Authors
Dargar, T., Lafont, E., Boulogne, L., Gomez, L., carre-pierrat, M., Del Vitto, V., Rausch De Traubenberg, A., Janin, A., Millat, G., Gaignerie, A., Derevier, A., Abitbol, M., Chevalier, P., Gache, v.
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, LMNAp.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.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 26 Sep 2026.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 5
- Comments 0