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, Pingsen Zhao, Fuping You
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.