VHLFrameshift Mutation as Target of Nonsense-Mediated mRNA Decay inDrosophila melanogasterand Human HEK293 Cell Line

Abstract

There are many well-studied examples of human phenotypes resulting from nonsense or frameshift mutations that are modulated by Nonsense-Mediated mRNA Decay (NMD), a process that typically degrades transcripts containing premature termination codons (PTCs) in order to prevent translation of unnecessary or aberrant transcripts. Different types of germline mutations in theVHLgene cause the von Hippel-Lindau disease, a dominantly inherited familial cancer syndrome with a marked phenotypic variability and age-dependent penetrance. By generating theDrosophilaUAS:Upf1D45Bline we showed the possible involvement of NMD mechanism in the modulation of the c.172delG frameshift mutation located in the exon 1 ofVhlgene. Further, by Quantitative Real-time PCR (QPCR) we demonstrated that the corresponding c.163delG human mutation is targeted by NMD in human HEK 293 cells. The UAS:Upf1D45Bline represents a useful system to identify novel substrates of NMD pathway inDrosophila melanogaster. Finally, we suggest the possible role of NMD on the regulation ofVHLmutations.