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Novel mutations in exon 2 of MATN3 affect residues within the alpha-helices of the A-domain and can result in the intracellular retention of mutant matrilin-3

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.

Publication metadata

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.


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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