Matrilin-3-type multiple epiphyseal dysplasia (MED) mutations in matnlin-1 and matrilin-4 new disease-causing loci for MED?

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Matrilins (matnlin1-4) are modular adaptor proteins of various connective tissues interacting with collagen fibrils and other martix constituents. All four matrilins are expressed in cartilage but only mutations in the human matrilin-3 gene {MATN3) are associated with multiple epiphyseal dysplasia (MED), a skeletal dysplasia charactenzed by mild dwarfism and early-onset osteoarthritis Most of the MATN3 MED mutations are missense, which pnmanly affect conserved residues of the ßsheet of the von Willebrand factor A-like (vWFA) domain of the protein Recent data indicate that mutant matnlin-3 is retained within the rER as misfolded protein and elicits unfolded protein response and ER stress signaling in chondrocytes The disorder is genetically heterogeneous, and in addition to MATN3, mutations in the genes encoding COMP, COL9A1-A3 anö DTDST have been identified in MED patients, however, the causative mutation(s)/gene(s) tn about 50% of the cases are not known Taking into account the conserved structure, expression pattern and hetero-oligomenzation properties of matnlin family members, MATN1 and MATN4 are good candidates for additional MED loci In this proposal, we plan to introduce MATNS-Xype MED mutations into the conserved sites of munne Matn1/Matn4 and express them in mammalian cells to investigate the effects of mutations on the trafficking and secretion of matnlin-1 and matnlin-4 in vitro In order to determine the in vivo consequence of such mutations, we will generate a munne model by introducing a specific MATN3 MED mutation into the first vWFA domain of mouse matnlin-4 In addition, we have initiated mutation screening of MATN1/MATN4 in MED patients via the "European Skeletal Dysplasia Network" Collectively, these approaches allow us to exclude or include MATN1/MATN4 as MED-causing loci.