COL5A1 signal peptide mutations interfere with protein secretion and cause classic Ehlers-Danlos syndrome

Hum Mutat. 2009 Feb;30(2):E395-403. doi: 10.1002/humu.20887.


Classic Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disease characterized by skin hyperextensibility, atrophic scarring, joint hypermobility and generalized tissue fragility. Mutations in COL5A1 and COL5A2, encoding the type V collagen proalpha1- and proalpha2-chain, are found in approximately 50% of patients with classic EDS. The majority of mutations lead to a non-functional COL5A1 allele, as a result of the introduction of a premature stopcodon in one COL5A1 transcript. A minority of mutations affect the structure of the type V collagen central helical domain. We show that mutations in the signal peptide (SP) domain of the preproá1(V)-collagen chain cause classic EDS. The missense mutations (p.L25R and p.L25P) are located in the crucial hydrophobic SP core, which is indispensible for preprotein translocation into the endoplasmic reticulum. As a result, mutant type V procollagen is retained within the cell, leading to a decreased amount of type V collagen in the extracellular matrix and disturbed collagen fibrillogenesis. Our findings further support the observation that decreased availability of type V (pro)collagen is a key factor and a shared mechanism in the pathogenesis of classic EDS.

Publication types

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

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Cell Line
  • Child
  • Child, Preschool
  • Collagen Type V / chemistry
  • Collagen Type V / genetics*
  • Collagen Type V / metabolism*
  • DNA Mutational Analysis
  • Ehlers-Danlos Syndrome / genetics*
  • Female
  • Fibrillar Collagens / ultrastructure
  • Heterozygote
  • Humans
  • Immunoblotting
  • Infant
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Plasmids / genetics
  • Protein Sorting Signals / genetics*


  • COL5A1 protein, human
  • Collagen Type V
  • Fibrillar Collagens
  • Mutant Proteins
  • Protein Sorting Signals