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.

Human Mutation
Maryline FresquetMichael D Briggs

Abstract

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 counsel...Continue Reading

Citations

Oct 24, 2009·Cell and Tissue Research·Raymond P Boot-Handford, Michael D Briggs
Jun 24, 2009·Genetics in Medicine : Official Journal of the American College of Medical Genetics·A Craig ChinaultLee-Jun C Wong
Jul 26, 2017·American Journal of Medical Genetics. Part a·Karthika BalasubramanianDaniel H Cohn
Mar 29, 2014·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Sara E Patterson, Caroline N Dealy
Oct 27, 2011·Journal of Oncology·Ren-Kui BaiLee-Jun C Wong
Jul 8, 2020·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Ella P DennisMichael D Briggs
Feb 20, 2013·International Journal of Experimental Pathology·Adam ByronMartin J Humphries
Dec 18, 2010·The International Journal of Biochemistry & Cell Biology·Andreas R KlattRaimund Wagener

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