Evolving concepts on human SMN pre-mRNA splicing - PubMed (original) (raw)
. 2007 Jan-Mar;4(1):7-10.
doi: 10.4161/rna.4.1.4535. Epub 2007 Jun 4.
Affiliations
- PMID: 17592254
- DOI: 10.4161/rna.4.1.4535
Evolving concepts on human SMN pre-mRNA splicing
Ravindra N Singh. RNA Biol. 2007 Jan-Mar.
Abstract
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 Tmutation 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, has 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.
Similar articles
- Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron.
Singh NK, Singh NN, Androphy EJ, Singh RN. Singh NK, et al. Mol Cell Biol. 2006 Feb;26(4):1333-46. doi: 10.1128/MCB.26.4.1333-1346.2006. Mol Cell Biol. 2006. PMID: 16449646 Free PMC article. - hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing.
Kashima T, Rao N, David CJ, Manley JL. Kashima T, et al. Hum Mol Genet. 2007 Dec 15;16(24):3149-59. doi: 10.1093/hmg/ddm276. Epub 2007 Sep 19. Hum Mol Genet. 2007. PMID: 17884807 - Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice.
Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. Hua Y, et al. Am J Hum Genet. 2008 Apr;82(4):834-48. doi: 10.1016/j.ajhg.2008.01.014. Epub 2008 Mar 27. Am J Hum Genet. 2008. PMID: 18371932 Free PMC article. - The regulation and regulatory activities of alternative splicing of the SMN gene.
Singh NN, Androphy EJ, Singh RN. Singh NN, et al. Crit Rev Eukaryot Gene Expr. 2004;14(4):271-85. doi: 10.1615/critreveukaryotgeneexpr.v14.i4.30. Crit Rev Eukaryot Gene Expr. 2004. PMID: 15663357 Review. - Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes.
Singh RN, Singh NN. Singh RN, et al. Adv Neurobiol. 2018;20:31-61. doi: 10.1007/978-3-319-89689-2_2. Adv Neurobiol. 2018. PMID: 29916015 Free PMC article. Review.
Cited by
- U1 snRNA interactions with deep intronic sequences regulate splicing of multiple exons of spinal muscular atrophy genes.
Ottesen EW, Singh NN, Seo J, Singh RN. Ottesen EW, et al. Front Neurosci. 2024 Jul 12;18:1412893. doi: 10.3389/fnins.2024.1412893. eCollection 2024. Front Neurosci. 2024. PMID: 39086841 Free PMC article. - CRISPR-dCas13d-based deep screening of proximal and distal splicing-regulatory elements.
Recinos Y, Ustianenko D, Yeh YT, Wang X, Jacko M, Yesantharao LV, Wu Q, Zhang C. Recinos Y, et al. Nat Commun. 2024 May 7;15(1):3839. doi: 10.1038/s41467-024-47140-8. Nat Commun. 2024. PMID: 38714659 Free PMC article. - Deep screening of proximal and distal splicing-regulatory elements in a native sequence context.
Recinos Y, Ustianenko D, Yeh YT, Wang X, Jacko M, Yesantharao LV, Wu Q, Zhang C. Recinos Y, et al. bioRxiv [Preprint]. 2023 Aug 21:2023.08.21.554109. doi: 10.1101/2023.08.21.554109. bioRxiv. 2023. PMID: 37662340 Free PMC article. Updated. Preprint. - What Genetics Has Told Us and How It Can Inform Future Experiments for Spinal Muscular Atrophy, a Perspective.
Blatnik AJ 3rd, McGovern VL, Burghes AHM. Blatnik AJ 3rd, et al. Int J Mol Sci. 2021 Aug 6;22(16):8494. doi: 10.3390/ijms22168494. Int J Mol Sci. 2021. PMID: 34445199 Free PMC article. - The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy.
Singh RN, Ottesen EW, Singh NN. Singh RN, et al. Neurosci Insights. 2020 Nov 23;15:2633105520973985. doi: 10.1177/2633105520973985. eCollection 2020. Neurosci Insights. 2020. PMID: 33283185 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
- R01 NS055925/NS/NINDS NIH HHS/United States
- R21 NS055149/NS/NINDS NIH HHS/United States
- R01NS055925/NS/NINDS NIH HHS/United States
- R21NS055149/NS/NINDS NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources