Survival motor neuron 2 (SMN2) pre-messenger RNA exon 7 and intronic splicing silencer N1 (ISS-N1) (SMN2 pre-mRNA exon 7/ISS-N1)

The Survival motor neuron 2 (SMN2) pre-mRNA exon 7 region and its associated intronic regulatory sequences, specifically the intronic splicing silencer N1 (ISS-N1), represent a pivotal therapeutic target for Spinal Muscular Atrophy (SMA) (Singh et al., 2006, Mol. Cell. Biol. [1]). SMA is a debilitating neuromuscular disease caused by the loss of the SMN1 gene, which leads to a deficiency in the survival motor neuron (SMN) protein (Lefebvre et al., 1995, Cell [2]). While humans possess a nearly identical SMN2 gene, a C-to-T transition in exon 7 disrupts a splicing enhancer, causing the majority of SMN2 transcripts to lack exon 7 and produce a non-functional, unstable protein (Lorson et al., 1999, PNAS [3]). Therapeutic strategies focus on modulating the splicing of SMN2 pre-mRNA to promote exon 7 inclusion, thereby increasing the levels of functional SMN protein. Drugs such as the antisense oligonucleotide nusinersen bind to the ISS-N1 sequence to block the recruitment of splicing repressors like hnRNP A1 (Hua et al., 2011, Sci. Transl. Med. [4]). Alternatively, small molecules like risdiplam act as splicing modifiers by stabilizing the interaction between the SMN2 pre-mRNA and the U1 small nuclear ribonucleoprotein (snRNP) complex (Ratni et al., 2018, J. Med. Chem. [5]). These interventions have transformed the treatment landscape for SMA, significantly improving motor milestones and survival in affected patients.

Other names

SMN2 pre-mRNAISS-N1SMN2 exon 7 splicing regulatory elementSurvival motor neuron 2 gene transcript

Modulation of pre-mRNA splicing to promote the inclusion of exon 7 by either sterically blocking intronic splicing silencers (ISS) or stabilizing the U1 small nuclear ribonucleoprotein (snRNP) complex at the 5' splice site.