{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T03:21:40Z","timestamp":1784776900717,"version":"3.55.0"},"reference-count":23,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Center for Individualized Medicine at Mayo Clinic"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The LMNA gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in LMNA cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson\u2013Gilford progeria (HGP). Among these, the phenotypic terms for LMNA-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an LMNA variant of uncertain significance, NM_170707.2 c. 4G&gt;A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (p &lt; 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family.<\/jats:p>","DOI":"10.3390\/genes15010112","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T03:50:56Z","timestamp":1705549856000},"page":"112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Nuclear Abnormalities in LMNA p.(Glu2Lys) Variant Segregating with LMNA-Associated Cardiocutaneous Progeria Syndrome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8302-7705","authenticated-orcid":false,"given":"Matheus V. M. B.","family":"Wilke","sequence":"first","affiliation":[{"name":"Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myra","family":"Wick","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya L.","family":"Schwab","sequence":"additional","affiliation":[{"name":"Department of Molecular Hematology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2350-7192","authenticated-orcid":false,"given":"Rodrigo Tzovenos","family":"Starosta","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, Washington University in Saint Louis, Saint Louis, MO 63130, USA"},{"name":"Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl J.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Biochemical and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi M.","family":"Connolly","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric W.","family":"Klee","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.4161\/nucl.36289","article-title":"Diverse Lamin-Dependent Mechanisms Interact to Control Chromatin Dynamics","volume":"5","author":"Camozzi","year":"2014","journal-title":"Nucleus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1038\/s41467-019-11684-x","article-title":"Structural Basis for Lamin Assembly at the Molecular Level","volume":"10","author":"Ahn","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"761","DOI":"10.3389\/fphys.2020.00761","article-title":"The Broad Spectrum of LMNA Cardiac Diseases: From Molecular Mechanisms to Clinical Phenotype","volume":"11","author":"Crasto","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101","DOI":"10.31491\/APT.2020.06.021","article-title":"Novel LMNA Mutations in Greek and Myanmar Patients with Progeroid Features and Cardiac Manifestations","volume":"2","author":"Hisama","year":"2020","journal-title":"Aging Pathobiol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.stem.2020.12.016","article-title":"Pathogenic LMNA Variants Disrupt Cardiac Lamina-Chromatin Interactions and de-Repress Alternative Fate Genes","volume":"28","author":"Shah","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Briand, N., and Collas, P. 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