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SMN1 and SMN2 represent two nearly identical copies of the Survival Motor Neuron gene in humans. Deletion of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1 leads to Spinal Muscular Atrophy (SMA), a leading genetic cause of infant mortality. SMN2 holds the promise for cure of SMA if skipping of exon 7 during pre-mRNA splicing of SMN2 could be prevented. Previous reports have shown that a C to T mutation at the 6th position of exon 7 (C6U substitution in the transcript) is the primary cause of SMN2 exon 7 skipping. Cumulative evidence suggests that C6U abrogates an enhancer associated with SF2/ASF, as well as, creates a silencer associated with hnRNP A1. There is also evidence to suggest that C6U creates an extended inhibitory context (Exinct). Recently, an intronic hnRNP A1 motif, which is not conserved between two human SMN genes, have been implicated in skipping of SMN2 exon 7. However, mechanism by which two SMN2-specific hnRNP A1 motifs interact is not known. Systematic approaches including site-specific mutations, in vivo selections, RNA structure probing and antisense oligonucleotide microwalks have revealed additional cis-elements in exon 7 as well as in flanking intronic sequences. A unique intronic splicing silencer (ISS-N1) has emerged as an effective target for correction of SMN2 exon 7 splicing by short antisense oligonucleotides (ASOs). Low nanomolar concentrations of ASOs against ISS-N1 fully restored SMN2 exon 7 inclusion and increased levels of SMN in SMA patient cells. Such a robust antisense response could be due to accessibility of the target as well as the complete nullification of a strong inhibitory impact rendered by ISS-N1. Bifunctional oligonucelotides with capability to recruit stimulatory splicing factors in the vicinity of weak splice sites of exon 7 have also shown promise for correction of SMN2 exon 7 splicing. Considering an antisense-based strategy confers a unique advantage of sequence specificity, availability of many target worthy cis-elements holds strong potential for antisense-mediated therapy of SMA.
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Singh, Ravindra N., "Evolving Concepts on Human SMN Pre-mRNA Splicing" (2007). Biomedical Sciences Publications. 8.