{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:06:30Z","timestamp":1791389190067,"version":"4.3.3"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"43","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL130253"],"award-info":[{"award-number":["R01HL130253"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL157281"],"award-info":[{"award-number":["R01HL157281"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P50HD087351"],"award-info":[{"award-number":["P50HD087351"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"The Robert A. Welch Foundation","doi-asserted-by":"crossref","award":["1-0025"],"award-info":[{"award-number":["1-0025"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Leducq Foundation Transatlantic Networks of Excellence","award":["Leducq"],"award-info":[{"award-number":["Leducq"]}]},{"DOI":"10.13039\/501100000274","name":"the British Heart Foundation","doi-asserted-by":"crossref","award":["BBC\/F\/21\/220106"],"award-info":[{"award-number":["BBC\/F\/21\/220106"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1K99HL171887-01A1"],"award-info":[{"award-number":["1K99HL171887-01A1"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,10,28]]},"abstract":"<jats:p>\n                    Mutations in the Lamin A (\n                    <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                    ) gene, which encodes the Lamin A and C proteins, cause severe human diseases collectively known as laminopathies. These conditions are often devastating and lack effective therapies. In this study, we developed precise base editing (BE) strategies targeting the human\n                    <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                    gene variants L35P and R249Q, which cause congenital muscular dystrophy (CMD) and dilated cardiomyopathy with conduction defects (DCM-CD), respectively. Induced pluripotent stem cell\u2013derived cardiomyocytes (iPSC-CMs) carrying the R249Q mutation displayed nuclear aberrations, DNA damage, and abnormal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients. Similarly, L35P iPSC-CMs exhibited abnormal contraction, DNA damage, and reduced Lamin A\/C protein expression. We also generated \u201chumanized\u201d mouse models carrying these pathogenic human mutations. R249Q homozygous mice exhibited cardiac conduction abnormalities, cardiac arrhythmias, and premature death. Mice with the homozygous L35P mutation displayed severe muscle-wasting and reduced lifespan, while heterozygous L35P mice displayed DCM. We developed an adenine base editing (ABE) approach for correcting the R249Q mutation and a cytosine base editing (CBE) strategy for the L35P variant. Precise correction of these mutations in iPSC-CMs successfully rescued all of the in vitro abnormalities. Furthermore, delivery of the BE components using adeno-associated virus prevented the pathological phenotypes and extended longevity of mice carrying the\n                    <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                    L35P and the R249Q mutations. These results demonstrate the efficacy of ABE and CBE in correcting pathogenic\n                    <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                    mutations that cause cardiac disease, highlighting BE as a promising therapeutic approach for human laminopathies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2515267122","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T19:02:41Z","timestamp":1760382161000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Precise gene editing of pathogenic Lamin A mutations corrects cardiac disease"],"prefix":"10.1073","volume":"122","author":[{"given":"Xurde M.","family":"Caravia","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4004-5451","authenticated-orcid":false,"given":"Brian","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4114-8349","authenticated-orcid":false,"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiheng","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damir","family":"Alzhanov","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenian","family":"Chen","sequence":"additional","affiliation":[{"name":"Quantitative Biomedical Research Center, Peter O\u2019Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"McAnally","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xu","sequence":"additional","affiliation":[{"name":"Quantitative Biomedical Research Center, Peter O\u2019Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1151-8262","authenticated-orcid":false,"given":"Eric N.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center","place":["Dallas"]},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2023.102313"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02003-5"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-023-02849-5"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-042220-034240"},{"key":"e_1_3_4_5_2","article-title":"LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy","volume":"17","author":"Wang Z.","year":"2025","unstructured":"Z. Wang , LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy. J. Adv. Res. 17, S2090-1232(25)00001-3 (2025).","journal-title":"J. Adv. 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M. Caravia Precise gene editing of pathogenic Lamin A mutations corrects cardiac disease. NCBI Gene Expression Omnibus (GEO) NCBI. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE308777. Deposited 23 September 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2515267122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T19:03:00Z","timestamp":1760382180000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2515267122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":29,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2025,10,28]]}},"alternative-id":["10.1073\/pnas.2515267122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2515267122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]},"assertion":[{"value":"2025-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2515267122"}}