The aim of this research proposal is to define the normal structure and function of the human cartilage specific chondroitin sulfate core protein and the associated link protein. Secondly, to determine the role mutations in the genes for these proteins play in heritable diseases of cartilage. The diseases include calcium pyrophosphate dehydrate crystal deposit disease, primary generalized osteoarthritis, and arthro-ophthalmopathy. Since these diseases are inherited as a dominant trait in a Mendelian pattern, genetic linkage analysis and modern methods of molecular biology can be used to identify the exact molecular defect causing the disease in the families. Studies will begin by defining the normal cDNA and gene structure of the human chondroitin sulfate core protein and the human link protein. Then restriction fragment length polymorphisms (RFLPs) will be defined for these genes and then will be used to determine linkage between the genes for these proteins and the families with inherited osteoarthritis. The exact nature of the molecular defect will then be determined by nucleotide sequencing of DNA amplified by the polymerase chain reaction. The results of this study will define the exact cause of heritable osteoarthritis in man as well as provide new methods for diagnosing the disease. In addition, information derived from this work will provide the basis for creating animal model systems for the disease in which the pathoetiology of the disease can be followed and provide systems to test new methods of treating these diseases in man.