The musculocontractural type of Ehlers–Danlos syndrome (MCEDS) is characterized by distinct craniofacial features, multisystem congenital malformations and progressive fragility of connective tissues (Zhang et al., 2010; Kosho, 2016). This rare intractable disorder is caused by recessive loss-of-function mutations in genes that encode dermatan sulfate (DS) biosynthetic enzymes, including dermatan 4-O-sulfotransferase 1 (CHST14) and DS epimerase-1 (DS-epi1). Glycosaminoglycans (GAGs), such as DS, chondroitin sulfate (CS) and heparan sulfate (HS), are side chains of repeating disaccharides, which are covalently attached to distinct core proteins in the Golgi complex to form cell surface and extracellular matrix proteoglycans (PGs) (Iozzo and Schaefer, 2015). DS is formed from CS by the partial conversion of glucuronic acid (GlcA) into iduronic acid (IdoA) (Trowbridge and Gallo, 2002; Thelin et al., 2013). The content of IdoA is variable and ranges from one IdoA residue per chain to nearly 100% IdoA; thus, the name CS/DS is assigned to describe the hybrid nature of the chain. DS-epi1 and DS-epi2, which are encoded by Dse and Dse-like (Dsel), respectively, mediate the epimerization of a carboxyl group at C5 to form IdoA
