Campus Units

Biomedical Sciences

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

4-2015

Journal or Book Title

Annals of the New York Academy of Sciences

Volume

1341

Issue

1

First Page

176

Last Page

187

DOI

10.1111/nyas.12727

Abstract

Humans carry two copies of the survival motor neuron gene: SMN1 and SMN2. Loss of SMN1 coupled with skipping of SMN2 exon 7 causes spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Our discovery of intronic splicing silencer N1 (ISS‐N1) is a promising target, currently in a phase III clinical trial, for an antisense oligonucleotide–mediated splicing correction in SMA. We have recently shown that the first residue of ISS‐N1 is locked in a unique RNA structure that we term ISTL1 (internal stem through long‐distance interaction–1). Complementary strands of ISTL1 are separated from each other by 279 nucleotides. Using site‐specific mutations and chemical structure probing, we confirmed the formation and functional significance of ISTL1. Located in the middle of intron 7, the 3′ strand of ISTL1 falls within an inhibitory region that we term ISS‐N2. We demonstrate that an antisense oligonucleotide–mediated sequestration of ISS‐N2 fully corrects SMN2 exon 7 splicing and restores high levels of SMN in SMA patient cells. These results underscore the therapeutic potential of the regulatory information present in a secondary and high‐order RNA structure of a human intron.

Comments

This is the peer-reviewed version of the following article: Singh, Natalia N., Brian M. Lee, and Ravindra N. Singh. "Splicing regulation in spinal muscular atrophy by an RNA structure formed by long‐distance interactions." Annals of the New York Academy of Sciences 1341, no. 1 (2015): 176-187, which has been published in final form at DOI: 10.1111/nyas.12727. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Posted with permission.

Copyright Owner

New York Academy of Sciences

Language

en

File Format

application/pdf

Published Version

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