CHARACTERIZATION OF TSC PROTEIN HAMARTIN AND TUBERIN

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DESCRIPTION (provided by applicant): Tuberous sclerosis complex is 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. The most severely affected system is the central nervous system with the occurrence in affected individuals of seizures (80-90 percent), mental retardation (50-60 percent), and autism (up to 50 percent). TSC is inherited as an autosomal dominant disorder, but approximately two-thirds of affected patients are sporadic due to new germline mutations. 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 TSC1 gene encodes a novel protein, hamartin that contains a single transmembrane domain and a large cytoplasmic tail with a coiled-coil domain. The TSC2 gene encodes a novel protein tuberin that contains a region of homology to the GTPase activating protein rap1GAP. We have performed a comprehensive mutational analysis of the TSC1 and TSC2 genes and noted that TSC1 mutations are significantly underrepresented in sporadic patients. However, the occurrence of the second somatic mutation in TSC lesions, particularly brain lesions is not clear. In order to understand whether this is due to cellular pleomorphism, or if haploinsufficiency of tuberin/hamartin is enough to promote tumor genesis, we will perform genetic analysis on laser capture microdissected lesions. We have identified a novel protein associated with Myc named Pam as an interacting protein for tuberin. Mutations in both the Drosophila (hiw) and C. elegans (rpm-1) homologs of Pam show synaptic overgrowth. Our hypothesis that Pam is an essential component of the tuberin-hamartin complex, particularly in the CNS where these proteins may have a critical role in cortical neuron function will be examined. The domain of Pam that interacts with tuberin reveals 90 percent similarity with the fly homolog HIW. The possible physical and genetic interaction between the Drosophila TSC2 product Gigas and HIW will be examined. Thus the studies aimed at defining the role of tuberin-hamartin in the mammalian CNS will be further strengthened by the Drosophila model system where genetic manipulations are possible. The information obtained here will elucidate the physiological functions of these tumor suppressors, which will aid in designing better therapies.