Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice

Germ-line mutations of the human TSC2 tumor suppressor gene cause tuberous sclerosis (TSC), a disease characterized by the development of hamartomas i n various organs. In the Eker rat, however, a germ-line Tsc2 mutation gives rise to renal cell carcinomas with a complete penetrance The molecular mec hanism for this phenotypic difference between man and rat is currently unkn own, and the physiological function of the TSC2/Tsc2 product (tuberin) is n ot fully understood. To investigate these unsolved problems, we have genera ted a Tsc2 mutant mouse Tsc2 heterozygous mutant (Tsc+/-) mice developed re nal carcinomas with a complete penetrance, as seen in the Eker rat, but not the angiomyolipomas characteristic of human TSC, confirming the existence of a species-specific mechanism of tumorigenesis caused by tuberin deficien cy. Unexpectedly, similar to 80% of Tsc2+/- mice also developed hepatic hem angiomas that are not observed in either TSC or the Eker rat, Tsc2 homozygo us (Tsc2-/-) mutants died around embryonic day 10.5, indicating an essentia l function for tuberin in mouse embryonic development. Some Tsc2-/- embryos exhibited an unclosed neural tube and/or thickened myocardium. The latter is associated with increased cell density that may be a reflection of loss of a growth-suppressive function of tuberin. The mouse strain described her e should provide a valuable experimental model to analyze the function of t uberin and its association with tumorigenesis.