Type IX Collagen Gene Mutations Can Result in Multiple Epiphyseal Dysplasia That Is Associated With Osteochondritis Dissecans and a Mild Myopathy

Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
American Journal of Medical Genetics Part A (Impact Factor: 2.05). 04/2010; 152A(4):863-9. DOI: 10.1002/ajmg.a.33240
Source: PubMed

ABSTRACT Multiple epiphyseal dysplasia (MED) is a clinically variable and genetically heterogeneous disease that is characterized by mild short stature and early onset osteoarthritis. Autosomal dominant forms are caused by mutations in the genes that encode type IX collagen, cartilage oligomeric matrix protein, and matrilin-3: COL9A1, COL9A2, COL9A3, COMP, and MATN3, respectively. Splicing mutations have been identified in all three genes encoding type IX collagen and are restricted to specific exons encoding an equivalent region of the COL3 domain in all three alpha(IX) chains. MED has been associated with mild myopathy in some families, in particular one family with a COL9A3 mutation and two families with C-terminal COMP mutations. In this study we have identified COL9A2 mutations in two families with MED that also have osteochondritis dissecans and mild myopathy. This study therefore extends the range of gene-mutations that can cause MED-related myopathy. (c) 2010 Wiley-Liss, Inc.

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Available from: Dominique Marcus-Soekarman, Jan 24, 2014
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    • "(2014), http:// (Jakkula et al., 2003; Jackson et al., 2010; Pirog and Briggs, 2010). Tendons from T585M mice were more lax than controls in cyclic strain tests (Pirog et al., 2010) and this tendon laxity most likely mimic the joint laxity often associated with PSACH (Unger and Hecht, 2001; Jakkula et al., 2003; Posey et al., 2004; Jackson et al., 2010; Pirog and Briggs, 2010). In the T585M-COMP mouse, thicker collagen fibrils were observed in tendons and ligaments and this change in structure may be related to the role of COMP in collagen fibril assembly (Rosenberg et al., 1998; Pirog et al., 2010). "
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    ABSTRACT: Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
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    • "Until now, there have been the following reports in reference to the COL9A3 gene: (A) heterozygous point mutations, causing (1) MED 3 [Lohiniva et al., 2000], sometimes associated with osteochondritis dissecans and a mild myopathy [Jackson et al., 2010]; (2) susceptibility to an intervertebral disc disease [Paassilta et al., 2001]; (3) hearing loss [Asamura et al., 2005]; and (B) large deletions causing complex phenotype including stiffness and pain with limited extension of joints in childhood, with some required surgery in adulthood [Traylor et al., 2010], but not MED. Herein, we report an intriguing case of a family (Figs. 1 and 2A) carrying an autosomal recessive loss of functions COL9A3 mutation and a STL syndrome with intellectual disability (ID). "
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    ABSTRACT: Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36165 · 2.05 Impact Factor
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    • "Type IX collagen is found to be covalently bonded through aldimine-derived crosslinks to the surface of large type II collagen fibrils (Wu et al., 1992) and it is believed to constrain the lateral expansion of these fibrils (Blaschke et al., 2000; Gregory et al., 2000). Missense mutations in the type IX collagen genes have been associated with lumbar disk disease (LDD) (Zhu et al., 2011) and multiple epiphyseal dysplasia (MED) (Jackson et al., 2010) which indirectly leads to the development of OA. "
    Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition, 02/2012; , ISBN: 978-953-51-0063-8
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