Next Generation Sequencing Facilitates Quantitative Analysis of wild type and Lmna R527C mutant mice spleen Transcriptomes with or without 4Gy irradiation.

Homozygous mutations in Ig-like domain of LMNA cause severe progeria. Unlike typical HGPS mediated by progerin due to LMNA WT /G608G mutation, it remains elusive how these homozygous mutations cause progeria. We found patients with LMNAR527C/R527C mutation developed an atypical progeria. Compare to LMNA WT /G608G, this mutation led to more severe inflammation in patients. MSCs from LMNA R527C/R527C patients exhibited overt inflammation and cellular senescence. Mechanistically, LMNA R527C/R527C mutation attenuated its binding to 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. Lmna R527C/R527C mice developed enhanced inflammation, accelerated aging and death after HFD feeding, which could be rescued by deficiency of AIM2 or inhibition of cGAS-STING. Together, we demonstrated that LMNA R527C/R527C mutation da mped its interaction with DNA binding proteins and activated DNA sensing pathways, which promoted the onset of accelerated aging. To examine if Lmna R527C mice developed more inflammation than wild type mice. RNA-seq analysis of the RNA from spleen showed that immune related genes were upregulated in mutant mice compared with wild type mice. No matter 4 Gy irradiation or not. mRNA profiles of wild type and Lmna R527C mutant mice spleen Transcriptomes with or without 4Gy irradiation.