{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:45:09Z","timestamp":1792791909814,"version":"4.5.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"27","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000297","name":"FRAXA Research Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000297","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM135087"],"award-info":[{"award-number":["R01 GM135087"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM046779"],"award-info":[{"award-number":["R01 GM046779"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"HHS | NIH | National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1 TR001453"],"award-info":[{"award-number":["UL1 TR001453"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS111990"],"award-info":[{"award-number":["R01 NS111990"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Massachusetts Chan Medical School BRIDGE Fund","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:p>\n                    Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here, we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissues of individuals with fragile X syndrome (FXS). Surprisingly, the\n                    <jats:italic>FMR1 (Fragile X Messenger Ribonucleoprotein 1)<\/jats:italic>\n                    gene is transcribed in &gt;70% of the FXS tissues. In all\n                    <jats:italic>FMR1<\/jats:italic>\n                    -expressing FXS tissues,\n                    <jats:italic>FMR1<\/jats:italic>\n                    RNA itself is mis-spliced in a CGG expansion\u2013dependent manner to generate the little-known\n                    <jats:italic>FMR1<\/jats:italic>\n                    -217 RNA isoform, which is comprised of\n                    <jats:italic>FMR1<\/jats:italic>\n                    exon 1 and a pseudo-exon in intron 1.\n                    <jats:italic>FMR1<\/jats:italic>\n                    -217 is also expressed in FXS premutation carrier\u2013derived skin fibroblasts and brain tissues. We show that in cells aberrantly expressing mis-spliced\n                    <jats:italic>FMR1<\/jats:italic>\n                    , antisense oligonucleotide (ASO) treatment reduces\n                    <jats:italic>FMR1<\/jats:italic>\n                    -217, rescues full-length\n                    <jats:italic>FMR1<\/jats:italic>\n                    RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably,\n                    <jats:italic>FMR1<\/jats:italic>\n                    gene reactivation in transcriptionally silent FXS cells using 5-aza-2\u2032-deoxycytidine (5-AzadC), which prevents DNA methylation, increases\n                    <jats:italic>FMR1<\/jats:italic>\n                    -217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length\n                    <jats:italic>FMR1<\/jats:italic>\n                    expression and restores FMRP. These findings indicate that misregulated RNA-processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing\n                    <jats:italic>FMR1-217<\/jats:italic>\n                    , ASO treatment may offer a therapeutic approach to mitigate the disorder.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2302534120","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T15:09:49Z","timestamp":1687792189000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":57,"title":["Antisense oligonucleotide rescue of CGG expansion\u2013dependent\n                    <i>FMR1<\/i>\n                    mis-splicing in fragile X syndrome restores FMRP"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0691-9566","authenticated-orcid":false,"given":"Sneha","family":"Shah","sequence":"first","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Sharp","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sithara","family":"Raju Ponny","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Lee","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5706-1734","authenticated-orcid":false,"given":"Jonathan K.","family":"Watts","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605"},{"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605"},{"name":"Li Weibo Rare Disease Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Berry-Kravis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612"},{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612"},{"name":"Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2753-2501","authenticated-orcid":false,"given":"Joel D.","family":"Richter","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"},{"name":"Li Weibo Rare Disease Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","unstructured":"J. C. Darnell FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 14 247\u2013261 (2011) 10.1016\/j.cell.2011.06.013.","DOI":"10.1016\/j.cell.2011.06.013"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky267"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.251405.119"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.02.086"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3353"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","unstructured":"S. Shah FMRP control of ribosome translocation promotes chromatin modifications and alternative splicing of neuronal genes linked to autism. Cell Rep. 30 4459\u20134472.e6 (2020) 10.1016\/j.celrep.2020.02.076.","DOI":"10.1016\/j.celrep.2020.02.076"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109475108"},{"key":"e_1_3_4_8_2","unstructured":"M. J. Gandal Transcriptome-wide isoform-level dysregulation in ASD schizophrenia and bipolar disorder. Science 362 eaat8127 (2018) 10.1126\/science.aat8127. eaat8127"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.035"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","unstructured":"M. Quesnel-Valli\u00e8res Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders. Mol. Cell 64 1023\u20131034 (2016) 10.1016\/j.molcel.2016.11.033.","DOI":"10.1016\/j.molcel.2016.11.033"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci9050096"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40348-014-0001-3"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2021.715346"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","unstructured":"J. D. Richter X. Zhao The molecular biology of FMRP: New insights into fragile X syndrome. Nat. Rev. Neurosci. 