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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.<\/jats:p>","DOI":"10.1093\/procel\/pwag061","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:13:03Z","timestamp":1787670783000},"source":"Crossref","is-referenced-by-count":0,"title":["LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways"],"prefix":"10.1093","author":[{"given":"Yingchi","family":"Zhao","sequence":"first","affiliation":[{"name":"Yuebei People's Hospital Affiliated to Shantou University Medical College Department of Laboratory Medicine, Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer, , Shao Guan, Guang Zhou 512025,","place":["China"]},{"name":"School of Basic Medical Science, Peking University Health Science Center, Peking University, Department of Microbiology & Infectious Disease Center, Beijing Key Laboratory for Research and Translation of Immunological and Molecular Diagnostic Technologies for Major Viral Infectious Diseases (BKLIMD), Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Institute of Systems Biomedicine, Beijing 1001914,","place":["China"]},{"name":"Department of Research and Development, Beijing Arion Cancer Center , Beijing 100070,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Yuebei People's Hospital Affiliated to Shantou University Medical College Department of Laboratory Medicine, Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory 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541004,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin , Tianjin 300170,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haocheng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Science, Peking University Health Science Center, Peking University, Department of Microbiology & Infectious Disease Center, Beijing Key Laboratory for Research and Translation of Immunological and Molecular Diagnostic Technologies for Major Viral Infectious Diseases (BKLIMD), Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Institute of Systems Biomedicine, Beijing 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