LMNA (Lamin A/C gene; HGPS)

LMNA encodes the nuclear lamina proteins Lamin A and Lamin C through alternative splicing; the lamins form a filamentous meshwork underlying the inner nuclear membrane that provides mechanical support and organizes peripheral chromatin, influencing gene expression, DNA repair, and nuclear shape. A de novo C→T transition at position 1824 (c.1824C>T; G608G) in exon 11 activates a cryptic splice site, producing a truncated and permanently farnesylated Lamin A isoform called progerin, which causes Hutchinson-Gilford Progeria Syndrome (HGPS) — a devastating childhood progeroid syndrome with accelerated cardiovascular disease and a median survival of approximately 14 years. Importantly, low levels of the same aberrant splice product accumulate in normal aging cells even without the HGPS mutation, and nuclear lamina integrity declines broadly with age, suggesting LMNA biology has relevance beyond the rare syndrome. Lonafarnib (Zokinvy), a farnesyltransferase inhibitor that blocks progerin farnesylation, received FDA approval in November 2020 for HGPS and extends median survival by approximately 2.5 years; additional progerin-targeting approaches are in early investigation.