Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia

Nat Genet. 2001 Aug;28(4):393-6. doi: 10.1038/ng573.


Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia, primarily characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. Mutations in the genes encoding cartilage oligomeric matrix protein (COMP) and type IX collagen (COL9A2 and COL9A3) have previously been shown to cause different forms of MED (refs. 4-13). These dominant forms of MED (EDM1-3) are caused by mutations in the genes encoding structural proteins of the cartilage extracellular matrix (ECM); these proteins interact with high affinity in vitro. A recessive form of MED (EDM4) has also been reported; it is caused by a mutation in the diastrophic dysplasia sulfate transporter gene (SLC26A). A genomewide screen of family with autosomal-dominant MED not linked to the EDM1-3 genes provides significant genetic evidence for a MED locus on the short arm of chromosome 2 (2p24-p23), and a search for candidate genes identified MATN3 (ref. 18), encoding matrilin-3, within the critical region. Matrilin-3 is an oligomeric protein that is present in the cartilage ECM. We have identified two different missense mutations in the exon encoding the von Willebrand factor A (vWFA) domain of matrilin-3 in two unrelated families with MED (EDM5). These are the first mutations to be identified in any of the genes encoding the matrilin family of proteins and confirm a role for matrilin-3 in the development and homeostasis of cartilage and bone.

MeSH terms

  • Adult
  • Child
  • Chromosomes, Human, Pair 2 / genetics
  • DNA Mutational Analysis
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Femur Head / diagnostic imaging
  • Femur Head / pathology
  • Genetic Linkage
  • Genetic Markers
  • Humans
  • Knee Joint / diagnostic imaging
  • Knee Joint / pathology
  • Lod Score
  • Male
  • Matrilin Proteins
  • Middle Aged
  • Mutation*
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / genetics*
  • Pedigree
  • Physical Chromosome Mapping
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Protein Structure, Tertiary / genetics
  • Radiography
  • von Willebrand Factor / genetics*


  • Extracellular Matrix Proteins
  • Genetic Markers
  • Matrilin Proteins
  • von Willebrand Factor