{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:09:59Z","timestamp":1785434999381,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"L-CMD Research Foundation"},{"name":"University of Maryland, College Park","award":["R21 1R21HD116032-01A1"],"award-info":[{"award-number":["R21 1R21HD116032-01A1"]}]},{"award":["R21 1R21HD116032-01A1"],"award-info":[{"award-number":["R21 1R21HD116032-01A1"]}],"id":[{"id":"https:\/\/ror.org\/047s2c258","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>LMNA-related congenital muscular dystrophy (L-CMD) is a rare genetic disorder that causes skeletal muscle weakening and wasting. Although L-CMD is caused by a variety of de novo point mutations in the LMNA gene, the p.R249W (Arg.249Trp.) pathogenic variant is the focus of this study because it is the most prevalent one among patients. We investigated the relationship between the p.R249W variant and the development of disease cellular phenotypes. We generated lentiviruses to separate p.R249W Lamin A\/C localization from wild-type Lamin A\/C localization, enabling us to examine how these proteins affect each other. We also developed an antibody specific for p.R249W Lamin A\/C. Not only did we validate previous cellular phenotypes such as nuclear elongation, but we also identified a novel cellular phenotype. We observed overall Lamin A\/C enrichment at the ends of nuclei in p.R249W patient cells. Our findings also suggest that wild-type Lamin A\/C may recruit p.R249W Lamin A\/C to the nuclear membrane, revealing molecular insights into the development of this dominant negative disease.<\/jats:p>","DOI":"10.3390\/cells15141275","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T06:49:36Z","timestamp":1784184576000},"page":"1275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The p.R249W Mutation in LMNA-Related Congenital Muscular Dystrophy Causes Nuclear Deformities and an Enrichment in Lamin A\/C at the Ends of the Nucleus"],"prefix":"10.3390","volume":"15","author":[{"given":"Catherine","family":"Harvey","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6538-0177","authenticated-orcid":false,"given":"Iden","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-2939","authenticated-orcid":false,"given":"Kan","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Donnaloja, F., Carnevali, F., Jacchetti, E., and Raimondi, M.T. (2020). Lamin A\/C Mechanotransduction in Laminopathies. Cells, 9.","DOI":"10.3390\/cells9051306"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1101\/gad.960502","article-title":"Nuclear lamins: Building blocks of nuclear architecture","volume":"16","author":"Goldman","year":"2002","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dubik, N., and Mai, S. (2020). Lamin A\/C: Function in Normal and Tumor Cells. Cancers, 12.","DOI":"10.3390\/cancers12123688"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/j.1399-0004.2006.00677.x","article-title":"The laminopathies: A clinical review","volume":"70","author":"Rankin","year":"2006","journal-title":"Clin. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/ana.21417","article-title":"De novo LMNA mutations cause a new form of congenital muscular dystrophy","volume":"64","author":"Mbieleu","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"fcab075","DOI":"10.1093\/braincomms\/fcab075","article-title":"International retrospective natural history study of LMNA-related congenital muscular dystrophy","volume":"3","author":"Yun","year":"2021","journal-title":"Brain Commun."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bertrand, A.T., Brull, A., Azibani, F., Benarroch, L., Chikhaoui, K., Stewart, C.L., Medalia, O., Ben Yaou, R., and Bonne, G. (2020). Lamin A\/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery-Dreifuss Muscular Dystrophy. Cells, 9.","DOI":"10.3390\/cells9040844"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gomez-Dominguez, D., Epifano, C., Miguel, F., Castano, A.G., Vilaplana-Marti, B., Martin, A., Amarilla-Quintana, S., Bertrand, A.T., Bonne, G., and Ramon-Azcon, J. (2020). Consequences of Lmna Exon 4 Mutations in Myoblast Function. Cells, 9.","DOI":"10.20944\/preprints202004.0232.v1"},{"key":"ref_9","first-page":"1753","article-title":"The muscle dystrophy-causing DeltaK32 lamin A\/C mutant does not impair the functions of the nucleoplasmic lamin-A\/C-LAP2alpha complex in mice","volume":"126","author":"Pilat","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1007\/s00018-012-1190-3","article-title":"Muscle development, regeneration and laminopathies: How lamins or lamina-associated proteins can contribute to muscle development, regeneration and