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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.

Skeletal dysplasia is a group of disorders of the skeleton that result from derangement of growth, development and/or differentiation of the skeleton. Nearly 300 disorders are included; most of them are monogenic diseases. Responsible genes for skeletal dysplasia have been identified in more than 150 diseases mainly through positional cloning. Identification of disease genes would improve patient care through genetic diagnosis as well as improving our understanding of the diseases and molecular mechanism of skeletal tissue formation. Studies of skeletal dysplasia would also help identify disease genes for common diseases affecting bones and joints. In this study, the author reviews recent advances and the current status of the genetic analysis of skeletal dysplasia and its impacts on research into skeletal biology.

Osteoarthrosis (OA) is a common cause of musculoskeletal disability characterized by late-onset degeneration of articular cartilage. Although several candidate genes have been reported, susceptibility genes for OA remain to be determined. Hereditary osteochondral dysplasias produce severe, early-onset OA and hence are models for common idiopathic OA. Among them are pseudoachondroplasia and multiple epiphyseal dysplasia, both of which are caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. Therefore, COMP may be a susceptibility gene for OA. We screened for polymorphisms by direct sequencing of all exons of the COMP gene with their flanking intron sequences and the promoter region. We identified 16 polymorphisms, of which 12 were novel. Using six polymorphisms spanning the entire COMP gene, we examined the association of COMP in Japanese patients with OA of the knee and hip joints. Genotype and allele frequencies of the polymorphisms were not significantly different between OA and control groups, and there was no significant difference in haplotypes. These results do not support an association between COMP and OA in the Japanese population.