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J. Biol. Chem., Vol. 276, Issue 41, 37916-37921, October 12, 2001

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The 5'-Untranslated Region of the FMR1 Message Facilitates Translation by Internal Ribosome Entry^*

Pei-Wen Chiang, Lauren E. Carpenter^§, and Paul J. Hagerman^§¶

From the  Program in Human Genetics, University of Colorado School of Medicine, Denver, Colorado 80262 and the ^§ Department of Biological Chemistry, University of California, School of Medicine, Davis, California 95616

Fragile X syndrome, the leading heritable form of mental impairment, is generally caused by large expansions of a CGG repeat in the promoter region of the FMR1 gene followed by transcriptional silencing. However, there is growing evidence that translation of the FMR1 message is also impaired, presumably 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, deletions were generated within a normal 5'-UTR with 16 CGG repeats for both monocistronic and dicistronic (luciferase) reporter constructs. Transient transfection experiments revealed a ~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 efficiency of IRES-mediated stimulation of downstream reporter activity (~18-fold over controls). Additional controls indicate that the enhanced activity of the downstream reporter is not due to readthrough from the upstream cistron, nor is it due to translation of cryptic monocistronic transcripts. The role of the FMR1 IRES element is not known at present; however, by analogy to other IRES-containing mRNAs expressed in neurons, the FMR1 IRES element may help to promote translation in dendrites.

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