Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by joint pain and stiffness, delayed and irregular ossification of epiphyses, and early‐onset osteoarthritis. Six genes responsible for MED have been identified, including COMP , COL9A1 , COL9A2 , COL9A3 , DSTDT and MATN3. MATN3 encodes matrilin‐3, a cartilage‐specific extracellular matrix protein. To date, seven different MATN3 mutations have been identified; all are located within the β‐sheet regions of the von Willebrand factor type A (vWFA) domain, which is encoded by exon 2. We examined MATN3 mutations in27 Japanese MED patients who were possibly autosomal dominant inheritance and had been excluded for COMP mutations. Ten of them had a positive family history. We examined all eight exons of MATN3 by PCR and direct sequencing from genomic DNA. We have identified four missense mutations in eight unrelated families; two are novel, and two have been characterized previously. Like previously characterized MATN3 mutations, those identified in this study are clustered within exon 2, specifically in and around the 2nd β‐sheet region of the vWFA domain (aa. 120‐127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the β‐sheet regions, one novel mutation (p.F105S) is located outside the β‐sheet region, within an α‐helix region. © 2004 Wiley‐Liss, Inc.