Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers–Danlos syndrome

Abstract

The sulfated polysaccharide dermatan sulfate (DS) forms proteoglycans with a number of distinct core proteins. Iduronic acid-containing domains in DS have a key role in mediating the functions of DS proteoglycans. Two tissue-specific DS epimerases, encoded by DSE and DSEL, and a GalNAc-4-O-sulfotransferase encoded by CHST14 are necessary for the formation of these domains. CHST14 mutations were previously identified for patients with the musculocontractural type of Ehlers-Danlos syndrome (MCEDS). We now identified a homozygous DSE missense mutation (c.803C>T, p.S268L) by the positional candidate approach in a male child with MCEDS, who was born to consanguineous parents. Heterologous expression of mutant full-length and soluble recombinant DSE proteins showed a loss of activity towards partially desulfated DS. Patient-derived fibroblasts also showed a significant reduction in epimerase activity. The amount of DS disaccharides was markedly decreased in the conditioned medium and the cell fraction from cultured fibroblasts of the patient when compared with a healthy control subject, whereas no apparent difference was observed in the chondroitin sulfate (CS) chains from the conditioned media. However, the total amount of CS disaccharides in the cell fraction from the patient was increased ∼1.5-fold, indicating an increased synthesis or a reduced conversion of CS chains in the cell fraction. Stable transfection of patient fibroblasts with a DSE expression vector increased the amount of secreted DS disaccharides. DSE deficiency represents a specific defect of DS biosynthesis. We demonstrate locus heterogeneity in MCEDS and provide evidence for the importance of DS in human development and extracellular matrix maintenance.

Glycosaminoglycan and proteoglycan in skin aging

“…Next, the GAG chain-synthesizing processes require the addition of D-glucuronic acid as a component of the disaccharide units, for chain elongation of CS and HS, and the epimerization of Dglucuronic acid into L-iduronic acid for the formation of DS and HP by dermatan sulfate epimerase (DSE) and D-glucuronyl C5-epimerase (GLCE), respectively [5,16]. Therefore, the basic disaccharide unit of CS is a pair of D-glucuronic acid (ß13) and N-acetyl-D-galactosamine (ß14) molecules and that of DS is a pair of L-iduronic acid (α13) and N-acetyl-D-galactosamine (ß14) molecules ( Table 1) [7].…”

Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

“…A mutation in DSE (p.Ser268Leu) has been shown to cause Ehlers-Danlos syndrome musculocontractural type 2 [87]. Clinical features including hypermobility of the finger, elbow, and knee joints, characteristic facial features, contracture of the thumbs and feet, and myopathy have been observed in these patients.…”

“…Clinical features including hypermobility of the finger, elbow, and knee joints, characteristic facial features, contracture of the thumbs and feet, and myopathy have been observed in these patients. Epimerase activity is markedly reduced not only in the recombinant mutant DSE (p.Ser268Leu) but also in the cell lysate from these patients [87]. In addition, a decrease in the biosynthesis of DS accompanied by an increase in that of CS has been reported in the fibroblasts of these patients.…”

A genome wide association study of fast beta EEG in families of European ancestry

“…Variation within DSE has been associated with several cancers (Gouignard et al, 2016a; Thelin et al, 2013, 2012), Heschl’s Gyrus thickness (Cai et al, 2014), and is also a notable risk factor for Ehlers-Danlos syndrome, with a subtype specifically linked to dysfunction of DSE (Müller et al, 2013). Recent work by Gouignard et al (Gouignard et al, 2016b) demonstrates a functional role for dse (the protein encoded by DSE ) in cranial neural crest cell migration and in cell adhesion providing a potential biological mechanism linking DSE dysfunction to Ehlers-Danlos syndrome and other neural crest related disorders (i.e., neurocristopathies); the knockdown of dse impaired the correct activation of transcription factors involved in the epithelial-mesenchymal transition and reduced the extent of neural crest cell migration, subsequently leading to a decrease in neural crest-derived craniofacial skeleton, melanocytes and dorsal fin structures.…”