Figure 1.
Overview of the Expression of the FMR1 Gene.
FMR1 mRNA levels increase with increasing CGG-repeat length (gold segments) throughout the premutation range, and undergo a transition to greatly diminished levels in the full mutation range because of hypermethylation of the FMR1 promoter region. In some instances, methylation mosaicism results in continued production of low-to-moderate levels of mRNA in the full mutation range. RNA toxicity in the premutation range is thought to arise through sequestration, by direct binding to the expanded CGG-repeat element within the FMR1 mRNA, of one or more RNA binding proteins that would normally be associated with other mRNAs. Sequestration in turn leads to loss of the normal function(s) of those proteins, which may include splice modulation and regulation of miRNA production, among other functions. Dysregulation of RNA processing is thought to lead to multiple forms of downstream cellular dysregulation.