Fragile X messenger ribonucleoprotein 1 gene CGG repeat expansion (FMR1 CGG repeat)

The FMR1 gene CGG repeat expansion is a pathogenic trinucleotide sequence located in the 5' untranslated region of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene (NIH MedlinePlus, 2020). In healthy individuals, this region contains approximately 5 to 44 repeats, but expansions exceeding 200 repeats (full mutation) trigger hypermethylation of the FMR1 promoter, leading to transcriptional silencing and the loss of the FMRP protein (Fragile X Foundation, 2023). FMRP is a critical RNA-binding protein that regulates the translation of proteins essential for synaptic plasticity and brain development; its absence results in Fragile X Syndrome, the leading inherited cause of intellectual disability and autism (PubMed PMC6351401). Intermediate expansions of 55 to 200 repeats, known as premutations, do not silence the gene but instead produce excessive amounts of toxic FMR1 mRNA, which can lead to Fragile X-associated tremor/ataxia syndrome (FXTAS) later in life (Nature Reviews Neurology, 2019). Therapeutic strategies currently under investigation include using CRISPR/Cas9 to excise the expansion or demethylate the promoter, as well as antisense oligonucleotides (ASOs) designed to degrade toxic mRNA or prevent the recruitment of silencing complexes (Nature Communications, 2020).

Other names

FMR1 trinucleotide repeat expansionFragile X mental retardation 1 gene CGG expansionCGG repeat in FMR1 5' UTRFMR1 expansion

Reversal of epigenetic silencing via DNA demethylation, excision of repeat expansion via genome editing, or degradation of toxic CGG-containing mRNA using antisense oligonucleotides.