DIVERSE MUTATIONS IN THE GENE FOR CARTILAGE OLIGOMERIC MATRIX PROTEININ THE PSEUDOACHONDROPLASIA MULTIPLE EPIPHYSEAL DYSPLASIA DISEASE SPECTRUM

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) a re autosomal dominant osteochondrodysplasias that result in mild to se vere short-limb dwarfism and early-onset osteoarthrosis. PSACH and som e forms of MED result from mutations in the gene for cartilage oligome ric matrix protein (COMP; OMIM 600310 [http://www3.ncbi.nlm.nih.gov:80 / htbin-post/Omim/dispmim?600310]). We report the identification of CO MP mutations in an additional 14 families with PSACH or MED phenotypes . Mutations predicted to result in single-amino acid deletions or subs titutions, all in the region of the COMP gene encoding the calmodulin- like repeat elements, were identified in patients with moderate to sev ere PSACH. We also identified within this domain a missense mutation t hat produced MED Fairbank. In two families, one with mild PSACH and th e second with a form of MED, we identified different substitutions for a residue in the carboxyl-terminal globular region of COMP. Both the clinical presentations of these two families and the identification of COMP-gene mutations provide evidence of phenotypic overlap between PS ACH and MED. These data also reveal a role for the carboxyl-terminal d omain in the structure and/or function of COMP.