title: Mild myopathy is associated with COMP but not MATN3 mutations in mouse models of genetic skeletal diseases.
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.
authors: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors: Katarzyna A
authors: KA
authors: Piróg
authors: Yoshihisa
authors: Y
authors: Katakura
authors: Aleksandr
authors: A
authors: Mironov
authors: Michael D
authors: MD
authors: Briggs
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000150:complications / Q000235:genetics*; D064236:Cartilage Oligomeric Matrix Protein / Q000235:genetics*; D004195:Disease Models, Animal; D064235:Matrilin Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D053580:Muscle Strength; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics*; D009154:Mutation
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; C577546:Matn3 protein, mouse; D064235:Matrilin Proteins