Expanded CGG trinucleotide repeat sequence in the 5' untranslated region of the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1 CGG repeat)

The expanded CGG trinucleotide repeat sequence in the 5' untranslated region (UTR) of the FMR1 gene is the primary genetic cause of Fragile X-related disorders (FXDs) (Hagerman et al., 2017). In healthy individuals, this region contains 5 to 55 CGG repeats and plays a role in regulating the translation of Fragile X Messenger Ribonucleoprotein (FMRP) in response to synaptic activity (Todd et al., 2020). Expansions beyond 200 repeats (full mutation) lead to hypermethylation and transcriptional silencing of the FMR1 gene, resulting in the loss of FMRP and causing Fragile X Syndrome (FXS) (Bagni et al., 2012). Intermediate expansions (55-200 repeats), known as premutations, lead to the production of toxic FMR1 mRNA that forms stable hairpin and G-quadruplex structures (Rovozzo et al., 2016). These structures sequester RNA-binding proteins and undergo repeat-associated non-AUG (RAN) translation to produce toxic polyglycine proteins (FMRpolyG), driving the pathogenesis of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) (Todd et al., 2020). Therapeutic strategies targeting this sequence include antisense oligonucleotides (ASOs) designed to block RAN translation or correct aberrant splicing (e.g., the FMR1-217 isoform) (Shah et al., 2023), and small molecules like TMPyP4 or repurposed drugs like Nitazoxanide that destabilize the RNA hairpins (Rovozzo et al., 2016; ACS Publications, 2025). Emerging approaches also explore CRISPR/Cas9-mediated gene editing to delete the expansion or demethylate the promoter to restore endogenous FMRP expression (Park et al., 2015).

Other names

CGG repeat expansionFMR1 5' UTR CGG repeatCGGexp RNAFRAXA locusFMR1-217 isoformr(CGG)exp

Therapeutic interventions target the expanded CGG repeat through several mechanisms: (1) antisense oligonucleotides (ASOs) bind to the repeat or adjacent regions to block repeat-associated non-AUG (RAN) translation or correct aberrant splicing (e.g., reducing the FMR1-217 isoform); (2) small molecules (e.g., TMPyP4, Nitazoxanide) bind to and destabilize the RNA hairpin or G-quadruplex structures to restore canonical translation or prevent protein sequestration; (3) epigenetic modulators (e.g., Decitabine) promote DNA demethylation to reactivate the silenced FMR1 gene; and (4) gene editing (e.g., CRISPR/Cas9) aims to excise the expansion or reverse hypermethylation at the DNA level.