The 5 '-untranslated region of the FMR1 message facilitates translation byinternal ribosome entry

Fragile X syndrome, the leading heritable form of mental impairment, is gen erally caused by large expansions of a CGG repeat in the promoter region of the FMR1 gene followed by transcriptional silencing. However, there is gro wing evidence that translation of the FMR1 message is also impaired, presum ably because of the expanded CGG element in the 5'-untranslated region (5'- UTR) of the FMR1 message. To study the properties of the FMR1 5'-UTR, delet ions were generated within a normal 5'-UTR with 16 CGG repeats for both mon ocistronic and dicistronic (luciferase) reporter constructs. Transient tran sfection experiments revealed a similar to 20-nucleotide region upstream of the CGG repeat element that functions as an internal ribosome entry site ( IRES). The normal CGG element itself does not appear to influence the effic iency of IRES-mediated stimulation of downstream reporter activity (similar to 18-fold over controls). Additional controls indicate that the enhanced activity of the downstream reporter is not due to readthrough from the upst ream cistron, nor is it due to translation of cryptic monocistronic transcr ipts. The role of the FMR1 IRES element is not known at present; however, b y analogy to other IRES-containing mRNAs expressed in neurons, the FMR1 IRE S element may help to promote translation in dendrites.