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Loss of <jats:italic>SMN1<\/jats:italic> coupled with skipping of <jats:italic>SMN2<\/jats:italic> exon 7 causes spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Our discovery of intronic splicing silencer N1 (ISS\u2010N1) is a promising target, currently in a phase III clinical trial, for an antisense oligonucleotide\u2013mediated splicing correction in SMA. We have recently shown that the first residue of ISS\u2010N1 is locked in a unique RNA structure that we term ISTL1 (internal stem through long\u2010distance interaction\u20131). Complementary strands of ISTL1 are separated from each other by 279 nucleotides. Using site\u2010specific mutations and chemical structure probing, we confirmed the formation and functional significance of ISTL1. Located in the middle of intron 7, the 3\u2032 strand of ISTL1 falls within an inhibitory region that we term ISS\u2010N2. We demonstrate that an antisense oligonucleotide\u2013mediated sequestration of ISS\u2010N2 fully corrects <jats:italic>SMN2<\/jats:italic> 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\u2010order RNA structure of a human intron.<\/jats:p>","DOI":"10.1111\/nyas.12727","type":"journal-article","created":{"date-parts":[[2015,2,27]],"date-time":"2015-02-27T22:30:30Z","timestamp":1425076230000},"page":"176-187","source":"Crossref","is-referenced-by-count":53,"title":["Splicing regulation in spinal muscular atrophy by an RNA structure formed by long\u2010distance interactions"],"prefix":"10.1111","volume":"1341","author":[{"given":"Natalia N.","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences Iowa State University  Ames Iowa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian M.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Iowa State University  Ames Iowa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravindra N.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Iowa State University  Ames Iowa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,2,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.24.10505-10514.2004"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2009.10.004"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2011.04.001"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2011.10.030"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.08.008"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3681"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004351"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-014-0293-y"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.2478\/s13380-013-0109-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.08.005"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.14.63"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.11.002"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12031"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-012-1171-5"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90460-3"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070399"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1884910"},{"key":"e_1_2_8_19_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-3-540-34449-0_6","article-title":"Spinal muscular atrophy and therapeutic prospects","volume":"44","author":"Wirth B.","year":"2006","journal-title":"Prog. 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