Cardiomyocyte-resrictred expression of Progerin confers hypertrophy

Hutchinson-Gilford progeria syndrome (HGPS) is a rapidly progressive aging disease caused by a point mutation in lamin A (LMNA, c.1824C>T), leading to alternate splicing of the gene. Progerin—the truncated protein product—functions as a dominant negative and disrupts the nuclear envelope, alters chromatin architecture, and promotes DNA damage. Recently, a longitudinal echocardiographic study identified a subset of children with HGPS develop cardiac hypertrophy and diastolic dysfunction.1 This pathology is unique to HGPS, as other LMNA mutations cause dilated cardiomyopathy in humans. We found that cardiomyocyte-resricted expression of progerin (using an AAV system with cardiac troponin promoter to express progerin in myocytes led to increased LV mass and worsening diastolic function in male mice over 9 months.