Histories of Dermatan Sulfate Epimerase and Dermatan 4- O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome

Genes (Basel). 2023 Feb 16;14(2):509. doi: 10.3390/genes14020509.

Abstract

Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-O-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.

Keywords: Ehlers-Danlos syndrome; chondroitin sulfate; dermatan 4-O-sulfotransferase; dermatan sulfate; dermatan sulfate epimerase; glycosaminoglycan; proteoglycan.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dermatan Sulfate* / metabolism
  • Ehlers-Danlos Syndrome* / genetics
  • Female
  • Humans
  • Mice
  • Phenotype
  • Pregnancy
  • Racemases and Epimerases / genetics
  • Sulfotransferases / genetics

Substances

  • Dermatan Sulfate
  • Sulfotransferases
  • Racemases and Epimerases

Grants and funding

This study was supported in part by a Grant-in Aid for Scientific Research (C) from the Japan Society for the Promotion of Science, Japan (19K07054 to S.M.; 21K06552 to S.Y.) and a Grant-in Aid for the Research Center for Pathogenesis of Intractable Diseases from the Research Institute of Meijo University (S.M. and S.Y.).