title: 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.
authors.affiliation: Department of Pediatrics I, Division of Human Genetics, Innsbruck Medical University, Anichstrasse 35, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Indrajit
authors.initials: I
authors.lastname: Suresh
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.forename: Munis
authors.initials: M
authors.lastname: Dundar
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Arno
authors.initials: A
authors.lastname: Lingenhel
authors.forename: Andreas
authors.initials: A
authors.lastname: Melmer
authors.forename: Silvia
authors.initials: S
authors.lastname: Lechner
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D002675:Child, Preschool; D003241:Consanguinity; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D058575:Decorin / Q000378:metabolism; D003871:Dermatan Sulfate / Q000096:biosynthesis; D004187:Disaccharides / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D058575:Decorin; D004187:Disaccharides; D009363:Neoplasm Proteins; D003871:Dermatan Sulfate; D015238:Sulfotransferases; C438013:dermatan-4-sulfotransferase-1; C405383:DSE protein, human