Campus Units

Biomedical Sciences

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

2018

Journal or Book Title

RNA Metabolism in Neurodegenerative Diseases

Volume

20

First Page

31

Last Page

61

DOI

10.1007/978-3-319-89689-2_2

Abstract

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.

Comments

This is a post-peer-review, pre-copyedit version of a book chapter published as Singh R.N., Singh N.N. "Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes." In Sattler R., Donnelly C. (eds.) RNA Metabolism in Neurodegenerative Diseases. Advances in Neurobiology, vol. 20. Springer, Cham (2018): 31-61. The final authenticated version is available online at DOI: 10.1007/978-3-319-89689-2_2. Posted with permission.

Copyright Owner

Springer International Publishing AG

Language

en

File Format

application/pdf

Published Version

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