Chondroca1cinosis is a general descript1ive term that describes arthropathies associated with the deposition of calciumcontaining crystals in joints. When the calcium crystals are composed of calcium pyrophosphate dihydrate, the disorder is known as calcium pyrophosphate dihydrate deposition disease (CPPDD) and may occur as a familial disease with an autosomal dominant mode of inheritance. We have established linkage between the disease phenotype and a locus on the short arm of chromosome 5 in two families with the disorder and, using haplotype analysis, we have refined the disease interval to a physical distance of.approximately I5Okbp.Utilizing the physical mapping resources that we have developed through, and adjacent to, the candidate interval, we have detected several potential candidate genes. This application, therefore, proposes to conclude our efforts to identify the CPPDD gene on chromosome 5p. To accomplish this goal we will (1) complete mutation screening on the most obvious and best-characterized candidate, MYOlO, which completely spans the CPPDD interval. We will also characterize the expression of the gene product in presumably disease relevant tissues, including cartilage; (2) if necessary, extend cDNA sequence for two ESTs that map within the candidate interval and that reside within two MYOIO introns. If MYOlO proves not to be the CPPDD gene, these two putative transcripts will be considered positional candidates and screened for potential disease-causing mutations; (3) again; if necessary, extend cDNAs that are adjacent to the candidate interval and that may extend into the interval. If our efforts in Specific Aims I and 2 do not result in the detection of disease-causing mutations in our families, these cDNAs will also be subjected to mutation analyses; and (4) once the CPPDD gene is identified, screen for mutations in other CPPDD families, and in some sporadic cases of CPPDD that resemble the phenotype displayed by our affected family members in order to establish some correlations between genotype and observed phenotypes. Although the candidate gene that we hope to identify as the causative gene for familial CPPDD may not be wholly responsible for calcium deposition in the sporadic and more common forms of CPPDD, a knowledge of the biochemistry of crystal deposition in heritable chondrocalcinosis may lead to a better understanding of mechanisms of calcium deposition in advanced osteoarthritis and other metabolic disorders.
