Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis
- 1Cardiovascular Research Institute, University of California, San Francisco
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.
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BibTeX
@misc{mella2026cardiomyocyte,
title = {{Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis}},
author = {J. Mella and A. Hein and N. Lally and J. Conrad and C. Yang and A. P. Landstrom and V. Vedantham and W. Coyote-Maestas and A. Buchwalter},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752442},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752442v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis
AU - J. Mella
AU - A. Hein
AU - N. Lally
AU - J. Conrad
AU - C. Yang
AU - A. P. Landstrom
AU - V. Vedantham
AU - W. Coyote-Maestas
AU - A. Buchwalter
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752442
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752442v1
AB - 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.
ER -