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

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.

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Publication Details

Journal
Nature Communications
Published
2025-04-01
DOI
https://doi.org/10.1038/s41467-025-58453-7
Citations
6
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
4.78

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article

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

S Wang, Guixin Wu, Xiayidan Alimu, Hou‐Zao Chen et al.
6 citations
Nature Communications
interferon and immune responses
4.78
article

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

S Wang, Guixin Wu, Xiayidan Alimu, Hou‐Zao Chen, Yibo Wang, Yu Zhang, Xiao Xiao, Fei Wang, Rutai Hui, Lei Song, Yue Wu, Jizheng Wang, Cheng Lv
article en
6 citations

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.

Nature CommunicationsVol. 16(1)
Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking Union Medical College Hospital (CN), First Affiliated Hospital of Xi'an Jiaotong University (CN), Fu Wai Hospital (CN)
National Natural Science Foundation of China, Chinese Academy of Medical Sciences, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 5%
interferon and immune responses
4.78
DOIOpen Access PDFOpenAlex
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