COL9A3: A third locus for multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia:(MED), an autosomal dominant osteochondrodysp lasia, is a clinically and genetically heterogeneous disorder characterized by mild short stature and early-onset osteoarthritis. The phenotypic spect rum includes the mild Ribbing type, the more severe Fairbank type, and some unclassified forms. Linkage studies have identified two loci for MED. One of these, EDM1, is on chromosome 19, in a region that contains the cartilag e oligomeric matrix protein (COMP) gene. Mutations have been identified in this gene in patients with the Ribbing type, the Fairbank type, and unclass ified forms of MED. The second locus, EDM2, maps to chromosome 1, in a regi on spanning COL9A2. Recently, a splice-site mutation was found in COL9A2, c ausing skipping of exon 3 in one family with MED. Because of the exclusion of the EDM1 and EDM2 loci in some families, the existence of a third locus has been postulated. We report here one family with MED, evaluated clinical ly and radiologically and tested for linkage with candidate genes, includin g COMP, COL9A1, COL9A2, and COL9A3. No linkage was found with COMP, COL9A1, or COL9A2, but an inheritance pattern consistent with linkage was observed with COL9A3. Mutation analysis of COL9A3 identified an A-->T transversion in the acceptor splice site of intron 2 in affected family members. The mut ation led to skipping of exon 3 and an in-frame deletion of 12 amino acid r esidues in the COL3 domain of the alpha 3(IX) chain and thus appeared to be similar to that reported for COL9A2. This is the first disease-causing mut ation identified in COL9A3. Our results also show that COL9A3, located on c hromosome 20, is a third locus for MED.