Missense LMNA Variant Compromises Nuclear Integrity and Sarcomeric Remodeling in Dilated Cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation, and pathogenic variants in LMNA are a well-established cause of inherited DCM. The LMNA gene encodes nuclear lamins A/C, which maintain nuclear integrity, regulate gene expression and mediate mechanotransduction. Here, we investigated the pathogenic consequences of the NM_170707.4(LMNA):c.274C>T NP_733821.1:p.(Leu92Phe) variant, previously associated with lipodystrophy features, using patient-derived induced pluripotent stem cells, differentiated into cardiomyocytes and show implication of LMNA in sarcomere remodeling and mitochondria efficiency. We generated iPSC lines from two DCM patients carrying LMNA p.Leu92Phe variant in heterozygous form and a healthy parental control. Cardiomyocytes differentiation efficiency was preserved, however, LMNA p.Leu92Phe iPSC-CMs exhibited laminopathies associated phenotypes, such as nuclear shape abnormalities and lamin A/C aggregation. Moreover, in vitro study revealed that LMNA p.Leu92Phe iPSC-CMs alter sarcomere reformation and decrease mitochondrial respiration after cardiomyocyte remodeling, which is associated with a worsening nuclear shape phenotype. Functional analyses highlight defects in calcium handling, thereby explaining arrhythmia and dilated cardiomyopathy features in patients. Our results show that the LMNA p.Leu92Phe variant compromises nuclear lamina integrity and disrupts functional cardiomyocyte properties, particularly during sarcomere remodeling, highlighting the long-term impact of this specific variant in LMNA-associated DCM. Author Summary Specific genetic change in the LMNA gene causes serious heart condition called dilated cardiomyopathy. This condition weakens the heart muscle and can lead to heart failure. We used stem cells from patients carrying a specific mutation and turned them into heart cells to identify altered mechanisms. We found that even though these cells developed normally at first, they showed clear problems once they matured. The nuclei inside the cells became misshapen, and the structural proteins clumped together abnormally. More importantly, we discovered that the mutation disrupted how heart muscle fibers rebuild themselves and reduced the energy production in mitochondria. We also observed problems with how the cells handle calcium, which could explain why patients experience irregular heartbeats. Our work shows that this particular genetic variant damage the nuclear structure and impairs critical heart cell functions, especially during muscle remodeling. This helps explain why people with this mutation develop progressive heart disease over time.