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Somatic NAP1L1 p.D349E promotes cardiac hypertrophy through cGAS-STING-IFN signaling

Author

Listed:
  • Cheng Lv

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Xiayidan Alimu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Xiao Xiao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Fei Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Jizheng Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Shuiyun Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Guixin Wu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yu Zhang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yue Wu

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Houzao Chen

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Rutai Hui

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Lei Song

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yibo Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, often caused by sarcomere gene mutations, though many sporadic cases remain genetically unexplained. Here we show that the somatic variant NAP1L1 p.D349E was involved in cardiac hypertrophy in sporadic HCM patients. Through next generation sequencing, we found that somatic variant NAP1L1 p.D349E was recurrent in the cardiomyocytes of gene-elusive sporadic HCM patients. Subsequent in vivo and in vitro functional analysis confirmed that NAP1L1 p.D349E contributes to HCM by triggering an innate immunity response. This mutation destabilizes nucleosome formation, causing DNA to leak into the cytoplasm. This leakage activates a key immune pathway, cGAS-STING, which leads to the release of inflammatory molecules and promotes heart muscle thickening. Our findings reveal a new mechanism driving HCM and suggest that somatic variants could be important in understanding and management of HCM.

Suggested Citation

  • Cheng Lv & Xiayidan Alimu & Xiao Xiao & Fei Wang & Jizheng Wang & Shuiyun Wang & Guixin Wu & Yu Zhang & Yue Wu & Houzao Chen & Rutai Hui & Lei Song & Yibo Wang, 2025. "Somatic NAP1L1 p.D349E promotes cardiac hypertrophy through cGAS-STING-IFN signaling," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58453-7
    DOI: 10.1038/s41467-025-58453-7
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    References listed on IDEAS

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    1. Ganesh R. Pathare & Alexiane Decout & Selene Glück & Simone Cavadini & Kristina Makasheva & Ruud Hovius & Georg Kempf & Joscha Weiss & Zuzanna Kozicka & Baptiste Guey & Pauline Melenec & Beat Fierz & , 2020. "Structural mechanism of cGAS inhibition by the nucleosome," Nature, Nature, vol. 587(7835), pages 668-672, November.
    2. Hiroki Ishikawa & Zhe Ma & Glen N. Barber, 2009. "STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity," Nature, Nature, vol. 461(7265), pages 788-792, October.
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