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

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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 osteoarthritis1,2,3. 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. 413). 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 vitro14,15. A recessive form of MED (EDM4) has also been reported; it is caused by a mutation in the diastrophic dysplasia sulfate transporter gene16 (SLC26A). A genomewide screen of family with autosomal-dominant MED not linked to the EDM1–3 genes17 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.

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Figure 1: Pedigree of family A.
Figure 2: Multipoint analysis of markers on chromosome 2.
Figure 3: Confirmation of mutations in MATN3 by pyrosequencing.
Figure 4: Sequence and restriction fragment length polymorphism analysis of family B.
Figure 5: Radiographs of the pelvis and knees in family B (proband DL and his affected father).

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We thank the families for their help and interest in this study, D. Tuckwell, A. Wallace and C. Baldock for helpful discussions and J. Leroy who originally diagnosed MED in family A. M.D.B. and J.L. are Research Fellows of the Arthritis Research Campaign (ARC) and the support of the ARC (grant B0644 to M.D.B. and M.E.G.), the Royal Society (grant 20911 to M.D.B.) and The Flanders Fund for Scientific Research (grant G.0013.97 to G.R.M.) is gratefully acknowledged. Genotyping was performed in the ARC Epidemiology Research Unit (ARC-ERU) at the University of Manchester. We thank S. Eyre (ARC-ERU) and K. Walker (Pyrosequencing AB) for their help with some of these studies.

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Correspondence to Michael D. Briggs.

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