LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways

Homozygous pathogenic variants in Ig-like domain of LMNA cause severe segmental progeroid syndromes. Unlike typical HGPS, it remains elusive how these pathogenic variants cause segmental progeroid syndromes. We here reported that affected individuals with LMNAR527C/R527C pathogenic variant developed an atypical segmental progeroid syndrome characterized by autoimmune features. Mesenchymal stem cells (MSCs) derived from these affected individuals exhibited significant inflammation and cellular senescence. In mice, LmnaR527C/R527C pathogenic variant triggered chronic interferon signaling, exacerbated aging-related pathologies, and even induced thymic lymphomas following ionizing radiation. In addition, this pathogenic variant increased susceptibility to inflammation induced by a high-fat diet or LCMV infection. R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING. Importantly, blocking DNA sensing pathways suppressed inflammation, rescued senescence in affected individual-derived MSCs, and alleviated premature aging in LmnaR527C/R527C mice. These findings establish a homozygous LMNA pathogenic variant as a key driver of inflammation-driven segmental progeroid syndrome and highlight DNA sensing pathways as promising therapeutic targets.

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Publication Details

Journal
Protein & Cell
Published
2026-08-25
DOI
https://doi.org/10.1093/procel/pwag061
Primary Topic
Nuclear Structure and Function
Type
article
Field-Weighted Citation Impact
0.00

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article

LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways

Xuemei Wei, Jianshuang Li, Ming Kuang, 孙雪 et al.
Protein & Cell
Nuclear Structure and Function
article

LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways

Xuemei Wei, Jianshuang Li, Ming Kuang, 孙雪, 李勇枝, Qinghua Zhou, Ridong Li, Yingchi Zhao, Hongqiang Du, Fuping You, Dan Lü, Xuyao Jiao, Wei Dong, Guangqian Zhou, Shize Liu, Pingsen Zhao, Shengde Liu, Huawei Xia, Wenmin Tian, Dandan Wang, Tongtong Liu, Zhe Zhou, Yujie Luo, Wei Shu, Jingxuan Chen, Xinran Liu, Lili Cao, Xuefei Guo, Yunfei Li, Haocheng Wang, Tao Liu, Xiang Gao, Xiaoyu Liu, Zeming Zhang, Tianyi Liu
article en

Abstract

Homozygous pathogenic variants in Ig-like domain of LMNA cause severe segmental progeroid syndromes. Unlike typical HGPS, it remains elusive how these pathogenic variants cause segmental progeroid syndromes. We here reported that affected individuals with LMNAR527C/R527C pathogenic variant developed an atypical segmental progeroid syndrome characterized by autoimmune features. Mesenchymal stem cells (MSCs) derived from these affected individuals exhibited significant inflammation and cellular senescence. In mice, LmnaR527C/R527C pathogenic variant triggered chronic interferon signaling, exacerbated aging-related pathologies, and even induced thymic lymphomas following ionizing radiation. In addition, this pathogenic variant increased susceptibility to inflammation induced by a high-fat diet or LCMV infection. R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING. Importantly, blocking DNA sensing pathways suppressed inflammation, rescued senescence in affected individual-derived MSCs, and alleviated premature aging in LmnaR527C/R527C mice. These findings establish a homozygous LMNA pathogenic variant as a key driver of inflammation-driven segmental progeroid syndrome and highlight DNA sensing pathways as promising therapeutic targets.

Protein & Cell
Qingdao University of Science and Technology (CN), Qilu University of Technology (CN), Guilin Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Shantou University (CN), Tianjin Third Central Hospital (CN), Peking University Cancer Hospital (CN), Yue Bei People's Hospital (CN), Shandong Iron and Steel Group (China) (CN), Institute of Laboratory Animal Science (CN), Shenzhen University Health Science Center (CN), Shenzhen Luohu People's Hospital (CN), Affiliated Hospital of Guilin Medical College (CN), Children's Hospital of Chongqing Medical University (CN), Qilu Hospital of Shandong University (CN), First Affiliated Hospital of Jinan University (CN), Tianjin Medical University (CN), Shaanxi University of Chinese Medicine (CN), Shandong University of Science and Technology (CN), Chongqing Medical University (CN)
National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 17%
Nuclear Structure and Function
DOIOpen Access PDFOpenAlex
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