This project proposes to investigate the role of defects in cartilage collagens in the chondrodysplasias. The chondrodysplasias are disorders of connective tissue clinically defined by disproportionate short stature and skeletal anomalies. Severity ranges from mild to lethal, and osteoarthritis is a common feature of many of these disorders. Defects in the type II collagen gene (COL2Al) have been characterized in a few cases of spondyloepiphyseal dysplasia (SED), achondrogenesis II, and hypochondrogenesis, and genetic linkage analysis has implicated defects in COL2A1 in some kindreds with Stickler syndrome (hereditary osteoarthropathy) and autosomal dominant osteoarthritis. We hypothesize that defects in other cartilage-specific collagen genes underlie additional chondrodysplasias. The goals of this proposal are 1) to further characterize mutations in COL2Al responsible for the disorders listed above, 2) to correlate the location and nature of the mutations with clinical phenotypes, and 3) to develop and implement molecular tools to determine the role of defects in other cartilage-specific collagens. To achieve these goals, cDNA will be analyzed from patients with SED, achondrogenesis, and hypochondrogenesis, using current molecular techniques. To study the roles of the other cartilage-specific collagens (types IX, X, and XI), DNA polymorphisms for these genes will be developed to facilitate testing these loci as """"""""candidate genes"""""""" in families with Stickler syndrome, multiple epiphyseal dysplasia, and similar disorders. Understanding the molecular defects that produce these diseases should clarify the chromosomal locations of the disorders and determine the contribution of mutations in additional collagen genes to heritable disorders of connective tissue.
