{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:14:14Z","timestamp":1788459254898,"version":"build-2803163510"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":243,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003768","name":"University of Strasbourg","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003768","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004794","name":"French National Centre for Scientific Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"French National Institute of Health and Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Initiative of Excellence"},{"name":"Ecole Universitaire de la Recherche"},{"DOI":"10.13039\/501100001665","name":"French National Research Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Dominant loss-of-function mutations in DNM2 cause Charcot\u2013Marie\u2013Tooth neuropathy characterized by sensory and motor deficits associated with myelin and\/or axonal abnormalities and muscle atrophy. Increasing DNM2 activity from embryogenesis has been reported to ameliorate neuromuscular phenotypes in the Dnm2K562E\/+ Charcot\u2013Marie\u2013Tooth mouse; however, this model displays predominantly muscle pathology and limited nerve involvement, precluding rigorous evaluation of neuropathic mechanisms and potential therapies. Here, we performed comprehensive behavioural, electrophysiological, histological and molecular analyses to characterize the Dnm2K562E\/SC\u2212 mouse, which combines systemic heterozygosity for the common K562E mutation together with Schwann cell-specific deletion of wild-type Dnm2. This model faithfully reproduces key clinical and pathological features of DNM2\u2013Charcot\u2013Marie\u2013Tooth, including motor deficits, reduced general force and coordination, and severe sensory and motor conduction deficits associated with axonal loss, demyelination and inflammation. Mechanistically, we delineate a coherent pathological sequence that explains the profound functional deficits. In particular, a downregulation of the transcription factor EGR2, a master regulator of myelin gene expression, and of the myelin protein MPZ correlates with demyelination. To evaluate the therapeutic potential of DNM2 supplementation, post-symptomatic intrathecal delivery of AAV9-DNM2 driven by the Schwann cell-specific MPZ promoter was performed at 4 weeks. Although DNM2 expression increased in peripheral nerves (\u223c1.9-fold), no significant improvements were observed across behavioural, electrophysiological, structural or molecular parameters. Together, these findings establish the Dnm2K562E\/SC\u2212 mouse as a robust preclinical model, recapitulating key features of DNM2\u2013Charcot\u2013Marie\u2013Tooth, and provide crucial insight into the biological and temporal constraints that must guide future therapeutic strategies for DNM2\u2013Charcot\u2013Marie\u2013Tooth.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag324","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:10:24Z","timestamp":1788250224000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>DNM2<\/i>\n                    \u2013Charcot\u2013Marie\u2013Tooth neuropathy stems from disrupted Schwann cell function and shows limited therapeutic reversibility"],"prefix":"10.1093","volume":"8","author":[{"given":"Marie","family":"Goret","sequence":"first","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg , Illkirch 67404, Strasbourg ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Arbogast","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg , Illkirch 67404, Strasbourg ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8256-5862","authenticated-orcid":false,"given":"Jocelyn","family":"Laporte","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg , Illkirch 67404, Strasbourg 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findings","volume":"18","author":"Bitoun","year":"2008","journal-title":"Neuromuscul Disord."},{"issue":"1","key":"2026090313252638900_fcag324-B10","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/neup.12432","article-title":"Phenotype variability and histopathological findings in patients with a novel DNM2 mutation","volume":"38","author":"Chen","year":"2018","journal-title":"Neuropathology"},{"issue":"7","key":"2026090313252638900_fcag324-B11","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1093\/brain\/awp115","article-title":"Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy","volume":"132","author":"Claeys","year":"2009","journal-title":"Brain"},{"issue":"4","key":"2026090313252638900_fcag324-B12","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.pmrj.2013.08.611","article-title":"Charcot-Marie-Tooth disease: An overview of genotypes, phenotypes, and clinical management strategies","volume":"6","author":"El-Abassi","year":"2014","journal-title":"PM R"},{"key":"2026090313252638900_fcag324-B13","author":"Washington University Neuromuscular Disease Center. Hereditary Motor Sensory Neuropathies: Charcot-Marie-Tooth (HMSN\/CMT). CMT with Intermediate NCV (DI-CMT; CMT-DI)"},{"issue":"2","key":"2026090313252638900_fcag324-B14","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/jns.12539","article-title":"Recent advances in the treatment of Charcot-Marie-Tooth neuropathies","volume":"28","author":"Bolino","year":"2023","journal-title":"J Peripheral Nervous Sys"},{"issue":"11","key":"2026090313252638900_fcag324-B15","doi-asserted-by":"crossref","DOI":"10.3390\/brainsci11111447","article-title":"Challenges in treating Charcot-Marie-Tooth disease and related neuropathies: Current management and future perspectives","volume":"11","author":"Pisciotta","year":"2021","journal-title":"Brain Sci."},{"issue":"18","key":"2026090313252638900_fcag324-B16","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1038\/emboj.2010.187","article-title":"Dynamin GTPase regulation is altered by PH domain mutations found in centronuclear myopathy 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