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

Cheng Lv, Xiayidan Alimu, Xiao Xiao, Fei Wang, Jizheng Wang, Shuiyun Wang, Guixin Wu, Yu Zhang, Yue Wu, Houzao Chen, Rutai Hui, Lei Song () and Yibo Wang ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58453-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58453-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58453-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().