5'-End RET splicing: absence of variants in normal tissues and intron retention in pheochromocytomas

The Ret tyrosine kinase is implicated in neuronal cell survival, kidney development and tumorigenesis. Several 3' and 5' transcript variants have been described resulting from alternative splicing of the RET pre-mRNA. The 3' variants code for three C-terminal isoforms, RET51, RET9 and RET43. The 5' variants RET2/4, RET2/5 and RET2/6 result from skipping exons 3, 3-4 and 3-5, respectively. These variants code for putative Ret proteins differing in their extracellular ligand-binding domains, and their expression is strongly regulated during kidney development. Here we analyzed the presence of these RET 5' variants in normal tissues and in MEN2 and sporadic pheochromocytomas. In all tissues examined, the abundance of these transcripts remained extremely low (less than 1% of all RET transcripts) thus indicating these species as rare variants with little biological meaning. On the other hand, in tumors, the 5' RET splicing pattern differed from that of normal tissues. Indeed, we identified a RET-derived transcript that results from the aberrant retention of intron 2. This transcript is enriched in tumor samples of both familial and sporadic origin, and indicates RET as a target for RNA splicing deregulation in tumor cells.