The p.Ser143Pro lamin A/C mutation leads to dilated cardiomyopathy and activates the unfolded protein response pathway in a knock-in mouse model

Variants in the LMNA gene, which encodesing for the nuclear lamins A and C, have been linked to familial form of the disease and the founder variant p.Ser143Pro is particularly common among Finnish DCM patients. To clarify elucidate the complex and poorly understood pathogenic mechanisms behind LMNA-related DCM, we generated a mouse model carrying the p.Ser143Pro mutation in the Lmna gene.

All genetically modified mice appeared normal at birth. However, based on echocardiographyic, necropsy, B-type natriuretic peptide (Nppb) expression levels, and histopathological data, homozygous males developed progressive left ventricular dilatation, myocardial fibrosis, and cardiac failure after six months of age, with all succumbing before ten months. A reduced disease penetrance was observed in heterozygous male and homozygous female mice, with one-year survival rates of 40% and 60%, respectively.