{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:50:55Z","timestamp":1790394655399,"version":"4.1.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritable atrial cardiomyopathy manifesting as progressive atrial\u2010selective electromechanical dysfunction, tachyarrhythmias, and bradyarrhythmias requiring pacemaker implantation. Myosin light\u2010chain 4 (\n                      <jats:italic>MYL4<\/jats:italic>\n                      ), encoding the atrial\u2010selective essential myosin light chain, was identified as a candidate gene. We used genetically modified rat models to investigate the role of\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4\n                      <\/jats:italic>\n                      in atrial cardiomyopathy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Exome sequencing and systematic bioinformatic analyses identified a rare missense variant of\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4\n                      <\/jats:italic>\n                      (c.31G&gt;A [\n                      <jats:italic>p.E11K<\/jats:italic>\n                      ]) in a large multiplex atrial cardiomyopathy family pedigree. The mutation cosegregated with atrial standstill (selected as the principal presenting trait) with a logarithm of the odds score of 5.3. The phenotype of rats with\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4\n                      <\/jats:italic>\n                      mutation knock\u2010in confirmed the causative role of the mutation.\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4\n                      <\/jats:italic>\n                      knockout rats showed a similar atrial cardiomyopathy phenotype, whereas rats with an adjacent 4\u2010amino\u2010acid deletion showed no phenotype. Both\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4 p.E11K\n                      <\/jats:italic>\n                      knock\u2010in rats and\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4\n                      <\/jats:italic>\n                      knockout rats showed progressive atrial electrophysiological, contractile, and fibrotic abnormalities, similar to affected patients. Biochemical analyses of\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4 p.E11K\n                      <\/jats:italic>\n                      mutation rats showed activation of proapoptotic and profibrotic signaling, along with increased atrial\u2010cardiomyocyte terminal deoxynucleotidyl transferase dUTP nick end labeling staining, suggesting enhanced apoptotic cell death, findings that were mimicked by in\u00a0vitro adenoviral transfer of the mutant gene to neonatal\u2010rat cardiomyocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Loss\u2010of\u2010function\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4\n                      <\/jats:italic>\n                      gene variants cause progressive atrial cardiomyopathy in humans and rats. Our findings identify\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>\n                        4\n                      <\/jats:italic>\n                      as a key gene required for atrial contractile, electrical and structural integrity. These results improve our understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.117.007030","type":"journal-article","created":{"date-parts":[[2017,10,28]],"date-time":"2017-10-28T20:10:13Z","timestamp":1509221413000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":70,"title":["Dysfunction of Myosin Light\u2010Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically\u2010Engineered Rats"],"prefix":"10.1161","volume":"6","author":[{"given":"Wenhui","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 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Medicine, Tongji University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"BGI\u2010Shenzhen, Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Xiao","sequence":"additional","affiliation":[{"name":"BGI\u2010Shenzhen, Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[{"name":"BGI\u2010Shenzhen, Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dali","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Regulatory Biology, 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