{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:18:12Z","timestamp":1787739492155,"version":"build-2784847793"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":237,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mutations in the\n                      <jats:italic>LMNA<\/jats:italic>\n                      gene underlie a broad spectrum of laminopathies, including muscular dystrophies, cardiomyopathies, and premature aging syndromes; however, the molecular mechanisms by which missense variants disrupt Lamin A structural integrity remain incompletely characterized. Systematic computational approaches for prioritizing pathogenic variants and elucidating their structural consequences are critically needed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An integrated multistep in silico framework was employed to investigate the structural and functional consequences of\n                      <jats:italic>LMNA<\/jats:italic>\n                      missense variants. Variant prioritization was performed using the Evo2 nucleotide language model via delta log\u2010likelihood scoring, followed by bioinformatic annotation using SIFT, PANTHER\u2010PSEP, PhD\u2010SNP, and E\u2010SNPs&amp;GO. Protein stability assessment was conducted with DynaMut, INPS\u2010MD, I\u2010Mutant2.0, and MUpro. Variants localized within globular domains\u2014N456D, N456T, and G465D\u2014together with the known pathogenic variant M540T as a positive control, were selected for three\u2010dimensional structural modeling using PyMOL and AlphaFold2, molecular docking with lonafarnib as a reference ligand via AutoDock Vina, and 100\u2009ns molecular dynamics simulations using GROMACS with the Amber ff14SB force field. Conformational dynamics were characterized through principal component analysis and free\u2010energy surface construction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Evo2\u2010based screening of the full LMNA coding sequence identified 50 high\u2010priority loss\u2010of\u2010function variants, of which N456D, N456T, and G465D were retained for structural investigation based on their globular domain localization and multitool pathogenicity predictions. All three variants were consistently predicted to alter physicochemical properties and reduce structural stability relative to wild\u2010type Lamin A. Molecular docking revealed mutation\u2010dependent changes in lonafarnib binding profiles. The known pathogenic control M540T exhibited comparable structural and dynamic behavior, supporting the reliability of the prioritization workflow. Molecular dynamics analyses demonstrated altered RMSD trajectories, increased residue\u2010level flexibility, and modified hydrogen bonding patterns in mutant systems. Free\u2010energy landscape analyses revealed expanded conformational basins, particularly pronounced in the G465D variant, indicating increased structural plasticity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This integrated computational framework provides a systematic strategy for prioritizing pathogenic\n                      <jats:italic>LMNA<\/jats:italic>\n                      variants and characterizing their structural consequences at the atomic level. The identified variants\u2014N456D, N456T, and G465D\u2014represent structurally disruptive substitutions consistent with the established role of globular domain destabilization in other laminopathy\u2010associated variants, offering testable hypotheses for experimental validation in cellular and animal models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/2444803","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:24:09Z","timestamp":1787736249000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational Characterization of Pathogenic LMNA Missense Variants: Structural Instability, Altered Binding, and Conformational Dynamics"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9422-3402","authenticated-orcid":false,"given":"Emre","family":"Akta\u015f","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3467-7913","authenticated-orcid":false,"given":"Ceren","family":"Nizamo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9652-6351","authenticated-orcid":false,"given":"Salvador","family":"Ventura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_11_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601058103"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-5-222"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2012.167"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3488"},{"key":"e_1_2_11_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.06.007"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1240104"},{"key":"e_1_2_11_7_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201308029"},{"key":"e_1_2_11_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.196"},{"key":"e_1_2_11_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2018.1454168"},{"key":"e_1_2_11_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2008.00676.x"},{"key":"e_1_2_11_11_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106671"},{"key":"e_1_2_11_12_2","doi-asserted-by":"publisher","DOI":"10.1086\/302869"},{"key":"e_1_2_11_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/jns.12489"},{"key":"e_1_2_11_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00480-z"},{"key":"e_1_2_11_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.7.3000"},{"key":"e_1_2_11_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12506"},{"key":"e_1_2_11_17_2","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2022.2078699"},{"key":"e_1_2_11_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-026-10176-5"},{"key":"e_1_2_11_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology14101453"},{"key":"e_1_2_11_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1241"},{"key":"e_1_2_11_21_2","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1002\/j.2040-4603.2022.tb00213.x","article-title":"Computational and Experimental Analysis of Genetic Variants","volume":"12","author":"Prokop J. 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