{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:23:12Z","timestamp":1790191392890,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"S2","license":[{"start":{"date-parts":[[2017,3,21]],"date-time":"2017-03-21T00:00:00Z","timestamp":1490054400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>We humans have evolved by acquiring diversity of alternative <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> metabolisms including alternative means of splicing and transcribing non\u2010coding genes, and not by acquiring new coding genes. Tissue\u2010specific and developmental stage\u2010specific alternative <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> splicing is achieved by tightly regulated spatiotemporal regulation of expressions and activations of <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010binding proteins that recognize their cognate splicing <jats:italic>cis<\/jats:italic>\u2010elements on nascent <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> transcripts. Genes expressed at the neuromuscular junction are also alternatively spliced. In addition, germline mutations provoke aberrant splicing by compromising binding of <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010binding proteins, and cause congenital myasthenic syndromes (<jats:styled-content style=\"fixed-case\">CMS<\/jats:styled-content>). We present physiological splicing mechanisms of genes for agrin (<jats:italic><jats:styled-content style=\"fixed-case\">AGRN<\/jats:styled-content><\/jats:italic>), acetylcholinesterase (<jats:italic><jats:styled-content style=\"fixed-case\">ACHE<\/jats:styled-content><\/jats:italic>), Mu<jats:styled-content style=\"fixed-case\">SK<\/jats:styled-content> (<jats:italic><jats:styled-content style=\"fixed-case\">MUSK<\/jats:styled-content><\/jats:italic>), acetylcholine receptor (<jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content>hR) \u03b11 subunit (<jats:italic><jats:styled-content style=\"fixed-case\">CHRNA<\/jats:styled-content>1<\/jats:italic>), and collagen Q (<jats:italic><jats:styled-content style=\"fixed-case\">COLQ<\/jats:styled-content><\/jats:italic>) in human, and their aberration in diseases. Splicing isoforms of <jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content>h<jats:styled-content style=\"fixed-case\">E<jats:sub>T<\/jats:sub><\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> AC<\/jats:styled-content>h<jats:styled-content style=\"fixed-case\">E<jats:sub>H<\/jats:sub><\/jats:styled-content>, and <jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content>h<jats:styled-content style=\"fixed-case\">E<jats:sub>R<\/jats:sub><\/jats:styled-content> are generated by hn<jats:styled-content style=\"fixed-case\">RNP<\/jats:styled-content> H\/F. Skipping of <jats:italic><jats:styled-content style=\"fixed-case\">MUSK<\/jats:styled-content><\/jats:italic> exon 10 makes a Wnt\u2010insensitive Mu<jats:styled-content style=\"fixed-case\">SK<\/jats:styled-content> isoform, which is unique to human. Skipping of exon 10 is achieved by coordinated binding of hn<jats:styled-content style=\"fixed-case\">RNP<\/jats:styled-content> C, <jats:styled-content style=\"fixed-case\">YB<\/jats:styled-content>\u20101, and hn<jats:styled-content style=\"fixed-case\">RNP<\/jats:styled-content> L to exon 10. Exon P3A of <jats:italic><jats:styled-content style=\"fixed-case\">CHRNA<\/jats:styled-content>1<\/jats:italic> is alternatively included to generate a non\u2010functional <jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content>hR \u03b11 subunit in human. Molecular dissection of splicing mutations in patients with <jats:styled-content style=\"fixed-case\">CMS<\/jats:styled-content> reveals that exon P3A is alternatively skipped by hn<jats:styled-content style=\"fixed-case\">RNP<\/jats:styled-content> H, polypyrimidine tract\u2010binding protein 1, and hn<jats:styled-content style=\"fixed-case\">RNP<\/jats:styled-content> L. Similarly, analysis of an exonic mutation in <jats:italic><jats:styled-content style=\"fixed-case\">COLQ<\/jats:styled-content><\/jats:italic> exon 16 in a <jats:styled-content style=\"fixed-case\">CMS<\/jats:styled-content> patient discloses that constitutive splicing of exon 16 requires binding of serine arginine\u2010rich splicing factor 1. Intronic and exonic splicing mutations in <jats:styled-content style=\"fixed-case\">CMS<\/jats:styled-content> enable us to dissect molecular mechanisms underlying alternative and constitutive splicing of genes expressed at the neuromuscular junction.<\/jats:p><jats:p><jats:bold>This is an article for the<\/jats:bold>\u00a0<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/journal\/10.1111\/(ISSN)1471-4159\/homepage\/special_issues.htm\">special issue XVth International Symposium on Cholinergic Mechanisms<\/jats:ext-link>.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13954-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13954","type":"journal-article","created":{"date-parts":[[2017,1,10]],"date-time":"2017-01-10T15:33:34Z","timestamp":1484062414000},"page":"64-72","source":"Crossref","is-referenced-by-count":27,"title":["Splicing regulation and dysregulation of cholinergic genes expressed at the neuromuscular junction"],"prefix":"10.1111","volume":"142","author":[{"given":"Kinji","family":"Ohno","sequence":"first","affiliation":[{"name":"Division of Neurogenetics Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Alinoor","family":"Rahman","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Nazim","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhana","family":"Nasrin","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingni","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010ichi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Masuda","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,21]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.011"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp023"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161720"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg616"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209383200"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410929200"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073774"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh393"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1683-5"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2008.01.007"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90152-H"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2288"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/30741"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2776"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M305462200"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-24-10672.1999"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M402596200"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14234"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2005.10.002"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn305"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1066752"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001735"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep06841"},{"key":"e_1_2_5_25_1","article-title":"Competitive regulation of alternative splicing and alternative polyadenylation by hnRNP H and CstF64 determines acetylcholinesterase isoforms","author":"Nazim M.","journal-title":"Nucleic Acids Res."},{"key":"e_1_2_5_26_1","first-page":"50","article-title":"Splicing abnormalities in congenital myasthenic syndromes","volume":"24","author":"Ohno K.","year":"2005","journal-title":"Acta Myol."},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.16.9654"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1086\/302551"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.026682"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1189"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq444"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21609"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep02931"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep13208"},{"key":"e_1_2_5_35_1","first-page":"00016","article-title":"Decoding abnormal splicing code in human diseases","volume":"2","author":"Rahman M. A.","year":"2015","journal-title":"J. Investig. Genomics"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813112106"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm647"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.261974.115"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2016.23"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.25.15675"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl171"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2006-7-s1-s12"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.010"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07509"},{"key":"e_1_2_5_45_1","first-page":"1275","article-title":"A unique intronic splicing enhancer controls the inclusion of the agrin Y exon","volume":"3","author":"Wei N.","year":"1997","journal-title":"RNA"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.13954","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/api.wiley.com\/onlinelibrary\/chorus\/v1\/articles\/10.1111%2Fjnc.13954","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.13954","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T01:16:38Z","timestamp":1695604598000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.13954"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,21]]},"references-count":44,"journal-issue":{"issue":"S2","published-print":{"date-parts":[[2017,8]]}},"alternative-id":["10.1111\/jnc.13954"],"URL":"https:\/\/doi.org\/10.1111\/jnc.13954","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,21]]}}}