{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:50:23Z","timestamp":1783471823280,"version":"3.55.0"},"reference-count":74,"publisher":"BMJ","issue":"11","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32271346"],"award-info":[{"award-number":["32271346"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81530035"],"award-info":[{"award-number":["81530035"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073753"],"award-info":[{"award-number":["82073753"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,5,8]]},"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations of survival of motor neuron 1 <jats:italic>(SMN1<\/jats:italic>) gene, which encodes the SMN protein. <jats:italic>SMN2<\/jats:italic>, a nearly identical copy of <jats:italic>SMN1<\/jats:italic>, with several single-nucleotide substitutions leading to predominant skipping of its exon 7, is insufficient to compensate for loss of <jats:italic>SMN1<\/jats:italic>. Heterogeneous nuclear ribonucleoprotein R (hnRNPR) has been previously shown to interact with SMN in the 7SK complex in motoneuron axons and is implicated in the pathogenesis of SMA. Here, we show that hnRNPR also interacts with <jats:italic>SMN1\/2<\/jats:italic> pre-mRNAs and potently inhibits exon 7 inclusion.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In this study, to examine the mechanism that hnRNPR regulates <jats:italic>SMN1\/2<\/jats:italic> splicing, deletion analysis in an <jats:italic>SMN2<\/jats:italic> minigene system, RNA-affinity chromatography, co-overexpression analysis and tethering assay were performed. We screened antisense oligonucleotides (ASOs) in a minigene system and identified a few that markedly promoted <jats:italic>SMN2<\/jats:italic> exon 7 splicing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We pinpointed an AU-rich element located towards the 3\u2032 end of the exon that mediates splicing repression by hnRNPR. We uncovered that both hnRNPR and Sam68 bind to the element in a competitive manner, and the inhibitory effect of hnRNPR is much stronger than Sam68. Moreover, we found that, among the four hnRNPR splicing isoforms, the exon 5-skipped one has the minimal inhibitory effect, and ASOs inducing <jats:italic>hnRNPR<\/jats:italic> exon 5 skipping also promote <jats:italic>SMN2<\/jats:italic> exon 7 inclusion.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We identified a novel mechanism that contributes to mis-splicing of <jats:italic>SMN2<\/jats:italic> exon 7.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109186","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T13:25:58Z","timestamp":1684934758000},"page":"1105-1115","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["HnRNPR strongly represses splicing of a critical exon associated with spinal muscular atrophy through binding to an exonic AU-rich 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