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

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

Department of Laboratory Medicine, Laboratory for Diagnosis of Clinical Microbiology and Infection, Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Yuebei People's Hospital Affiliated to Shantou University Medical College; Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine; Shaoguan Municipal Quality Control Center for Surveillance of Bacterial Resistance; Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer, Shaoguan 512025, China.Department of Laboratory Medicine, Laboratory for Diagnosis of Clinical Microbiology and Infection, Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Yuebei People's Hospital Affiliated to Shantou University Medical College; Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine; Shaoguan Municipal Quality Control Center for Surveillance of Bacterial Resistance; Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer, Shaoguan 512025, China. · pubmed

Paper

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.

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Research summary

The study identifies a specific mechanism (cGAS-STING hyperactivation due to LMNA mutation) linking nuclear envelope defects to inflammation and premature aging, demonstrating that inhibiting this pathway can rescue age-related phenotypes in mice. This work is relevant because it elucidates a root cause of cellular senescence and inflammation, which are hallmarks of aging, and proposes a targeted therapeutic strategy to mitigate these processes rather than just treating symptoms.

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