LMNA R527C mutation causes an inflammation driven progeria via triggering DNA-sensing pathways

Abstract Homozygous mutations in Ig-like domain of LMNA cause severe progeria. Unlike typical HGPS mediated by progerin due to LMNAWT/G608G mutation, it remains elusive how these homozygous mutations cause progeria. We here found that patients with LMNAR527C/R527C mutation developed an atypical progeria with autoimmune symptoms. Compare to LMNAWT/G608G mutation, this mutation led to more severe inflammation in patients. MSCs from LMNAR527C/R527C patients exhibited overt inflammation and cellular senescence. Mechanistically, LMNAR527C/R527C mutation attenuated its binding to DNA binding protein BAF, which led to aberrant aggregation of Lamin A and activation of DNA sensing pathways. Inhibition of DNA sensors, cGAS or AIM2, can suppress inflammation and rescue the senescence of patient-derived MSCs. LmnaR527C/R527C mice showed enhanced inflammation, and developed accelerated aging and dead at an early age after high-fat diet (HFD) feeding, which could be rescued by deficiency of AIM2 or treatment by a small molecule inhibitor of cGAS-STING. Therefore, we demonstrated that LMNAR527C/R527C mutation damped its interaction with DNA-binding proteins and exposed damaged DNA to the cytosolic DNA sensors, which triggered aberrant inflammatory responses and promoted the onset of accelerated aging. The present study uncovered that an inflammation driven progeria was caused by LMNA mutation and DNA sensing pathways could be potential therapeutic targets for progeria syndromes caused by homozygous mutations in Ig-like domain of LMNA.