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: 2.16). 04/2010; 152A(4):863-9. DOI: 10.1002/ajmg.a.33240
Source: PubMed


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.
    Full-text · Article · Jan 2014
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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.
    Full-text · Article · Jan 2014 · American Journal of Medical Genetics Part A
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    • "Several patients with type IX collagen mutations presenting with MED and mild myopathy have recently been described [8,9]. Moreover, muscle biopsy from a type IX collagen MED patient showed variability in muscle fiber diameters but normal collagen fibers in the perimysial tissue (cross ectional area, fiber distribution and fiber spacing) [27], indicating that type IX collagen mutations may have a direct effect on muscle morphology. "
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    ABSTRACT: Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are skeletal disorders resulting from mutations in COMP, matrilin-3 or collagen IX and are characterised by short-limbed dwarfism and premature osteoarthritis. Interestingly, recent reports suggest patients can also manifest with muscle weakness. Here we present a detailed analysis of two mouse models of the PSACH/MED disease spectrum; ΔD469 T3-COMP (PSACH) and V194D matrilin-3 (MED). In grip test experiments T3-COMP mice were weaker than wild-type littermates, whereas V194D mice behaved as controls, confirming that short-limbed dwarfism alone does not contribute to PSACH/MED-related muscle weakness. Muscles from T3-COMP mice showed an increase in centronuclear fibers at the myotendinous junction. T3-COMP tendons became more lax in cyclic testing and showed thicker collagen fibers when compared with wild-type tissue; matrilin-3 mutant tissues were indistinguishable from controls. This comprehensive study of the myopathy associated with PSACH/MED mutations enables a better understanding of the disease progression, confirms that it is genotype specific and that the limb weakness originates from muscle and tendon pathology rather than short-limbed dwarfism itself. Since some patients are primarily diagnosed with neuromuscular symptoms, this study will facilitate better awareness of the differential diagnoses that might be associated with the PSACH/MED spectrum and subsequent care of PSACH/MED patients.
    Full-text · Article · Nov 2013 · PLoS ONE
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