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Tissue-specific pathogenesis arises when mutant protein dysfunction collides with the unique demands of a specific cell type. Here, we decipher the cell-type-specific consequences of \u223c15,000\n                  <jats:italic>LMNA<\/jats:italic>\n                  mutations by completing the first saturation mutagenesis screens in human induced pluripotent cells (hiPSCs) and hiPSC-derived cardiomyocytes using our newly developed\n                  <jats:underline>s<\/jats:underline>\n                  ingle\n                  <jats:underline>l<\/jats:underline>\n                  arge serine\n                  <jats:underline>i<\/jats:underline>\n                  ntegrase\n                  <jats:underline>c<\/jats:underline>\n                  assette\n                  <jats:underline>e<\/jats:underline>\n                  xchange (SLICE) platform. We find that destabilization is a predominant consequence of pathogenic\n                  <jats:italic>LMNA<\/jats:italic>\n                  mutations, is selected against in human populations, and is associated with cardiomyopathy. Mutation sensitivity maps reveal Lamin A quality control at both the subunit and multimer level, resolve lateral and head-to-tail polymerization interfaces, and uncover a convergence between disruption of lamin polymer assembly and pathogenesis. Uniquely in cardiomyocytes, lamin A polymer assembly defects drive profound protein loss, nuclear abnormalities, and cellular toxicity, explaining the origins of cardiac specificity in laminopathy syndromes.\n                <\/jats:p>","DOI":"10.64898\/2026.09.17.752442","type":"posted-content","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:15:28Z","timestamp":1789748128000},"source":"Crossref","is-referenced-by-count":0,"title":["Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7541-6789","authenticated-orcid":false,"given":"Jessica","family":"Mella","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute, University of California, San Francisco, USA"},{"name":"Tetrad Graduate Program, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2477-6327","authenticated-orcid":false,"given":"Abigail","family":"Hein","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, University of California, San Francisco, USA"},{"name":"Tetrad Graduate Program, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2233-1318","authenticated-orcid":false,"given":"Navraj","family":"Lally","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, University of California, San Francisco, USA"},{"name":"Biomedical Sciences Graduate Program, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0734-4593","authenticated-orcid":false,"given":"Julia","family":"Conrad","sequence":"additional","affiliation":[{"name":"Tetrad Graduate Program, University of California, San Francisco, USA"},{"name":"Department of Biochemistry, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7398-414X","authenticated-orcid":false,"given":"Cathy","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1878-9631","authenticated-orcid":false,"given":"Andrew P.","family":"Landstrom","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology, Children\u2019s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1032-700X","authenticated-orcid":false,"given":"Vasanth","family":"Vedantham","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, University of California, San Francisco, USA"},{"name":"Cardiology Division, Department of Medicine, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9614-5340","authenticated-orcid":false,"given":"Willow","family":"Coyote-Maestas","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, USA"},{"name":"Chan Zuckerberg Biohub, San Francisco, USA"},{"name":"Quantitative Biosciences Institute, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7181-6961","authenticated-orcid":false,"given":"Abigail","family":"Buchwalter","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, University of California, San Francisco, USA"},{"name":"Tetrad Graduate Program, University of California, San Francisco, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092212301695000_2026.09.17.752442v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-050520-112001"},{"key":"2026092212301695000_2026.09.17.752442v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31686-6"},{"key":"2026092212301695000_2026.09.17.752442v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.01.011"},{"key":"2026092212301695000_2026.09.17.752442v1.4","doi-asserted-by":"crossref","unstructured":"Bhaskaran, A. et al. 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