{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:00:16Z","timestamp":1789664416788,"version":"4.0.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009438","name":"National Center of Neurology and Psychiatry","doi-asserted-by":"publisher","award":["20FC1036"],"award-info":[{"award-number":["20FC1036"]}],"id":[{"id":"10.13039\/501100009438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21H04815"],"award-info":[{"award-number":["JP21H04815"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21K06392"],"award-info":[{"award-number":["JP21K06392"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20H03561"],"award-info":[{"award-number":["JP20H03561"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22ek0109488"],"award-info":[{"award-number":["JP22ek0109488"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22bm0804005"],"award-info":[{"award-number":["JP22bm0804005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>At the neuromuscular junction, the downstream of tyrosine kinase 7 (DOK7) enhances the phosphorylation of muscle-specific kinase (MuSK) and induces clustering of acetylcholine receptors (AChRs). We identified a patient with congenital myasthenic syndrome (CMS) with two heteroallelic mutations in DOK7, c.653-1G&amp;gt;C in intron 5 and c.190G&amp;gt;A predicting p.G64R in the pleckstrin homology domain. iPS cells established from the patient (CMS-iPSCs) showed that c.653-1G&amp;gt;C caused in-frame skipping of exon 6 (120 bp) and frame-shifting activation of a cryptic splice site deleting seven nucleotides in exon 6. p.G64R reduced the expression of DOK7 to 10% of wild-type DOK7, and markedly compromised AChR clustering in transfected C2C12 myotubes. p.G64R-DOK7 made insoluble aggresomes at the juxtanuclear region in transfected C2C12 myoblasts and COS7 cells, which were co-localized with molecules in the autophagosome system. A protease inhibitor MG132 reduced the soluble fraction of p.G64R-DOK7 and enhanced the aggresome formation of p.G64R-DOK7. To match the differentiation levels between patient-derived and control induced pluripotent stem cells (iPSCs), we corrected c.190G&amp;gt;A (p.G64R) by CRISPR\/Cas9 to make isogenic iPSCs while retaining c.653-1G&amp;gt;C (CMS-iPSCsCas9). Myogenically differentiated CMS-iPSCs showed juxtanuclear aggregates of DOK7, reduced expression of endogenous DOK7 and reduced phosphorylation of endogenous MuSK. Another mutation, p.T77M, also made aggresome to a less extent compared with p.G64R in transfected COS7 cells. These results suggest that p.G64R-DOK7 makes aggresomes in cultured cells and is likely to compromise MuSK phosphorylation for AChR clustering.<\/jats:p>","DOI":"10.1093\/hmg\/ddac306","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T12:52:55Z","timestamp":1672318375000},"page":"1511-1523","source":"Crossref","is-referenced-by-count":10,"title":["A mutation in <i>DOK7<\/i> in congenital myasthenic syndrome forms aggresome in cultured cells, and reduces DOK7 expression and MuSK phosphorylation in patient-derived iPS cells"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4853-4525","authenticated-orcid":false,"given":"Shaochuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bisei","family":"Ohkawara","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikako","family":"Ito","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhou","family":"Huang","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Nakata","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetoshi","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Kyoto University Center for iPS Cell Research and Application (CiRA), , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Komaki","sequence":"additional","affiliation":[{"name":"National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira Department of Pediatrics, , Tokyo 187-8551 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Kamon","sequence":"additional","affiliation":[{"name":"National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira Department of Peripheral Nervous System Research, , Tokyo 187-8551 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3625-2042","authenticated-orcid":false,"given":"Toshiyuki","family":"Araki","sequence":"additional","affiliation":[{"name":"National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira Department of Peripheral Nervous System Research, , Tokyo 187-8551 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-2750","authenticated-orcid":false,"given":"Kinji","family":"Ohno","sequence":"additional","affiliation":[{"name":"Nagoya University Graduate School of Medicine Division of Neurogenetics, Center for Neurological Diseases and Cancer, , Nagoya 466-8550 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"2023042013410980600_ref1","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S1474-4422(14)70201-7","article-title":"Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment","volume":"14","author":"Engel","year":"2015","journal-title":"Lancet Neurol."},{"key":"2023042013410980600_ref2","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.cbi.2016.04.019","article-title":"Roles of collagen Q in MuSK antibody-positive myasthenia gravis","volume":"259","author":"Ohno","year":"2016","journal-title":"Chem. 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