TRANSLATIONAL SUPPRESSION BY TRINUCLEOTIDE REPEAT EXPANSION AT FMR1

Fragile X syndrome is the result of the unstable expansion of a trinuc leotide repeat in the 5'-untranslated region of the FMR1 gene. Fibrobl ast subclones from a mildly affected patient, each containing stable F MR1 alleles with 57 to 285 CGG repeats, were shown to exhibit normal s teady-state levels of FMR1 messenger RNA. However, FMR protein was mar kedly diminished from transcript with more than 200 repeats. Such tran scripts were associated with stalled 40S ribosomal subunits. These res ults suggest that a structural RNA transition beyond 200 repeats imped es the linear 40S migration along the 5'-untranslated region. This res ults in translational inhibition by trinucleotide repeat expansion.