Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions

Annals of the New York Academy of Sciences
Natalia N SinghRavindra N Singh

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.

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Citations

Sep 19, 2015·Future Medicinal Chemistry·Natalia N SinghRavindra N Singh
Nov 23, 2016·Molecular Therapy. Nucleic Acids·Tobias BonifertBernd Wissinger
Nov 15, 2017·Nature Communications·Manaswini SivaramakrishnanFriedrich Metzger
Dec 1, 2017·Frontiers in Microbiology·Eric W OttesenRavindra N Singh
Jan 31, 2019·Nucleic Acids Research·Eric W OttesenRavindra N Singh
May 26, 2018·Nature Communications·Amparo Garcia-LopezLeonardo Scapozza
Dec 31, 2016·Pharmacological Reviews·David O BatesLucy F Donaldson
Aug 31, 2017·Human Genetics·Catherine E DominguezDawn S Chandler
Jun 17, 2020·Expert Opinion on Therapeutic Targets·Ravindra N SinghNatalia N Singh
Sep 16, 2020·Wiley Interdisciplinary Reviews. RNA·Bingbing XuYongfeng Jin
Apr 10, 2019·Annals of the New York Academy of Sciences·Alicia J AngelbelloMatthew D Disney
Jul 15, 2017·Molecular Genetics and Genomics : MGG·Tatsiana V Ramanouskaya, Vasily V Grinev
Oct 23, 2019·Nature Chemical Biology·Sébastien CampagneFrédéric H-T Allain
Apr 29, 2020·International Journal of Molecular Sciences·Siran ZhuGracjan Michlewski
Jun 20, 2020·Nature·Phillip J TomezskoSilvi Rouskin
Jan 8, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Piotr Konieczny, Rubén Artero
Dec 8, 2020·Neuroscience Insights·Ravindra N SinghNatalia N Singh
Jan 8, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Natalia N SinghRavindra N Singh
May 11, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Natalia N SinghRavindra N Singh
Jul 8, 2021·Der Orthopäde·T-L Vu-HanM Pumberger
Aug 28, 2021·International Journal of Molecular Sciences·Eric William OttesenRavindra Narayan Singh

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