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

Abstract

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 beta-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 beta-sheet region of the vWFA domain (aa. 120-127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the beta-sheet regions, one novel mutation (p.F105S) is located outside the beta-sheet region, within an alpha-helix region.

Increased expression of matrilin‐3 not only in osteoarthritic articular cartilage but also in cartilage‐forming tumors, and down‐regulation of SOX9 via epidermal growth factor domain 1–dependent signaling

“…Involvement of several missense MATN3 mutations has been observed in MED (6,7). These mutations cause misfolding of the protein (24), resulting in accumulation and stress in the endoplasmic reticulum and apoptosis of chondrocytes due to alterations in the secretion machinery of the chondrocytes (25).…”

“…Several MATN3 mutations are involved in multiple epiphyseal dysplasia (MED) (6,7), and another mutation of MATN3 is statistically significantly associated with hand osteoarthritis (8). Furthermore, osteoarthritis in humans is accompanied by increased MATN3 accumulation in the extracellular matrix (9).…”

Recent advances in association studies of osteoarthritis susceptibility genes

“…Matrillin 3 has a VWA domain, and MATN3 mutations that cause multiple epiphyseal dysplasia are clustered in this domain. 17,18 The DVWA protein binds to b-tubulin, and the binding is influenced by the missense SNPs. The isoform produced from the overrepresented allele in knee OA (Y169-C260) showed a weaker interaction with b-tubulin than those produced from other alleles.…”

Novel mutations in exon 2 ofMATN3affect residues within the α-helices of the A-domain and can result in the intracellular retention of mutant matrilin-3

“…Of the 12 MATN3 mutations reported to date, 10 of these affect residues in the 6 β-strands, indeed mutations have now been reported in 5 of the 6 β-strands that comprise the β-sheet (Cotterill, et al, 2005;Jackson, et al, 2004;Mabuchi, et al, 2004;Maeda, et al, 2005;Mostert, et al, 2003). The two exceptions to this rule are p.Arg70His, located in a linker region and only 7 residues downstream from the amino-terminal cysteine residue of the A-domain (Maeda, et al, 2005), and p.Phe105Ser in the α1 helix of the A-domain (Mabuchi, et al, 2004). In addition, a non-synonymous polymorphism has been identified in the α7 helix that has an allele frequency in the general population of 0.05 (Jackson, et al, 2004).…”

“…Many of the mutations in these genes cluster in distinct DOI: 10.1002/humu.9518 regions of the protein and usually affect conserved residues that are important for the structure and/or function of the relevant gene products (Briggs and Chapman, 2002). This is particularly the case with MATN3 and to date all MED-causing mutations affect residues within, or closely associated with, the single A-domain of matrilin-3 (Cotterill, et al, 2005;Jackson, et al, 2004;Mabuchi, et al, 2004;Maeda, et al, 2005;Mostert, et al, 2003).…”