SMN2Splicing

SMN2 splicing refers to the processing of SMN2 pre-mRNA into mature transcripts, which largely produce a truncated, nonfunctional SMN protein due to skipping of exon 7. In humans, SMN2 is a paralog of SMN1 located on chromosome 5q13. A single nucleotide difference in exon 7 (a C-to-T transition) alters an exonic splicing regulatory element and biases splicing toward exon 7 exclusion, reducing the amount of full-length SMN (FL-SMN) protein. The resulting SMN2-dependent full-length transcripts constitute only a fraction of the total SMN2 transcripts, with most being SMNΔ7 lacking exon 7.

Splicing of SMN2 is controlled by a balance of cis-acting elements and trans-acting factors. Exonic splicing enhancers and silencers, as well as intronic elements, influence whether exon 7 is included. A well-described intronic splicing silencer, ISS-N1, in intron 7 plays a major role in promoting exon 7 skipping. Various splicing factors, such as hnRNP family members and SR proteins, modulate this regulation, and cellular context can shift the proportion of full-length versus truncated SMN2 transcripts.

Therapeutically, modulating SMN2 splicing aims to increase exon 7 inclusion and thereby raise functional SMN protein levels. Antisense oligonucleotides (ASOs) like nusinersen bind ISS-N1 to promote exon 7 inclusion. Small-molecule splicing modifiers, such as risdiplam, also enhance full-length SMN2 transcripts. Collectively, these approaches complement SMN1 restoration strategies in spinal muscular atrophy management, with efficacy largely dependent on treatment timing and SMN2 copy number.