Renal disease is an important cause of morbidity in tuberous sclerosis complex (TSC), a Mendelian disorder with autosomal dominant inheritance. TSC is a tumor suppressor gene disorder characterized by the development of benign tumors (hamartomas) in multiple organs including the kidneys. Kidney angiomyolipomas are benign tumors consisting of blood vessels, fat cells and smooth muscle cells, and they occur in approximately 75% of TSC patients over the age of 5 years old. Kidney cysts are also common and occur in about 25% of TSC patients. TSC is a genetic disorder with high penetrance but variable expression. Although the variability in expression is not entirely understood, there is recent evidence that some of the variability in renal disease may be explained by modifier genes. It has been shown that high levels of interferon-gamma in TSC mouse models significantly reduce the severity of renal disease in these animals. It has also been demonstrated that a high expressing allele of interferon-gamma is associated with a decreased frequency of kidney angiomyolipomas in a population of patients with TSC2 mutations. TSC is an excellent model disease for investigating the role of modifier genes in genetic disorders causing renal disease. The goal of the projects outlined below will be to further investigate the role of interferon- gamma as a modifier of renal disease in TSC using mouse models, in vitro studies, and genotype/phenotype studies in a large TSC population. Because of the TSC mouse models available for these studies as well as our prior work on genotype/phenotype studies for TSC, we are in a unique position to further define the role of interferon-gamma in this disorder. Furthermore, because interferon-gamma is an approved drug, we will direct significant effort towards testing interferon-gamma as a prevention or treatment agent in preclinical studies using the TSC mouse models. We anticipate that this work will not only improve our understanding of the role of interferon-gamma as a genetic modifier of kidney disease in TSC, but will also contribute to the development of novel therapeutic strategies for TSC renal disease and related disorders as well as lead to the identification of novel genetic modifiers.
