We performed a genome-wide linkage analysis to identify susceptibility loci in a large six-generation extended family previously reported with early-onset osteoarthritis (OA) DNA sequencing was performed to investigate involvement of the COMP (Cartilage oligomeric matrix protein) gene in this family. The region covering D19S884, D19S226, and D19S414 on chromosome 19p following genome-wide scan from 70 individuals of this kindred showed significant linkage, with a maximum point LOD (logarithm of the odds ratio) score of 2.51 at D19S226. Direct sequencing of the COMP gene, the most plausible candidate gene in the region, identified a c.2152C>T substitution in exon 18 which resulted in a substitution of tryptophan for arginine at position 718 located in the C terminal globular domain of the gene product. A total of 26 individuals were identified with this mutation of which 21 affected individuals had the mutation, and the other five younger individuals (18.6 ± 11.3 years of age) carried the mutation without symptoms. The results indicate that COMP is the disease susceptibility gene and the c.2152C>T mutation in exon 18 could cause early-onset OA phenotypes in this kindred, which is compatible with a previous report that this mutation also causes a mild form of multiple epiphyseal dysplasia (MED).
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