The LMNA p.R541C mutation causes dilated cardiomyopathy in human and mice.

Dilated cardiomyopathy (DCM) is a major cause of heart failure. LMNA variants contribute to 6-10% DCM cases, but the underlying mechanisms remain incompletely understood. Here, we reported two patients carrying the LMNA c.1621C > T/ p.R541C variant and generated a knock-in mouse model (Lmna) to study the role of this variant in DCM pathogenesis. We found Lmna mice exhibited ventricular dilation and reduced systolic functions at 6 months after birth. The Lmna cardiomyocytes increased in size but no nuclear morphology defects were detected. Transcriptomic and microscopic analyses revealed suppressed gene expression and perturbed ultrastructure in Lmna mitochondria. These defects were associated with increased heterochromatin structures and epigenetic markers including H3K9me2/3. Together, these data implied that the LMNA c.1621C > T/ p.R541C variant enhanced heterochromatic gene suppression and disrupted mitochondria functions as a cause of DCM.