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The most common disease-causing mutation (\n                    <jats:italic>DOK7<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>1124_1127 dup<\/jats:italic>\n                    <\/jats:sup>\n                    ) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (\n                    <jats:italic>Dok7<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>CM<\/jats:italic>\n                    <\/jats:sup>\n                    mice) and a mouse with point mutations in the two tyrosine residues (\n                    <jats:italic>Dok7<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>2YF<\/jats:italic>\n                    <\/jats:sup>\n                    ). We show that\n                    <jats:italic>Dok7<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>CM<\/jats:italic>\n                    <\/jats:sup>\n                    mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in\n                    <jats:italic>Dok7<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>CM<\/jats:italic>\n                    <\/jats:sup>\n                    mice. These findings identify an unexpected cause for disease and a potential therapy for both\n                    <jats:italic>DOK7<\/jats:italic>\n                    CM and other forms of CM caused by mutations in\n                    <jats:italic>AGRIN<\/jats:italic>\n                    ,\n                    <jats:italic>LRP4<\/jats:italic>\n                    or\n                    <jats:italic>MUSK<\/jats:italic>\n                    , and illustrate the potential of targeted therapy to rescue congenital lethality.\n                  <\/jats:p>","DOI":"10.1038\/s41586-021-03672-3","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T12:02:44Z","timestamp":1624449764000},"page":"404-408","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia"],"prefix":"10.1038","volume":"595","author":[{"given":"Julien","family":"Oury","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Leloup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Koide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis D.","family":"Corrado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-8595","authenticated-orcid":false,"given":"Gayatri","family":"Ketavarapu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takamitsu","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-4358","authenticated-orcid":false,"given":"Shohei","family":"Koide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3550-6891","authenticated-orcid":false,"given":"Steven J.","family":"Burden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"3672_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S1462399407000427","volume":"9","author":"JS M\u00fcller","year":"2007","unstructured":"M\u00fcller, J. S., Mihaylova, V., Abicht, A. & Lochm\u00fcller, H. Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Expert Rev. Mol. Med. 9, 1\u201320 (2007).","journal-title":"Expert Rev. Mol. Med."},{"key":"3672_CR2","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/S1474-4422(14)70201-7","volume":"14","author":"AG Engel","year":"2015","unstructured":"Engel, A. G., Shen, X. M., Selcen, D. & Sine, S. M. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 14, 420\u2013434 (2015).","journal-title":"Lancet Neurol."},{"key":"3672_CR3","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/35097557","volume":"2","author":"JR Sanes","year":"2001","unstructured":"Sanes, J. R. & Lichtman, J. W. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat. Rev. Neurosci. 2, 791\u2013805 (2001).","journal-title":"Nat. Rev. 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S.J.B., S.K., J.O., A.K. and N.L. are inventors on a patent application (no. 1474662.02232) for \u2018Therapeutic MUSK Antibodies\u2019 filed by New York University. These patents have been licensed to Argenx BVBA. S.J.B. and S.K. received research funding from Argenx BVBA. S.K. is a scientific advisory board member and holds equity in and receives consulting fees from Black Diamond Therapeutics, and receives research funding from Puretech Health.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}