LMNA R527C mutation may cause a premature aging syndrome with inflammation by activating DNA detection pathways

Homozygous pathogenic variants in the Ig-like domain of LMNA are associated with severe segmental progeroid syndromes.

• Individuals with the LMNAR527C/R527C variant developed an atypical segmental progeroid syndrome featuring autoimmune characteristics.
• Mesenchymal stem cells from affected individuals exhibited significant inflammation and signs of aging.
• In mice, the LmnaR527C/R527C variant led to chronic interferon signaling and exacerbated aging-related pathologies.
• The variant increased susceptibility to inflammation from a high-fat diet or LCMV infection.
• R527C disrupted the interaction between Lamin A and DNA-binding proteins, resulting in abnormal protein aggregation and heightened activity of the cGAS-STING pathway.
• Blocking DNA sensing pathways reduced inflammation and improved the aging symptoms in both MSCs from affected individuals and LmnaR527C/R527C mice.

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