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.
Highlights
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are skeletal dysplasias associated with short limbed dwarfism, lower limb deformities and early onset osteoarthritis [1,2]
They form a distinct spectrum of disease severity and the autosomal dominant forms result from mutations in the genes encoding three extracellular matrix (ECM) molecules, cartilage oligomeric matrix protein (COMP; PSACH and severe MED) [1,3], matrilin-3 (MED) [4] and type IX collagen (MED) [5,6]
COMP protein was detected in the cartilage growth plate (GP), articular cartilage (AC), patellar tendon (PT), meniscus (M), skeletal muscle, Achilles tendon, fibrocartilage of the endo-osseous junction and in the myotendinous junction (Figure S1 and data not shown) [26].We observed no retention of mutant COMP in the skeletal muscle tissue at 3 weeks
Summary
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are skeletal dysplasias associated with short limbed (upper and lower limbs) dwarfism, lower limb deformities and early onset osteoarthritis [1,2] They form a distinct spectrum of disease severity and the autosomal dominant forms result from mutations in the genes encoding three extracellular matrix (ECM) molecules, cartilage oligomeric matrix protein (COMP; PSACH and severe MED) [1,3], matrilin-3 (MED) [4] and type IX collagen (MED) [5,6]. PSACH and MED are defined as skeletal dysplasias, or chondrodysplasias, indicating the underlying cartilage pathology Patients with these diseases (predominantly those with COMP and type IX collagen gene mutations) are occasionally referred to neuromuscular clinics with symptoms of a ‘non-defined’ mild myopathy before being correctly diagnosed with chondrodysplasia [7,8,9]. We have previously described clinical data suggesting that myopathy can be associated with T3COMP mutations in patients with PSACH and MED [9,26]
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