Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the widespread development of benign growths, often composed of mesenchymal cells, in many tissues and organs. There is unpredictable distribution and severity of these tumor lesions, particularly within the brain, eyes, skin, kidneys, heart and lungs which results in a wide variety of signs, symptoms, and complications. This implies that TSC is a multigenic disorder. The primary genetic defect has been elucidated, the TSC1 and TSC2 genes, but the other genes involved in the tumorigenic pathway remain unknown.

A number of years ago, our laboratory identified HMGA2 as the gene that is inappropriately expressed in a number of benign, mesenchymal tumors. Some of these tumors include pulmonary hamartomas, cardiac rhabdomyoma, and pulmonary lymphangiomyomatosis, which have a considerably higher incidence, of otherwise rare proliferative diseases in TSC patients. Intriguingly, there are two rodent models that harbor mutations in the Tsc2 gene. Even though the spectrum of tumors in these models differs from the human, the tumors lose the Tsc2 gene (as in humans) and were found to express Hmga2. Taken together, this evidence strongly suggests that there could be a link between the HMGA2 and TSC2 pathways.

In order to prove the hypothesis that the two pathways interact, both cell culture and animal experiments will be performed. It is our hypothesis that the loss of Tsc2 expression causes expression of Hmga2, which ultimately leads to tumor formation. In fact, the ELT3 cell line derived from a tumor from the Eker rat uterus does not express Tsc2 but does indeed express Hmga2. In contrast, the normal uterus does not express Hmga2. So, to test our hypothesis, we will express Tsc2 in ELT3 cells and observe the effect on Hmga2 expression. Since tumorigenesis is a phenomenon that occurs in the whole animal, the incidence and pattern of tumor formation will be investigated in the Tsc2 mutant mice by modulating the level of Hmga2 expression. This can be achieved by breeding the Tsc2 mutant mice with mice that have a specific mutation in the Hmga2 gene. The effect of a 50% reduction and zero expression of Hmga2 will be analyzed on tumorigenesis in the Tsc2 mutant mice.

Although the primary gene defect in TSC is known, the other genes involved in the TSC pathway and other interacting pathways are still not satisfactorily determined. Identification of these genes is essential in order to provide a greater understanding of the variability of the disease. The genes may become potential targets for drug discovery and eventually lead to a successful therapy for the disease.