Missense LMNA Variant Compromises Nuclear Integrity and Sarcomeric Remodeling in Dilated Cardiomyopathy
- 1INSERM ADR Provence Alpes Cote d'Azur et Corse
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.
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BibTeX
@misc{dargar2026missense,
title = {{Missense LMNA Variant Compromises Nuclear Integrity and Sarcomeric Remodeling in Dilated Cardiomyopathy}},
author = {T. Dargar and E. Lafont and L. Boulogne and L. Gomez and M. carre-pierrat and V. Del Vitto and A. Rausch De Traubenberg and A. Janin and G. Millat and A. Gaignerie and A. Derevier and M. Abitbol and P. Chevalier and v. Gache},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753175},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753175v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Missense LMNA Variant Compromises Nuclear Integrity and Sarcomeric Remodeling in Dilated Cardiomyopathy
AU - T. Dargar
AU - E. Lafont
AU - L. Boulogne
AU - L. Gomez
AU - M. carre-pierrat
AU - V. Del Vitto
AU - A. Rausch De Traubenberg
AU - A. Janin
AU - G. Millat
AU - A. Gaignerie
AU - A. Derevier
AU - M. Abitbol
AU - P. Chevalier
AU - v. Gache
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753175
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753175v1
AB - 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.
ER -