disease","volume":"70","author":"Rzepecki","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1080\/19491034.2016.1260803","article-title":"Comparing lamin proteins post-translational relative stability using a 2A peptide-based system reveals elevated resistance of progerin to cellular degradation","volume":"7","author":"Wu","year":"2016","journal-title":"Nucleus"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.15252\/embj.201488658","article-title":"Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain","volume":"33","author":"Kageyama","year":"2014","journal-title":"EMBO J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/acel.12434","article-title":"Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria","volume":"15","author":"Xiong","year":"2016","journal-title":"Aging Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.18632\/aging.100434","article-title":"Automated image analysis of nuclear shape: What can we learn from a prematurely aged cell?","volume":"4","author":"Driscoll","year":"2012","journal-title":"Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e14375","DOI":"10.1111\/acel.14375","article-title":"Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature","volume":"24","author":"Vakili","year":"2025","journal-title":"Aging Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1080\/19491034.2017.1320460","article-title":"Lamin A and microtubules collaborate to maintain nuclear morphology","volume":"8","author":"Tariq","year":"2017","journal-title":"Nucleus"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4161\/nucl.28068","article-title":"Nuclear localization signal deletion mutants of lamin A and progerin reveal insights into lamin A processing and emerin targeting","volume":"5","author":"Wu","year":"2014","journal-title":"Nucleus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"89ra58","DOI":"10.1126\/scitranslmed.3002346","article-title":"Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells","volume":"3","author":"Cao","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.celrep.2018.03.091","article-title":"Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering","volume":"23","author":"Maffioletti","year":"2018","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Steele-Stallard, H.B., Pinton, L., Sarcar, S., Ozdemir, T., Maffioletti, S.M., Zammit, P.S., and Tedesco, F.S. (2018). Modeling Skeletal Muscle Laminopathies Using Human Induced Pluripotent Stem Cells Carrying Pathogenic LMNA Mutations. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.01332"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"jcs262207","DOI":"10.1242\/jcs.262207","article-title":"N-terminal tags impair the ability of lamin A to provide structural support to the nucleus","volume":"137","author":"Odell","year":"2024","journal-title":"J. Cell Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.nmd.2014.02.004","article-title":"Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel mutation in the LMNA gene","volume":"24","author":"Bonati","year":"2014","journal-title":"Neuromuscul. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Walker, S.G., Langland, C.J., Viles, J., Hecker, L.A., and Wallrath, L.L. (2023). Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases. Cells, 12.","DOI":"10.3390\/cells12081142"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gregory, E.F., Kalra, S., Brock, T., Bonne, G., Luxton, G.W.G., Hopkins, C., and Starr, D.A. (2023). Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA. PLoS Genet., 19.","DOI":"10.1371\/journal.pgen.1010895"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2288476","DOI":"10.1080\/19491034.2023.2288476","article-title":"The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B","volume":"14","author":"Odinammadu","year":"2023","journal-title":"Nucleus"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1007\/s00018-019-03093-6","article-title":"Adult stem cells at work: Regenerating skeletal muscle","volume":"76","author":"Schmidt","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2121816119","DOI":"10.1073\/pnas.2121816119","article-title":"Nuclear lamin isoforms differentially contribute to LINC complex-dependent nucleocytoskeletal coupling and whole-cell mechanics","volume":"119","author":"Vahabikashi","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1275\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T04:17:08Z","timestamp":1784348228000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":27,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15141275"],"URL":"https:\/\/doi.org\/10.3390\/cells15141275","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}