Survival motor neuron 2 pre-mRNA intronic splicing silencer N1 (ISS-N1)

The Survival motor neuron 2 (SMN2) pre-mRNA intronic splicing silencer N1 (ISS-N1) is a 15-nucleotide regulatory sequence located in intron 7 of the SMN2 gene (Singh et al., 2006, Mol Cell Biol). It plays a pivotal role in the regulation of alternative splicing by acting as a binding site for inhibitory proteins like heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2. These proteins suppress the inclusion of exon 7 into the mature mRNA transcript, which normally results in a truncated and unstable SMN protein (Hua et al., 2008, Am J Hum Genet). In Spinal Muscular Atrophy (SMA), where the SMN1 gene is deficient, the ISS-N1-mediated exclusion of exon 7 prevents SMN2 from compensating for the loss of SMN protein. The therapeutic targeting of ISS-N1 is achieved through antisense oligonucleotides (ASOs) like nusinersen, which bind specifically to this sequence (Nusinersen Prescribing Information, FDA). By masking ISS-N1, these drugs prevent the binding of splicing repressors, thereby promoting the inclusion of exon 7 and the production of functional, full-length SMN protein. This mechanism has proven highly effective in modifying the disease course and improving motor outcomes in pediatric and adult SMA patients.

Other names

SMN2 ISS-N1Intronic splicing silencer N1SMN2 intron 7 splicing silencerISS-N1

Antisense oligonucleotide binding to the ISS-N1 site to sterically hinder the recruitment of splicing repressors (hnRNP A1/A2), thereby promoting the inclusion of exon 7 in SMN2 mRNA transcripts.