Usherin pre-messenger RNA (c.7595-2144A>G mutation) (USH2A pre-mRNA)

The Usherin (USH2A) pre-messenger RNA containing the deep-intronic c.7595-2144A>G mutation is a specific therapeutic target for treating Usher syndrome type 2A and non-syndromic retinitis pigmentosa. This mutation, located in intron 40, creates a cryptic splice donor site that leads to the inclusion of a 152-base pair pseudoexon in the mature mRNA (Slijkerman et al., 2016). The inclusion of this pseudoexon causes a frameshift and a premature stop codon, resulting in a lack of functional usherin protein, which is essential for the structural integrity of retinal photoreceptors and cochlear hair cells (Dulla et al., 2021). Therapeutic strategies utilize antisense oligonucleotides (ASOs), such as ulrevigersen (QR-421a), to bind to the pre-mRNA and mask the cryptic splice site or branch point (ProQR Therapeutics, 2023). This masking prevents the inclusion of the pseudoexon during splicing, thereby restoring the wild-type mRNA sequence and the production of functional usherin protein. This approach is designed to slow or halt the progression of vision loss in patients carrying this specific genetic defect.

Other names

USH2A intron 40 mutationc.7595-2144A>GUsherin precursor mRNAUSH2A deep-intronic mutation

Splice modulation via pseudoexon exclusion