{
  "abstract": "Hundreds of mutations to the broadly expressed LMNA gene cause disease primarily within cardiac, muscular, and adipose tissues (1). 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 ~15,000 LMNA mutations by completing the first saturation mutagenesis screens in human induced pluripotent cells (hiPSCs) and hiPSC-derived cardiomyocytes using our newly developed single large serine integrase cassette exchange (SLICE) platform. We find that destabilization is a predominant consequence of pathogenic LMNA 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.",
  "abstract_shown": true,
  "affiliations": [
    "Cardiovascular Research Institute, University of California, San Francisco"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "J. Mella"
    },
    {
      "name": "A. Hein"
    },
    {
      "name": "N. Lally"
    },
    {
      "name": "J. Conrad"
    },
    {
      "name": "C. Yang"
    },
    {
      "name": "A. P. Landstrom"
    },
    {
      "name": "V. Vedantham"
    },
    {
      "name": "W. Coyote-Maestas"
    },
    {
      "affs": [
        0
      ],
      "name": "A. Buchwalter"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e3kkvh5x7k8jf.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.17.752442",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752442v1.full",
  "id": "e3kkvh5x7k8jf",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752442v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cell biology"
    ],
    [
      "openalex",
      "1312|Nuclear Structure and Function"
    ]
  ],
  "openalex": "W7213546345",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752442v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-17",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e3kkvh5x7k8jf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:04Z",
      "native_id": "10.64898/2026.09.17.752442",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752442v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis",
  "title_text": "Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:04Z",
  "url": "https://research.draconitic.com/paper/e3kkvh5x7k8jf",
  "venue": "bioRxiv",
  "versions": []
}