{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:53:07Z","timestamp":1781635987322,"version":"3.54.5"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,6,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Emery-Dreifuss muscular dystrophy (EDMD) is a rare genetic disorder characterized by early-onset joint contractures, progressive muscle atrophy, and cardiac abnormalities. Patients with EDMD carrying\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      sequence variations often exhibit severe cardiac manifestations, including frequent atrioventricular block and ventricular tachycardia. Approximately 20% of those patients may ultimately require heart transplantation. The molecular mechanisms by which\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      sequence variations lead to EDMD remain unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Five clinically diagnosed patients with EDMD carrying\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      sequence variations were recruited. Patient-specific induced pluripotent stem cells (iPSCs) were generated using a nonintegrating Sendai virus. Previously generated iPSCs, derived from 2 healthy donors, were used as controls. The\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      L204P sequence variation was corrected by genome editing in EDMD iPSC lines to generate isogenic controls. All iPSC-derived cardiomyocytes (iPSC-CMs) were generated using a monolayer-based differentiation protocol. Three-dimensional, strip-format, and force-generating human engineered heart tissues were generated from iPSC-CMs. A knock-in mouse model carrying the\n                      <jats:italic toggle=\"yes\">Lmna<\/jats:italic>\n                      L204P sequence variation was also generated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      EDMD-specific iPSC-CMs exhibited a variety of deleterious phenotypes, including disorganized sarcomeres, abnormal nuclear envelope structure, arrhythmias, and contractile dysfunction, when compared with control and gene-corrected iPSC-CMs. Multi-omics analysis further revealed that\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      directly binds the\n                      <jats:italic toggle=\"yes\">WNT5A<\/jats:italic>\n                      promoter and the Leu204Pro sequence variation reduces chromatin accessibility and\n                      <jats:italic toggle=\"yes\">WNT5A<\/jats:italic>\n                      transcription in EDMD iPSC-CMs. WNT5a (Wnt family member 5a)\/RhoA (Ras homolog family member A) signaling inactivation was shown to lead to actin depolymerization and inhibition of actin polymerization in EDMD iPSC-CMs. This results in a deformed nuclear envelope, contractile dysfunction, and impaired trafficking of Cx43 (connexin 43). The impairment of Cx43 trafficking causes reduced distribution of Cx43 at cell\u2013cell borders, contributing to the arrhythmic phenotype in EDMD iPSC-CMs. Pharmacological interventions of exogenous WNT5a supplementation, RhoA activator, or an actin polymerization stabilizer effectively rescued the pathogenic phenotypes of EDMD iPSC-CMs. EDMD engineered heart tissues displayed dysfunctional contractile force generation, which was significantly alleviated by RhoA activator.\n                      <jats:italic toggle=\"yes\">Lmna<\/jats:italic>\n                      L204P heterozygous knock-in mice exhibited impaired cardiac function and developed cardiac arrhythmias in response to sympathetic stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      We present WNT5a-mediated aberrant actin filament dynamics as a novel mechanism underlying cardiac pathogenic phenotypes in\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      -related EDMD. Our findings indicate that activating WNT5a\/RhoA and stabilizing actin assembly may serve as novel therapeutic strategies for this condition.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.075604","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T09:00:13Z","timestamp":1776416413000},"page":"1719-1742","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["WNT5a-Mediated Aberrant Actin Filament Dynamics Drive Cardiac Pathogenic Phenotypes in\n                    <i>LMNA<\/i>\n                    -Related Emery-Dreifuss Muscular Dystrophy"],"prefix":"10.1161","volume":"153","author":[{"given":"Hangping","family":"Fan","sequence":"first","affiliation":[{"name":"Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (H.F., 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