A recurrent R718W mutation in COMP results in multiple epiphyseal dysplasia with mild myopathy: clinical and pathogenetic overlap with collagen IX mutations.

M ultiple epiphyseal dysplasia (MED) is clinically and genetically a heterogeneous disorder that affects growth centres and results in delayed and irregular mineralisation of the ossification centres. 2 Recessively inherited MED (rMED; MIM 226900) accounts for a significant proportion of MED cases and is associated with mutations in the sulphate transporter gene, DTDST/ SLC26A2. 4 More often, MED is inherited as a dominant trait. Thus far, five different genes have been implicated in dominantly inherited MED: the gene for cartilage oligomeric matrix protein, COMP (MIM 600310); the genes for the a1, a2, and a3 chains of collagen IX, COL9A1 (MIM 120165), COL9A2 (MIM 120260), and COL9A3 (MIM 120270); and the gene for matrilin-3, MATN3 (MIM 602109). Patients with the severe forms of MED have short stature and major disability because of joint pain and stiffness. In the milder forms, height can be normal and joint complaints minimal. Mutations in COMP typically lead to the severe forms of dominant MED (MIM 132400) and can also cause a related but more severe disorder—pseudoachondroplasia (PSACH, MIM 177170). COMP is a pentameric extracellular glycoprotein that belongs to the thrombospondin protein family. It consists of a coiled coil N-terminal domain responsible for pentamerisation, four epidermal growth factor (EGF)-like repeats, eight thrombospondin type 3 (T3) repeats, and a large C-terminal globular domain. Mutations in COMP that cause MED are located in the T3 repeats. 2 Mutations in these repeats alter the conformation of the protein and affect its ability to bind calcium. No mutations have been reported in the N-terminal domain or the EGF-like domains in MED. Only four mutations causing MED have been found in the C-terminal domain—two (T585R and T585M) in patients with unclassified MED, 11 and the other two (R718W and N742fsX743) in patients with ‘‘severe MED’’ and ‘‘ribbing type MED’’, respectively. Altogether eight mutations have been identified in the collagen IX genes in MED patients. 13–18 All reported mutations are clustered in the splice donor or acceptor site of exon 3 of COL9A2 or COL9A3 or in the splice acceptor site of exon 8 of COL9A1. The consequence of these mutations is skipping of exon 3 within the COL3 domain, leading to an inframe 12 amino acid deletion from either the a2(IX) or a3(IX) chain, respectively; or in the case of the a1(IX) chain, skipping of exon 8 and/or exon 10, leading to an in-frame 25, 21, or 49 amino acid deletion within the COL3 domain. Patients with collagen IX mutation are typically of normal >to near normal height. Dysplastic changes are mainly seen in the knees, and the hips are relatively spared. 19 In contrast, the presence of dysplastic capital femoral epiphyses and severely irregular acetabuli is suggestive of COMP mutations. 19 We undertook a clinical and molecular study of two families with an MED phenotype very similar to those individuals previously reported with mutations in the collagen IX genes. Surprisingly, affected members in both families had a mutation in COMP, R718W, suggesting that this mutation and mutations in collagen IX may share the same molecular pathogenesis.