Tuberous sclerosis complex (TSC) is a genetic disease characterized by 
multiorgan benign tumors as well as neurological manifestations. Epilepsy and 
autism are two of the more prevalent neurological complications and are usually 
severe. TSC is caused by mutations in either the TSC1 (encodes hamartin) or the 
TSC2 (encodes tuberin) genes with TSC2 mutations being associated with worse 
outcomes. Tuberin contains a highly conserved GTPase-activating protein (GAP) 
domain that indirectly inhibits mammalian target of rapamycin complex 1 
(mTORC1). mTORC1 dysregulation is currently thought to cause much of the 
pathogenesis in TSC but mTORC1-independent mechanisms may also contribute. We 
generated a novel conditional allele of Tsc2 by flanking exons 36 and 37 with 
loxP sites. Mice homozygous for this knock-in Tsc2 allele are viable and fertile 
with normal appearing growth and development. Exposure to Cre recombinase then 
creates an in-frame deletion involving critical residues of the GAP domain. 
Homozygous conditional mutant mice generated using Emx1(Cre) have increased 
cortical mTORC1 signaling, severe developmental brain anomalies, seizures, and 
die within 3 weeks. We found that the normal levels of the mutant Tsc2 mRNA, 
though GAP-deficient tuberin protein, appear unstable and rapidly degraded. This 
novel animal model will allow further study of tuberin function including the 
requirement of the GAP domain for protein stability.