Mutations in the cartilage oligomeric matrix protein (COMP) gene are responsible for two dominantly inherited skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). Mutation analysis of the COMP gene in Korean patients with PSACH and MED was performed. All nine patients with PSACH had mutations in the COMP gene, while three of the five patients with MED had detectable COMP mutations. Eight mutations, including three novel mutations, were identified in the COMP gene in the patients with PSACH and MED. Six mutations were found within the calmodulin-like repeats (CLRs) domain, especially in the seventh CLR and the other two mutations were in exon 16 outside of CLRs, which encode the C-terminal globular domain. Among the three novel mutations, two were missense mutations (Asp473Tyr, Asp482His) and one was a consecutive two-codon deletion, delAspAsp(469-473) in the five consecutive aspartic acid residues. All three novel mutations produced the PSACH phenotype.Keywords Pseudoachondroplasia AE PSACH AE Multiple epiphyseal dysplasia AE MED AE Cartilage oligomeric matrix protein AE COMP AE Mutation Introduction Pseudoachondroplasia (PSACH; MIM 177170) is a rare dominantly inherited skeletal dysplasia caused by mutations in the cartilage oligomeric matrix protein (COMP; MIM 600310) gene (Briggs et al. 1995;Hecht et al. 1995). It is characterized clinically by short-limb dwarfism, a waddling gait, ligament laxity, and early onset severe osteoarthritis of weight-bearing joints. Some mutations in COMP can lead to a form of multiple epiphyseal dysplasia (MED; MIM 132400), a milder form of the skeletal dysplasia. MED has also been associated with mutations in the genes coding for a1, a2, and a3 chains of collagen IX, SLC26A2 and matrilin-3 (Chapman et al. 2001;Czarny-Ratajczak et al. 2001).The predominant features of MED are mild short stature and stiff or painful joints. The phenomenon of overlap between the mild form of PSACH and the severe form of MED has been noticed not only in clinical and radiographic characteristics but also in biochemical findings (Manabe et al. 1998;Stanescu et al. 1993). Therefore, it is now clear that there is a phenotype overlap between these two diseases.The COMP gene consists of 19 exons and is located on chromosome 19p12-13.1. COMP is a secreted pentameric-adhesive glycoprotein as a member of the thrombospondin family, which is found predominantly in the extracellular matrix of cartilage, tendon, and ligament (Briggs et al. 2002). COMP consists of an N-terminal pentameric domain, four epidermal growth factor (EGF)-like domains, and eight calmodulin-like repeats (CLRs). COMP has been shown to bind calcium cooperatively and to interact with collagen I, II and IX with high affinity.Recently, we studied clinical and molecular characteristics of Korean patients with PSACH. Here we report the COMP gene mutations in patients with PSACH and MED for evaluation of the genotypephenotype relationship.
Spondyloepiphyseal dysplasia congenita (SEDC), an inherited chondrodysplasia, occurs through a mutation in the COL2A1 gene encoding the type II procollagen alpha1 chain, proalpha1 (II). Recently, the authors studied two Korean patients with SEDC. Both these patients had short stature, os odontoideum with or without atlantoaxial instability, platyspondyly, and epiphyseal dysplasia limited to the femoral heads. The more seriously affected patient had shorter height (125 cm), atlantoaxial instability associated with os odontoideum, flat feet, and cleft palate, absence of the femoral head on radiographic and magnetic resonance imaging (MRI), and dislocated proximal femur. The less seriously affected patient was taller (145 cm) and had no atlantoaxial instability, absence of the femoral head on radiography with visible cartilage anlage on MRI, and subluxated cartilaginous femoral head. A mutation analysis was performed using direct sequencing. Two novel dominant mutations were found in the COL2A1 gene of these two patients: G277V and G238S, respectively. Although glycine was substituted with valine and serine in the proalpha1 (II) of these two patients, their phenotypes were significantly different in physical and radiologic evaluations.
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