Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis

Hum Mutat. 2015 May;36(5):535-47. doi: 10.1002/humu.22774. Epub 2015 Apr 6.


Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.

Keywords: CHST14; DSE; EDS; Ehlers-Danlos syndrome; dermatan 4-O-sulfotransferase-1; dermatan sulfate epimerase-1.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Biopsy
  • Child
  • Collagen / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dermatan Sulfate / biosynthesis*
  • Ehlers-Danlos Syndrome / diagnosis
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / metabolism*
  • Exons
  • Extracellular Matrix / metabolism
  • Facies
  • Female
  • Fibronectins / metabolism
  • Genetic Heterogeneity*
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Pedigree
  • Phenotype*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sequence Alignment
  • Skin / pathology
  • Skin / ultrastructure
  • Sulfotransferases / chemistry
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism
  • Young Adult


  • Antigens, Neoplasm
  • DNA-Binding Proteins
  • Fibronectins
  • Neoplasm Proteins
  • RNA, Messenger
  • Dermatan Sulfate
  • Collagen
  • Sulfotransferases
  • dermatan-4-sulfotransferase-1
  • DSE protein, human

Supplementary concepts

  • Ehlers-Danlos syndrome, progeroid form