Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus

The vascular endothelial growth factor receptor 3 (VEGFR-3/FLT4) is a recep tor tyrosine kinase that regulates angiogenesis and vasculogenesis in respo nse to the binding of the ligands VEGF-C and VEGF-D. Mutations in VEGFR-3 h ave been identified in patients with primary lymphoedema. It has been noted previously that whilst in the mouse there is only a single Vegfr-3 transcr ipt, in humans there are two transcripts of 5.8 and 4.5 kb, of which the sh orter encodes a protein that lacks the C-terminal 65 amino acids. These two isoforms also differ in their biological activity. Analysis of the human V EGFR-3 cDNA and genomic sequence reveals that these two isoforms arise by a lternative splicing of the terminal exons. The shorter transcript is genera ted by splicing into the long terminal repeat of a human endogenous retrovi rus located between the last two exons, thus explaining the lack of the sho rter transcript in the mouse. The retention of the retroviral sequences in the FLT4 locus suggests that this retrotransposition event has contributed significant additional function to this gene. This provides support for a r ole for integrated retroviruses in modulating gene activity and participati ng in evolutionary processes.