Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II

Am J Hum Genet. 1997 Mar;60(3):547-54.


The Ehlers-Danlos syndrome (EDS) is a heterogeneous connective-tissue disorder of which at least nine subtypes are recognized. Considerable clinical overlap exists between the EDS I and II subtypes, suggesting that both are allelic disorders. Recent evidence based on linkage and transgenic mice studies suggest that collagen V is causally involved in human EDS. Collagen V forms heterotypic fibrils with collagen I in many tissues and plays an important role in collagen I fibrillogenesis. We have identified a mutation in COL5A1, the gene encoding the pro(alpha)1(V) collagen chain, segregating with EDS I in a four-generation family. The mutation causes the substitution of the most 5' cysteine residue by a serine within a highly conserved sequence of the pro(alpha)1(V) C-propeptide domain and causes reduction of collagen V by preventing incorporation of the mutant pro(alpha)1(V) chains in the collagen V trimers. In addition, we have detected splicing defects in the COL5A1 gene in a patient with EDS I and in a family with EDS II. These findings confirm the causal role of collagen V in at least a subgroup of EDS I, prove that EDS I and II are allelic conditions, and represent a, so far, unique example of a human collagen disorder caused by substitution of a highly conserved cysteine residue in the C-propeptide domain of a fibrillar collagen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Collagen / genetics*
  • Collagen / ultrastructure
  • Conserved Sequence
  • Cysteine / genetics
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / pathology
  • Female
  • Genetic Linkage
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Procollagen / chemistry
  • Procollagen / genetics
  • Serine / genetics
  • Skin / ultrastructure


  • Procollagen
  • Serine
  • Collagen
  • Cysteine