Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting 1 in 6,000 births, that is characterized by benign tumors (hamartomas and hamartias) in multiple organ systems. Its major clinical manifestations are due to brain involvement- seizures, mental retardation, and autism and related disorders, each of which occurs in about half of TSC patients. Two genes (TSC1 and TSC2) have been identified that cause this disorder. We propose studies in both patients and using mouse models to explore the pathogenesis of this disorder. First, using patient material we will explore the following questions. What is the molecular basis of TSC in patients without identified mutations in TSC1 or TSC2? Is there a third TSC gene? Is there a hereditable, mild form of TSC? What is its molecular basis? What explains the variability in clinical phenotype in this disorder? Second, using multiple cell types derived from Tsc2 null mouse embryos, we will examine the biochemical function of tuberin, including analysis of rap1, rho, and PI3-kinase signaling. The tuberin-hamartin complex will be purified and binding partners identified. Third, we have generated a conditional 'floxed' Tsc2 allele. Through breeding of these animals with tissue-specific cre recombinase expressing animals, we will obtain organ-specific Tsc2 null mice to explore the pathogenesis of brain, cardiac, and renal disease in these animals. We will be able to determine the cells involved in and developmental course of Tsc2 lesion development. Primary cells will also be obtained from several sites in these animals, and subjected to cre expression in culture to derive null cells for additional biochemical studies. Last, the in vivo interaction in the mouse between Tsc2 null alleles and null alleles for p53, p27KIP, p21CIP, Msh2, and gelsolin will be explored.
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