Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background

Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder in which benign hamartomas develop in multiple organs, caused by mutations in eithe r TSC1 or TSC2. We developed a murine model of Tsc2 disease using a gene ta rgeting approach. Tsc2-null embryos die at embryonic days 9.5-12.5 from hep atic hypoplasia. Tsc2 heterozygotes display 100% incidence of multiple bila teral renal cystadenomas, 50% incidence of liver hemangiomas, and 32% incid ence of lung adenomas by 15 months of age. Progression to renal carcinoma, fatal bleeding from the liver hemangiomas, and extremity angiosarcomas all occur at a rate of less than 10%. The renal cystadenomas develop from inter calated cells of the cortical collecting duct and uniformly express gelsoli n at high levels, enabling detection of early neoplastic lesions. The tumor expression pattern of the mice is influenced by genetic background, with f ewer large renal cystadenomas in the outbred Black Swiss background and mor e angiosarcomas in 129/SvJae chimeric mice. The slow growth of the tumors i n the heterozygote mice matches the limited growth potential of the great m ajority of TSC hamartomas, and the influence of genetic background on pheno type correlates with the marked variability in expression of TSC seen in pa tients.