{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T22:05:10Z","timestamp":1792533910483,"version":"4.5.0"},"reference-count":62,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T00:00:00Z","timestamp":1588809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EXC\u20102049\u2010390688087"],"award-info":[{"award-number":["EXC\u20102049\u2010390688087"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB958\/Z02"],"award-info":[{"award-number":["SFB958\/Z02"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Congenital myasthenic syndromes (CMS) are characterized by muscle weakness, ptosis and episodic apnoea. Mutations affect integral protein components of the neuromuscular junction (NMJ). Here we searched for the genetic basis of CMS in female monozygotic twins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We employed whole\u2010exome sequencing for mutation detection and Sanger sequencing for segregation analysis. Immunohistology was done with antibodies against CHD8, rapsyn, \u03b2\u2010catenin (\u03b2CAT) and golgin on fi\u2010bro\u2010blasts, human and mouse muscle. We recorded superresolution images of the NMJ using 3D\u2010structured illumination microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We discovered a spontaneous missense mutation in <jats:italic>CHD8<\/jats:italic> [chr14:g.21,884,051G&gt;A, GRCh37.p11\u00a0|\u00a0c.1732C&gt;T, NM_00117062\u00a0|\u00a0p.(R578C)], the gene encoding chromodomain helicase DNA\u2010binding protein 8. This is the first missense mutation affecting Duplin, the short 110\u00a0kDa isoform of CHD8. It is known that CHD8\/Duplin negatively regulates \u03b2CAT signalling in the WNT pathway and plays a role in chromatin remodelling. Inactivating <jats:italic>CHD8<\/jats:italic> mutations are associated with autism spectrum disorder and intellectual disability in combination with facial dysmorphism, overgrowth and macrocephalus. No muscle\u2010specific phenotype has been reported to date. Co\u2010immunostaining with rapsyn on human and mouse muscle revealed a strong presence of CHD8 at the NMJ being located towards the sarcoplasmic side of the rapsyn cluster, where it co\u2010localizes with \u03b2CAT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We hypothesize CHD8 to have a role in the maintenance of the structural integrity and function of the NMJ. Both patients benefited from treatment with 3,4\u2010diaminopyridine, a reversible blocker of voltage\u2010gated potassium channels at the nerve terminal that prolongs the action potential and increases acetylcholine release.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12617","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T12:28:19Z","timestamp":1586348899000},"page":"588-601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A spontaneous missense mutation in the chromodomain helicase DNA\u2010binding protein 8 (<i>CHD8<\/i>) gene: a novel association with congenital myasthenic syndrome"],"prefix":"10.1111","volume":"46","author":[{"given":"C. Y.","family":"Lee","sequence":"first","affiliation":[{"name":"NeuroCure Cluster of Excellence Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"},{"name":"Department of Neuropediatrics Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8639-0764","authenticated-orcid":false,"given":"M.","family":"Petkova","sequence":"additional","affiliation":[{"name":"NeuroCure Cluster of Excellence Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"},{"name":"Department of Neuropediatrics Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Morales\u2010Gonzalez","sequence":"additional","affiliation":[{"name":"NeuroCure Cluster of Excellence Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"},{"name":"Department of Neuropediatrics Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Gimber","sequence":"additional","affiliation":[{"name":"Advanced Medical Bioimaging Core Facility (AMBIO) Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Schmoranzer","sequence":"additional","affiliation":[{"name":"Advanced Medical Bioimaging Core Facility (AMBIO) Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Meisel","sequence":"additional","affiliation":[{"name":"Department of Neurology Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"B\u00f6hmerle","sequence":"additional","affiliation":[{"name":"Department of Neurology Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1143-2103","authenticated-orcid":false,"given":"W.","family":"Stenzel","sequence":"additional","affiliation":[{"name":"Department of Neuropathology Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2824-3891","authenticated-orcid":false,"given":"M.","family":"Schuelke","sequence":"additional","affiliation":[{"name":"NeuroCure Cluster of Excellence Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"},{"name":"Department of Neuropediatrics Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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