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Lookup NU author(s): Professor John LoughlinORCiD
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Multiple epiphyseal dysplasia (MED) is a clinically variable and genetically heterogeneous chondrodysplasia characterized by mild to moderate short stature and early onset osteoarthritis. Some forms of MED result from mutations in the gene encoding the cartilage structural protein matrilin-3 (MATN3). The majority of MATN3 mutations affect conserved residues within the beta-sheet of the single A-domain of matrilin-3. These mutations cause the protein to misfold and prevent its secretion from the rER, both in vitro and in vivo. More recently a single mutation (p.Phe105Ser) has been identified within the alpha1-helix of the A-domain, but its affect on the structure and/or function of matrilin-3 is unknown. In this paper we describe the characterization of two additional alpha-helical mutations (p.Ala173Asp and p.Lys231Asn) and show that both p.Phe105Ser and pAla173Asp prevent the secretion of A-domain in vitro. In contrast, p.Lys231Asn does not prevent the secretion of matrilin-3 A-domain, nor does it disrupt the structure of this domain or inhibit its binding to type II or type IX collagen. Therefore, despite extensive biochemical analysis the disease mechanism of p.Lys231Asn remains unresolved and care should be taken in counseling for these types of mutation in MATN3.
Author(s): Fresquet M, Jackson GC, Loughlin J, Briggs MD
Publication type: Article
Publication status: Published
Journal: Human Mutation
Year: 2008
Volume: 29
Issue: 2
Pages: 330
ISSN (print): 1059-7794
ISSN (electronic): 1098-1004
Publisher: John Wiley & Sons, Inc.
URL: http://dx.doi.org/10.1002/humu.9518
DOI: 10.1002/humu.9518
Notes: 071161/Z/03/Z/United Kingdom Wellcome Trust Journal Article Research Support, Non-U.S. Gov't United States
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