST1), which transfers active sulfate from 3′‐phosphoadenosine 5′‐phosphosulfate to position 4 of the N‐acetyl‐D‐galactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS. Hum Mutat 31:1–9, 2010.