Preprint: LMNA missense variant disrupts nuclear integrity and sarcomere remodelling in iPSC-derived heart cells

Pathogenic variants in LMNA, which encodes the nuclear envelope proteins lamin A and lamin C, are a well-established cause of inherited dilated cardiomyopathy (DCM), a leading indication for heart failure and cardiac transplantation. A preprint posted to bioRxiv investigates the molecular consequences of a specific missense variant, NM_170707.4(LMNA):c.274C>T (p.Leu92Phe), which has previously been associated with lipodystrophy features rather than primary cardiomyopathy.

The researchers generated induced pluripotent stem cells (iPSCs) from variant carriers and differentiated them into cardiomyocytes to create a patient-relevant cellular model. Their findings indicate that the Leu92Phe variant compromises nuclear integrity — consistent with the known role of lamins in maintaining nuclear architecture — and additionally implicates LMNA in sarcomeric remodelling, a process critical to the contractile machinery of heart muscle cells.

The work extends understanding of genotype-phenotype relationships in LMNA-associated disease and may be relevant to variant classification discussions for this locus. The preprint has not yet undergone peer review, and findings should be interpreted accordingly.

This study is of primary interest to researchers in cardiac genetics, cell biology, and iPSC disease modelling, and to genetic counsellors working with families in whom LMNA variants have been identified.