Germ-line Tsc2 mutation in a dominantly inherited cancer model defines a novel family of rat intracisternal-A particle elements.

A spontaneous hereditary cancer syndrome in the Eker rat serves as a useful model for studying tissue-specific tumorigenesis. The genetic basis of this germline mutation was found to involve the tuberous sclerosis 2 (Tsc2) gene. In this study, we have identified and characterized a full-length rat intracisternal A-particle (IAP) element that has undergone an intronic transposition as the mechanism of inactivating the Tsc2 gene. The insertion of this 6253 basepair element disrupted the transcription of the gene to give rise to multiple abnormal mRNA. Genomic organization of this novel IAP element is similar to a typical retroviral structure including the gag, pol and env domains with flanking LTRs. This Eker rat associated (ERA) IAP sequence was found to contain multiple termination codons rendering it non-functional with respect to its endogenous genes. The element is conserved among different rat strains and the distribution of the estimated approximately 580 copies throughout the rat genome would support their random integration. The net effect of the mutation causes the expression of abnormal predicted proteins devoid of the rap1GAP-like catalytic domain that lies 3' to the insertion. These results provide evidence that cancer predisposition can be the direct consequence of germ-like insertional mutation by retrotransposition targeting a tumor suppressor gene.