Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting 1 in 6,000 births, characterized by development of distinctive benign tumors (hamartomas) and malformations (hamartias) in multiple organ systems. Although cortical tubers cause the greatest morbidity of the disease in young children, progressive growth of hamartomas in the brain (subependymal giant cell astrocytomas), kidney (angiomyolipomas), and lung (lymphangioleiomyomatosis) have the most severe clinical impact in older children, adolescents, and adults. Two genes cause TSC: TSC1 and TSC2, each of which sustains inactivating mutations that lead to disease pathogenesis through a two hit, tumor suppressor gene mechanism in most tissues. Recent studies have highlighted the association of certain missense mutations in TSC2 with a variant TSC-like disease phenotype. We propose studies in both patients and mouse models to explore the pathogenesis of TSC and this related TSC-like disorder. First, we will examine resected subependymal giant cell astrocytomas, angiomyolipomas, and lymphangioleiomyomatosis for genetic changes that account for disease progression. We hypothesize that additional genetic events beyond the second hit occur in the small fraction of these lesions which progressively grow. Second, we will perform a screen for genetic events that enhance tumorigenesis in ourTsc2 mouse model, using the Sleeping Beauty transposon. Third, we will develop knock-in missense mutations in Tsc2 to match those seen in variant TSC families, to examine developmental events in heterozygous and homozygous mice, and signaling and differentiation effects in their derivative tissues and cell lines. Fourth, we will develop a mouse model of the combined Tsc2-Pkd1 deletion syndrome, in which accelerated polycystic kidney disease is seen. This model will permit analysis of genetic and signaling events occurring during renal cyst pathogenesis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Mamounas, Laura
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Brigham and Women's Hospital
United States
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Tyburczy, Magdalena E; Wang, Ji-An; Li, Shaowei et al. (2014) Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex. Hum Mol Genet 23:2023-9
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