cDNA structure, alternative splicing and exon-intron organization of the predisposing tuberous sclerosis (Tsc2) gene of the Eker rat model.

The Eker rat hereditary renal carcinoma (RC) is an excellent example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis gene (TSC2) gives rise to the dominantly inherited cancer in the Eker rat model. We now describe the entire cDNA (5375 bp without exons 25 and 31) and genomic structure of the rat Tsc2 gene. The deduced amino acid sequence (1743 amino acids) shows 92% identity to the human counterpart. Surprisingly, there are a great many (> or = 41) coding exons with small sized introns spanning only approximately 35 kb of genomic DNA. Two alternative splicing events [involving exons 25 (129 bp) and 31 (69 bp)] make for a complex diversity of the Tsc2 product. The present determination of the Tsc2 gene and establishment of strong conservation between the rat and man provide clues for assessing unknown gene functions apart from that already predicted from the GTPase activating proteins (GAP3) homologous domain and for future analysis of intragenic mutations in tumors using methods such as PCR-SSCP and for insights into diverse phenotypes between species.