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

The Survival of 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 [1.1.1]. In patients with spinal muscular atrophy (SMA), the loss of the SMN1 gene makes them dependent on the nearly identical SMN2 gene; however, a single nucleotide difference in SMN2 leads to the frequent skipping of exon 7, resulting in a truncated and unstable SMN protein [1.1.4, 1.2.1]. ISS-N1 acts as a potent inhibitory element that recruits negative splicing factors, such as heterogeneous nuclear ribonucleoproteins (hnRNP A1 and A2), to suppress exon 7 inclusion [1.2.1, 1.2.4]. Therapeutic intervention using antisense oligonucleotides, such as Nusinersen, specifically targets and masks the ISS-N1 sequence [1.2.5]. This masking prevents the binding of repressor proteins, effectively promoting the inclusion of exon 7 during pre-mRNA splicing [1.2.1, 1.2.5]. Consequently, this increases the production of full-length, functional SMN protein, which is essential for the survival and maintenance of motor neurons [1.1.4, 1.4.3].

Other names

Intronic splicing silencer N1SMN2 intron 7 ISS-N1SMN2 ISS-N1SMN2 intronic splicing silencer N1

Antisense oligonucleotide binding to the ISS-N1 site prevents the recruitment of splicing repressor proteins such as hnRNP A1 and A2, thereby promoting the inclusion of exon 7 in the SMN2 transcript and increasing the production of functional SMN protein.