Mutated Usherin (USH2A) pre-mRNA containing c.7595-2144A>G pseudoexon 40 intronic region (USH2A c.7595-2144A>G)

The target is a specific mutated form of the USH2A pre-mRNA, characterized by a deep-intronic A-to-G transition at position c.7595-2144 in intron 40. This mutation creates a cryptic splice donor site that leads to the inclusion of a 152-base pair pseudoexon (PE40) into the mature mRNA transcript. The inclusion of PE40 causes a frameshift and introduces a premature stop codon, which typically results in nonsense-mediated decay of the mRNA or the production of a non-functional, truncated usherin protein. Usherin is a large transmembrane protein essential for the structural integrity and maintenance of photoreceptor cells in the retina and hair cells in the inner ear. Mutations in USH2A are the leading cause of Usher syndrome type 2A, which presents as congenital hearing loss and progressive retinitis pigmentosa, as well as non-syndromic retinitis pigmentosa. Therapeutic strategies targeting this mutated pre-mRNA, such as the antisense oligonucleotide QR-411, aim to mask the cryptic splice site and restore normal splicing, thereby allowing for the production of functional, full-length usherin protein.

Other names

USH2A deep-intronic c.7595-2144A>G mutationUSH2A pseudoexon 40 (PE40)USH2A intron 40 cryptic splice siteUSH2A c.7595-2144A>G pre-mRNArs786200928

Splice modulation via masking of a cryptic splice donor site to prevent pseudoexon inclusion and restore normal USH2A mRNA splicing.