Fragile X messenger ribonucleoprotein 1 transcript isoform 217 (FMR1-217) (FMR1-217)

FMR1-217 RNA is an aberrantly spliced transcript isoform of the Fragile X messenger ribonucleoprotein 1 (FMR1) gene, which is the primary gene associated with Fragile X syndrome (FXS) [1, 4]. This isoform is generated in a CGG expansion-dependent manner, typically occurring when the repeat length exceeds 140, and involves the inclusion of a pseudo-exon from intron 1 into the mature mRNA [1, 12]. The presence of FMR1-217 prevents the formation of full-length FMR1 mRNA, leading to a deficiency in the Fragile X messenger ribonucleoprotein (FMRP), a protein essential for synaptic plasticity and cognitive development [1, 10]. While FXS was traditionally thought to involve complete transcriptional silencing, recent research has shown that over 70% of FXS individuals still express FMR1, but primarily in the form of this non-functional FMR1-217 isoform [1, 5]. This discovery has established FMR1-217 as a novel therapeutic target for antisense oligonucleotides (ASOs), which can be designed to block the aberrant splicing event [4, 7]. By inhibiting the inclusion of the pseudo-exon, ASOs can rescue the production of functional FMRP, offering a potential disease-modifying treatment for FXS and related disorders [1, 6].

Other names

FMR1-217 RNAFMR1-217 transcriptMis-spliced FMR1 RNAENST00000621447.1

Splice-switching antisense oligonucleotides target the pseudo-exon in intron 1 of the FMR1-217 transcript to block its inclusion, thereby restoring the production of full-length FMR1 mRNA and functional FMRP protein.