Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency

Abstract Purpose Dermatan sulfate (DS) plays a number of roles in a wide range of biological activities such as cell signaling and tissue morphogenesis through interactions with various extracellular matrix proteins including collagen. Mutations in the carbohydrate sulfotransferase 14 gene (CHST14) encoding CHST14/dermatan 4- O -sulfotransferase-1 (D4ST1), which is responsible for the biosynthesis of DS, cause a recently delineated form of Ehlers-Danlos syndrome (EDS, musculocontractural type 1), an autosomal recessive connective tissue disorder characterized by congenital malformations (specific craniofacial features, and congenital multiple contractures) and progressive fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; and large subcutaneous hematomas). In an attempt to develop a diagnostic screening method for this type of EDS, the amount of DS in the urine of patients was analyzed. Methods Urinary DS was quantified by an anion-exchange chromatography after treatment with DS-specific degrading enzyme. Results DS was not detected in the urine of patients with homo- or compound heterozygous mutations in CHST14 . These results suggest that the quantification of DS in urine is applicable to an initial diagnosis of DS-defective EDS. Conclusions This is the first study to perform a urinary disaccharide compositional analysis of chondroitin sulfate (CS)/DS chains in patients with EDS caused by a CHST14/D4ST1 deficiency, and demonstrated the absence of DS chains. This result suggests systemic DS depletion in this disorder, and also proposes the usefulness of a urinary disaccharide compositional analysis of CS/DS chains as a non-invasive screening method for this disorder.