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

Dilated cardiomyopathy (DCM) is characterized by progressive ventricular dilation, systolic dysfunction, and an increased risk of arrythmias and sudden cardiac arrest. 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. No signs of skeletal myopathy were observed in mice carrying the mutation. Whole-transcriptome RNA sequencing analysis of left ventricular cardiac tissue from asymptomatic two-month-old homozygous male mice revealed an upregulation of classical heart failure markers, such as atrial natriuretic peptide (Nppa ) and myosin heavy chain β (Myh7), and an elevated unfolded protein response signaling, as shown by elevated DNA damage-inducible transcript 3 (Ddit), Bcl-2-associated athanogene 3 (Bag3) and CCAAT/enhancer-binding protein beta (Cebpb) levels especially in the homozygous males compared to wild-type mice. In conclusion, p.Ser143Pro-Lmna mice closely mimic the clinical phenotype observed in patients with the p.Ser143Pro LMNA variant and offerserve as a valuablepotential in vivo model for investigatingstudying the underlying pathogenic mechanisms of LMNA-related DCM in greater detail.