The goals of this project are to identify and characterize the molecular bases for two forms of inherited liver disease, cholestasis-lymphedema syndrome (CLS) and familial hyperbileacidemia (FHB). We will work toward this goal through the following three specific aims: 1) identify the gene mutated in CLS, and further genetically characterize this disorder; 2) characterize the expression pattern of the CLS gene and protein; and 3) identify the gene mutated in FHB, and further genetically characterize this disorder. These genes will be genetically localized through use of recently developed, highly efficient genetic mapping techniques, and then candidate genes identified through analysis of available sequence databases, and use of laboratory-based gene identification techniques. Mutations causing CLS and FHB will be identified, and clinical data examined to identify any correlations between the type of mutation present in a patient, and the characteristics of that patient's disease. The types of cells in which the CLS gene is expressed will be identified using in situ hybridization approaches, and the cellular and subcellular localization of the CLS protein will be characterized, using immunohistochemical techniques. The identification of genes mutated in hereditary disorders, and the subsequent characterization of their protein products, has become a valuable tool for increasing our understanding of the pathophysiology of diseases, including disorders of the hepatobiliary system, which affect millions of people in the U.S. Identification of the genetic cause of a disease assists in diagnosis, and also aids further study that may lead to better treatment and prevention. Most importantly, the identification of a disease gene provides specific insight into the biological pathways that are deranged in the illness, and tools for further study of these pathways.
