Progerin is a truncated form of lamin A, a protein needed to ensure the cell nucleus has a normal structure. In patients with Hutchinson-Gilford progeria syndrome, lamin A mutation leads to a large amounts of progerin, widespread cell dysfunction, the appearance of accelerated aging, and early mortality. In normal aging, progerin is expressed to some degree in some cells, and may or may not be significant; as in all potential contributing mechanisms of aging, it is very hard to assign the degree to which that mechanism is important relative to all of the other ongoing issues. Here, researchers provide evidence for somatic mutations in lamin A that occur in stem cells or progenitor cells, and that thus then expand out into somatic cells in tissue, to arise in chronic kidney disease and contribute to the pathology of that condition.
Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries.
Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.
Link: https://doi.org/10.1038/s43587-025-00882-6
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