A potential approach to correct the FMR1 gene defect underlying fragile X syndrome (FXS) relies on the body’s own DNA repair mechanisms. This is described by researchers in the journal Cell. FXS is a neurodevelopmental disorder and one of the most common causes of inherited intellectual disability in male individuals. It stems from an expansion of a repeated trinucleotide DNA sequence (CGG) in the 5’ region of the FMR1 gene on the X chromosome. While, typically, individuals have on average 30 repeats of this CGG triplet in the FMR1 gene, people with FXS carry an expansion of 200 repeats and more. This expansion adds methyl groups to the DNA, inhibiting gene transcription. As a result, FMR1 is silenced and its product, the fragile X messenger ribonucleoprotein (FMRP), is no longer formed. FMRP is important for brain development, with active roles for example in regulating the translation of synaptic proteins.

In their study, the researchers used patient cell models to investigate conditions that would induce FMR1 reactivation. They discovered that cells treated by inhibitors of the two kinases MEK and BRAF showed strongly contracted CGG repeat expansion and fully restored FMR1 gene expression. They traced this contraction phenomenon to DNA demethylation and site-specific formation of R loops, i.e. loops involving DNA and RNA strands. A positive feedback loop involving demethylation, de novo FMR1 transcription and R-loop formation triggered the cells’ own mechanisms of DNA repair, which then excised the CGG repeat expansion. In their experiments, this occurred specifically for FMR1. The study thus describes a potential method for treating FXS in the future.