Intronic splicing silencer N1 in intron 7 of survival motor neuron 2 pre-mRNA (ISS-N1) (ISS-N1)

ISS-N1 (Intronic Splicing Silencer N1) is a potent 15-nucleotide inhibitory RNA element located within intron 7 of the survival motor neuron 2 (SMN2) gene (Singh et al., 2006, Mol. Cell. Biol.). In patients with spinal muscular atrophy (SMA), the loss of the SMN1 gene makes them reliant on the nearly identical SMN2 gene; however, SMN2 undergoes alternative splicing that frequently excludes exon 7, resulting in a truncated and unstable protein. ISS-N1 acts as a primary recruitment site for negative splicing factors, specifically heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNP A1/A2), which actively promote this exon skipping (Hua et al., 2008, Genes Dev.). By targeting ISS-N1 with the antisense oligonucleotide nusinersen, the binding of these repressors is sterically blocked, thereby promoting the inclusion of exon 7 into the mature mRNA transcript. This therapeutic redirection of splicing restores the production of full-length, functional SMN protein, which is essential for the maintenance and survival of lower motor neurons in the spinal cord (Finkel et al., 2017, N. Engl. J. Med.). Consequently, ISS-N1 represents a pivotal target for disease-modifying therapy in SMA.

Other names

ISS-N1SMN2 ISS-N1Intronic splicing silencer N1N1 silencer

Nusinersen is an antisense oligonucleotide (ASO) that binds specifically to the ISS-N1 site in intron 7 of SMN2 pre-mRNA. This binding sterically hinders the recruitment of splicing repressor proteins, primarily hnRNP A1 and A2, which normally bind to ISS-N1 to promote the skipping of exon 7. By preventing these repressors from binding, the ASO promotes the inclusion of exon 7 during splicing, leading to increased production of full-length, functional survival motor neuron (SMN) protein (Singh et al., 2006; Hua et al., 2008).