The LMNA R527C variant was linked to inflammation triggered by the cellular response to damaged DNA
The LMNA R527C variant was linked to inflammation triggered by the cellular response to damaged DNA
On August 25, Protein & Cell published a study of six children from three families who carried two copies of the R527C variant in LMNA. The authors traced this inflammatory pathway in patient cells, a human cell model, and mice.
The LMNA gene encodes lamin A, a protein found in the inner layer of the nuclear envelope. Lamin A binds BAF, a protein associated with DNA. BAF prevents cGAS, a cellular DNA sensor, from reaching the DNA. When cGAS does bind DNA, it produces cGAMP, a signaling molecule that activates the STING protein and an inflammatory program.
Lamin A bound BAF less effectively in cells carrying R527C. The authors found cGAS clusters and higher cGAMP levels in these cells. Both R527C and the classic G608G variant, which produces the protein progerin, caused DNA damage. However, cGAS formed clusters and produced cGAMP only in cells carrying R527C. The authors attribute this difference to the weaker interaction between lamin A and BAF caused by R527C, which leaves damaged DNA accessible to cGAS.
To separate the effect of R527C from other inherited differences among the patients, the researchers created two human stem cell lines that differed only at this variant and differentiated them into connective tissue cells. Inflammatory genes were again activated in cells carrying R527C. This result attributes the inflammatory program to the LMNA substitution itself rather than to other inherited differences among the patients.
On a high-fat diet, mice carrying R527C stopped gaining weight, developed shorter telomeres, and showed signs of heart failure. After eight months, more than half of the mutant mice had died, while all control mice survived. Genetic inactivation of Aim2, another DNA sensor, reduced inflammation and prevented the early death of mice carrying R527C on this diet. In human cells carrying R527C, the STING inhibitor C-176 increased viability.
In another model of progeria, partial suppression of STING with H-151 extended the lifespan of mice. In that model, lamins A/C helped the cell remove STING. In the R527C model, the defect begins earlier in the pathway. The weakened interaction between lamin A and BAF leaves damaged DNA accessible to cGAS, which then activates STING.