{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T20:07:44Z","timestamp":1778789264784,"version":"3.51.4"},"reference-count":58,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IdEx Unistra","award":["ANR-10-IDEX-0002"],"award-info":[{"award-number":["ANR-10-IDEX-0002"]}]},{"name":"SFRI-STRATUS","award":["ANR-20-SFRI-0012"],"award-info":[{"award-number":["ANR-20-SFRI-0012"]}]},{"name":"EUR IMCBio","award":["ANR-17-EURE-0023"],"award-info":[{"award-number":["ANR-17-EURE-0023"]}]},{"name":"Agence National de la Recherche","award":["ANR-18-CE17-0006-02"],"award-info":[{"award-number":["ANR-18-CE17-0006-02"]}]},{"name":"Cifre","award":["ANRT,2017\/1270"],"award-info":[{"award-number":["ANRT,2017\/1270"]}]},{"DOI":"10.13039\/501100002915","name":"Fondation Recherche M\u00e9dicale","doi-asserted-by":"crossref","award":["PLP20170939073"],"award-info":[{"award-number":["PLP20170939073"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,8]]},"abstract":"<jats:p>\n                    Centronuclear myopathies (CNMs) are rare congenital disorders characterized by muscle weakness, fiber hypotrophy, and organelle mislocalization. Most cases arise from mutations in\n                    <jats:italic>MTM1<\/jats:italic>\n                    or\n                    <jats:italic>DNM2<\/jats:italic>\n                    , encoding myotubularin and dynamin-2, respectively. DNM2 is a GTPase that binds lipids, oligomerizes around membranes, and mediates fission. We previously showed that DNM2 levels are elevated in\n                    <jats:italic>MTM1<\/jats:italic>\n                    -CNM patients and\n                    <jats:italic>\n                      Mtm1\n                      <jats:sup>\u2013\/y<\/jats:sup>\n                    <\/jats:italic>\n                    mice, and that normalizing DNM2 rescues disease phenotypes. However, the specific DNM2 functions driving pathology remain unclear. Here, we expressed AAV-delivered WT and DNM2 mutants in WT and\n                    <jats:italic>\n                      Mtm1\n                      <jats:sup>\u2013\/y<\/jats:sup>\n                    <\/jats:italic>\n                    mouse muscles to disrupt specific DNM2 molecular functions. In WT mice, overexpression of WT DNM2 and most mutants induced CNM-like phenotypes, including reduced force, fiber hypotrophy, and centralized nuclei, consistent with gain-of-function mechanisms. The lipid-binding-defective mutant K562E did not induce disease-like phenotype. In\n                    <jats:italic>\n                      Mtm1\n                      <jats:sup>\u2013\/y<\/jats:sup>\n                    <\/jats:italic>\n                    mice, K562E mutant markedly improved muscle force, mass, and fiber size, while others failed to rescue. Therefore, we generated\n                    <jats:italic>\n                      Mtm1\n                      <jats:sup>\u2013\/y<\/jats:sup>\n                      Dnm2\n                      <jats:sup>K562E\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice, which showed full rescue of survival, motor function, and muscle force, with improved muscle mass, fiber size, and organelle positioning despite persistently elevated DNM2 levels. This study reveals that DNM2 lipid binding, not protein abundance or GTPase activity, drives pathology, and represents the most rational therapeutic target for DNM2 therapy in\n                    <jats:italic>MTM1<\/jats:italic>\n                    -CNM.\n                  <\/jats:p>\n                  <jats:p>In vivo dissection of DNM2 functions identifies lipid binding as the principal driver of myotubular myopathy, revealing a precise therapeutic target.<\/jats:p>","DOI":"10.1172\/jci.insight.204423","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T18:00:48Z","timestamp":1778176848000},"source":"Crossref","is-referenced-by-count":0,"title":["DNM2 lipid binding drives centronuclear myopathy and represents a potential therapeutic 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