Pre-messenger RNA splice sites (Pre-mRNA splice sites)

Pre-messenger RNA (pre-mRNA) splice sites are conserved nucleotide sequences located at the boundaries of exons and introns (5' donor and 3' acceptor sites) that are essential for the precise removal of introns by the spliceosome [1]. Mutations within these sites or nearby regulatory elements, such as exonic splicing enhancers (ESEs) or intronic splicing silencers (ISSs), can lead to aberrant splicing, resulting in the production of truncated, non-functional, or toxic protein isoforms [2]. These sites serve as critical therapeutic targets for antisense oligonucleotides (ASOs) and small molecule splicing modifiers designed to correct these defects. For example, drugs like Nusinersen and Risdiplam target the SMN2 pre-mRNA to promote the inclusion of exon 7, thereby increasing the production of functional SMN protein in patients with spinal muscular atrophy [3,4]. Similarly, exon-skipping therapies like Eteplirsen target specific splice sites in the DMD gene to restore the reading frame and produce a truncated but functional dystrophin protein [5]. By modulating the recognition of these sites, these therapies address the underlying genetic cause of disease at the transcript level. [1] Wang, Z., & Burge, C. B. (2008). RNA. [2] Scotti, M. M., & Swanson, M. S. (2016). Nature Reviews Genetics. [3] Hua, Y., et al. (2011). Genes & Development. [4] Ratni, H., et al. (2018). Journal of Medicinal Chemistry. [5] Lim, K. H., et al. (2020). Journal of Gene Medicine.

Other names

5' splice site3' splice siteSplice junctionDonor siteAcceptor siteCryptic splice siteAberrant splice siteSplicing regulatory elements

Splice modulation via steric hindrance of splicing enhancers/silencers or stabilization of ribonucleoprotein binding to promote exon inclusion, exon skipping, or the blocking of cryptic splice sites.