A germ-line Tsc1 mutation causes tumor development and embryonic lethalitythat are similar, but not identical to, those caused by Tsc2 mutation in mice

Tuberous sclerosis (TS) is characterized by the development of hamartomas i n various organs and is caused by a germ-line mutation in either TSC1 or TS C2 tumor suppressor genes, From the symptomatic resemblance among TS patien ts, involvement of TSC1 and TSC2 products in a common pathway has been sugg ested. Here, to analyze the function of the Tsc1 product, we established a line of Tsc? (TSC1 homologue) knockout mouse by gene targeting. Heterozygou s Tsc1 mutant (Tsc1(+/-)) mice developed renal and extra-renal tumors such as hepatic hemangiomas, In these tumors, loss of wild-type Tsc? allele was observed. Homozygous Tsc1 mutants died around embryonic days 10.5-11.5, fre quently associated with neural tube unclosure. As a whole, phenotypes of Ts c1 knockout mice resembled those of Tsc2 knockout mice previously reported, suggesting that the presumptive common pathway for Tsc1 and Tsc2 products may also exist in mice. Notably, however, development of renal tumors in Ts c1(+/-) mice was apparently slower than that in Tsc2(+/-) mice. The Tsc1 kn ockout mouse described here will be a useful model to elucidate the functio n of Tsc1 and Tsc2 products as well as pathogenesis of TS.