Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by the widespread development of growths known as hamartomas in many tissues and organs, particularly within the brain, eyes, skin, kidneys, heart, lungs and skeleton. TSC is inherited as an autosomal dominant disorder, but a significant portion of patients appear sporadically. Genetic linkage studies have shown locus heterogeneity for the disease, with at least two TSC determining genes on chromosomes 9 and 16 which have been termed TSC1 and TSC2 respectively. The TSC2 gene on chromosome 16 has been recently isolated by positional cloning strategies and intragenic mutations within this gene have been documented in some TSC cases. The TSC2 gene product named tuberin encodes a 1784 amino acid protein that shows a small stretch of homology to the GTPase activating protein rap 1GAP. This proposal is aimed at extending our previous linkage analysis of TSC to molecular genetic and biochemical studies to better understand the disease phenotype. A detailed mutational analysis of the TSC2 gene will be performed in TSC2 families to precisely define the nature of mutations in affected individuals. This analysis will be extended to TSC1 gene in TSC1 families once this is isolated in Project 3. The mutation spectrum of both TSC1 and TSC2 genes will be defined in sporadic cases. A systematic approach will be used for scanning the mutations. The information that we gain will be very useful for providing a DNA based diagnostics in TSC families, in understanding the genetic heterogeneity in this disorder and finally will yield a wealth of information for correlating the structure function relationship of tuberin and the TSC1 protein. We also propose to generate tuberin specific antibodies to different domains of tuberin expressed as fusion proteins in order to define its expression pattern in normal and TSC2 individuals. A knowledge about the subcellular localization of this protein in tissue culture cells derived from normal and TSC2 cases, and its behavior in response to various cellular stimuli would reveal the target cells in TSC2. The putative rap1 GAP activity of tuberin will be tested employing the bacterial and baculoviral constructs. The studies proposed here should provide the basis for a better understanding of how loss of tuberin results in this multisystem disease. In the long term, this will lead to isolating the proteins with which tuberin interacts as well as unraveling the connection between tuberin and TSC1 protein once this is identified.
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