{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:13:09Z","timestamp":1790439189284,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T00:00:00Z","timestamp":1565136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004923","name":"AFM-T\u00e9l\u00e9thon","doi-asserted-by":"publisher","award":["20870"],"award-info":[{"award-number":["20870"]}],"id":[{"id":"10.13039\/501100004923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004923","name":"AFM-T\u00e9l\u00e9thon","doi-asserted-by":"publisher","award":["22569"],"award-info":[{"award-number":["22569"]}],"id":[{"id":"10.13039\/501100004923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kindness for Kids","award":["."],"award-info":[{"award-number":["."]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["162265"],"award-info":[{"award-number":["162265"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by impaired function of the neuromuscular junction (NMJ). This is due to defects in one of the many proteins associated with the NMJ. In three patients with CMS, missense mutations in a gene encoding an unconventional myosin protein, MYO9A, were identified as likely causing their disorder. Preliminary studies revealed a potential involvement of the RhoA\/ROCK pathway and of a key NMJ protein, agrin, in the pathophysiology of MYO9A-depletion. In this study, a CRISPR\/Cas9 approach was used to generate genetic mutants of MYO9A zebrafish orthologues, myo9aa\/ab, to expand and refine the morphological analysis of the NMJ. Injection of NT1654, a synthetic agrin fragment compound, improved NMJ structure and zebrafish movement in the absence of Myo9aa\/ab. In addition, treatment of zebrafish with fasudil, a ROCK inhibitor, also provided improvements to the morphology of NMJs in early development, as well as rescuing movement defects, but not to the same extent as NT1654 and not at later time points. Therefore, this study highlights a role for MYO9A at the NMJ, the first unconventional myosin motor protein associated with a neuromuscular disease, and provides a potential mechanism of action of MYO9A-pathophysiology.<\/jats:p>","DOI":"10.3390\/cells8080848","type":"journal-article","created":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T10:56:38Z","timestamp":1565175398000},"page":"848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Modulation of Agrin and RhoA Pathways Ameliorates Movement Defects and Synapse Morphology in MYO9A-Depleted Zebrafish"],"prefix":"10.3390","volume":"8","author":[{"given":"Emily","family":"O\u2019Connor","sequence":"first","affiliation":[{"name":"John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Cairns","sequence":"additional","affiliation":[{"name":"Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8L1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9579-3514","authenticated-orcid":false,"given":"Sally","family":"Spendiff","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Burns","sequence":"additional","affiliation":[{"name":"Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Hettwer","sequence":"additional","affiliation":[{"name":"Neurotune AG. Wagistrasse 27a, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"M\u00e4der","sequence":"additional","affiliation":[{"name":"Neurotune AG. Wagistrasse 27a, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarke","family":"Slater","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2324-8001","authenticated-orcid":false,"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada"},{"name":"Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center\u2014University of Freiburg, 79106 Freiburg, Germany"},{"name":"Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"},{"name":"Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON K1H 7X5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3233\/JND-170257","article-title":"Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions","volume":"4","author":"Nicole","year":"2017","journal-title":"J. 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