{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:18:59Z","timestamp":1790475539990,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T00:00:00Z","timestamp":1592352000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007721","name":"Cure SMA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007721","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Recent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n\u00a0=\u00a031) and age\u2010 and gender\u2010matched controls (n\u00a0=\u00a034).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed the first large\u2010scale whole blood transcriptomic screen with L1000, a rapid, high\u2010throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The primary downregulated KEGG pathway in adult SMA type 3 patients was \"Regulation of Actin Cytoskeleton,\u201d and downregulated expression of key genes in this pathway, including <jats:italic>ROCK1<\/jats:italic>, <jats:italic>RHOA<\/jats:italic>, and <jats:italic>ACTB,<\/jats:italic> was confirmed in the same whole blood samples using RT\u2010qPCR. SMA type 3 patient\u2010derived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first\u2010degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize <jats:italic>ROCK1<\/jats:italic>, <jats:italic>RHOA<\/jats:italic>, and <jats:italic>ACTB<\/jats:italic> mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings from whole blood and patient\u2010derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51092","type":"journal-article","created":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T09:45:03Z","timestamp":1592387103000},"page":"1158-1165","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Whole\u2010blood dysregulation of actin\u2010cytoskeleton pathway in adult spinal muscular atrophy patients"],"prefix":"10.1002","volume":"7","author":[{"given":"Jennifer J.","family":"Siranosian","sequence":"first","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia C.","family":"Nery","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2646-9689","authenticated-orcid":false,"given":"Christiano R. R.","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"},{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Siranosian","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Lyons","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Eichelberger","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reid","family":"Garner","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salom\u00e9","family":"Da Silva Duarte Lepez","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec J.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravind","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4593-6342","authenticated-orcid":false,"given":"Kathryn J.","family":"Swoboda","sequence":"additional","affiliation":[{"name":"Department of Neurology Center for Genomic Medicine Massachusetts General Hospital Boston MA USA"},{"name":"Broad Institute of MIT and Harvard Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2018.4"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.77"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033572"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20473"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073807305665"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31408-8"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1702752"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-306647"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.10.049"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a018267"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10059-010-0053-8"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858417705059"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr425"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.08.002"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0021296"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21838"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.10050"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00295.2007"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.27"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2016.09.027"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0181-9"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2937"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2005.05.014"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-007-0024-5"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035462"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.779"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008762"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Facn3.51092","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51092","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.51092","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51092","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T17:12:40Z","timestamp":1693847560000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,17]]},"references-count":28,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2020,7]]}},"alternative-id":["10.1002\/acn3.51092"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51092","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,17]]},"assertion":[{"value":"2020-03-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}