22 209\u2013222 (2021) 10.1038\/s41583-021-00432-0.","DOI":"10.1038\/s41583-021-00432-0"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1419161111"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.033"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","unstructured":"S. S. Tran Widespread RNA editing dysregulation in brains from autistic individuals. Nat. Neurosci. 22 25\u201336 (2019) 10.1038\/s41593-018-0287-x.","DOI":"10.1038\/s41593-018-0287-x"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.02.026"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.01.012"},{"key":"e_1_3_4_20_2","first-page":"4870","article-title":"The FMR1 promoter is selectively hydroxymethylated in primary neurons of fragile X syndrome patients","volume":"25","author":"Esanov R.","year":"2016","unstructured":"R. Esanov, N. S. Andrade, S. Bennison, C. Wahlestedt, Z. Zeier The FMR1 promoter is selectively hydroxymethylated in primary neurons of fragile X syndrome patients. Hum. Mol. Genet.25, 4870\u20134880 (2016), 10.1093\/hmg\/ddw311.","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108991"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","unstructured":"M. P. Moazami Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system. bioRxiv [Preprint] (2021). https:\/\/doi.org\/10.1101\/2021.02.14.431096. Accessed 15 February 2021.","DOI":"10.1101\/2021.02.14.431096"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes7080049"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-016-0060-x"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","unstructured":"S. D. Sheridan Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS One 6 e26203 (2011) 10.1371\/journal.pone.0026203.","DOI":"10.1371\/journal.pone.0026203"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1097\/DBP.0b013e31829d1f20"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.1.109"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","unstructured":"J. D. Graef Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons. Eur. J. Neurosci. 51 2143\u20132157 (2020) 10.1111\/ejn.14660.","DOI":"10.1111\/ejn.14660"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00282"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0165499"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.08.084"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31408-8"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","unstructured":"S. A. M. Mulders Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. Proc. Natl. Acad. Sci. U.S.A. 106 13915\u201313920 (2009).","DOI":"10.1073\/pnas.0905780106"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.115.226969"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11362"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25424"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.10.015"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01557-6"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22038"},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","unstructured":"Y. Q. Jiang A. Andrade D. Lipscombe Spinal morphine but not ziconotide or gabapentin analgesia is affected by alternative splicing of voltage-gated calcium channel CaV2.2 pre-mRNA. Mol. Pain 9 67 (2013) 10.1186\/1744-8069-9-67.","DOI":"10.1186\/1744-8069-9-67"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","unstructured":"C. Milazzo Antisense oligonucleotide treatment rescues UBE3A expression and multiple phenotypes of an Angelman syndrome mouse model. JCI Insight 6 e145991 (2021) 10.1172\/jci.insight.145991.","DOI":"10.1172\/jci.insight.145991"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abf4077"},{"key":"e_1_3_4_43_2","first-page":"249","volume-title":"Contemporary Intellectual Assessment: Theories, Tests, and Issues","author":"Roid G. H.","year":"2012","unstructured":"G. H. Roid, M. Pomplun, Contemporary Intellectual Assessment: Theories, Tests, and Issues (The Guilford Press, New York, NY, ed. 3, 2012), pp. 249\u2013268.","edition":"3"},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","unstructured":"S. S. Tran Widespread RNA editing dysregulation in brains from autistic individuals. Nat. Neurosci. 22 25\u201336 (2019) 10.1038\/s41593-018-0287-x. NCBI GEO (Gene Expression Omnibus) https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE117776. Deposited 27 July 2018.","DOI":"10.1038\/s41593-018-0287-x"},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","unstructured":"D. Vershkov FMR1 reactivating treatments in Fragile X iPSC-derived neural progenitors in vitro and in vivo. Cell Rep. 26 2531\u20132539.e4 (2019). NCBI GEO (Gene Expression Omnibus) https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE112145. Deposited 21 March 2018.","DOI":"10.1016\/j.celrep.2019.02.026"},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","unstructured":"X. S. Liu Rescue of Fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172 979\u2013991.e6 (2018). NCBI GEO (Gene Expression Omnibus) https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE108498. Deposited 24 December 2017.","DOI":"10.1016\/j.cell.2018.01.012"},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","unstructured":"A. Kucukural . DolphinNext: A graphical user interface for creating deploying and executing Nextflow pipelines. J Biomol Tech. 31 S25 (2020). https:\/\/doi.org\/10.1101\/689539.","DOI":"10.1101\/689539"},{"key":"e_1_3_4_48_2","unstructured":"S. Shah Antisense Oligonucleotide Rescue of CGG Expansion-Dependent FMR1 Mis-Splicing in Fragile X Syndrome Restores FMRP. NCBI GEO (Gene Expression Omnibus). https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE202179. Deposited 03 May 2022."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2302534120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T09:23:38Z","timestamp":1695288218000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2302534120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,26]]},"references-count":48,"journal-issue":{"issue":"27","published-print":{"date-parts":[[2023,7,4]]}},"alternative-id":["10.1073\/pnas.2302534120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2302534120","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.742692996.793599606","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,26]]},"assertion":[{"value":"2023-02-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2302534120"}}