LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways
Year: 2026
Type: article
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.
Source: Protein & Cell
Authors: Yingchi Zhao, Tianyi Liu, Wei Shu, Dandan Wang, Haocheng Wang, Xiaoyu Liu, Xuyao Jiao, Jianshuang Li, Tao Liu, Ming Kuang, Ridong Li, Hongqiang Du, Zeming Zhang, Zhe Zhou, Xuefei Guo, Xuemei Wei, Tongtong Liu, Yunfei Li, Shengde Liu, Jingxuan Chen, Yujie Luo, Huawei Xia, Lili Cao, Wenmin Tian, Xue Sun, Wei Dong, Guangqian Zhou, Xiang Gao, Yongzhi Li, Shize Liu, Xinran Liu, Dan Lu, Qinghua Zhou, Fuping You, Pingsen Zhao
Institutions: Peking University, Shantou University, Peking University Cancer Hospital, Yue Bei People's Hospital, Shenzhen Luohu People's Hospital, Guilin Medical University, Affiliated Hospital of Guilin Medical College, Tianjin Third Central Hospital, Qilu University of Technology, Shandong University, Shandong Iron and Steel Group (China), Qilu Hospital of Shandong University, First Affiliated Hospital of Jinan University, Children's Hospital of Chongqing Medical University, Chongqing Medical University, Shaanxi University of Chinese Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Laboratory Animal Science, Shenzhen University Health Science Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,700
OpenAlex ID: W7204158247
FWCI:
Cites:
Cited by:
Related to: