Cardiomyopathic mutations of lamin A perturb mutual interactions of lamin, nuclear membrane, and chromatin leading to LLPS

Lamins are nuclear intermediate filaments constituting the nuclear lamina which maintains the structural integrity of the nucleus and play a key role in the spatial organisation of the genome. Mutations in lamin A/C are associated with multiple diseases collectively known as laminopathies, often characterized by misshapen or fragile nuclei with altered 3D chromatin organization. In this study, we focus on two lamin A mutants—E161K and K97E—which are widely reported in patients afflicted with dilated cardiomyopathy (DCM). Through confocal imaging and 3D FISH, we establish that these mutations cause large-scale disruption of the peripheral lamina and consequent heterochromatin organisation, along with the formation of lamin A aggregates inside the nucleoplasm. Through coarse-grained polymer simulations, we reveal the role of interactions between lamins, the membrane and chromatin in maintaining Wild-type (WT) lamin-chromatin organisation and demonstrate that disruptions in these interactions can reproduce the experimental observations in the lamin A mutants. Additionally, we observe the dynamic properties of lamin aggregates and internal rearrangements at a mesoscopic scale, reminiscent of liquid-liquid phase separation (LLPS). This is the first report to elucidate the presence of LLPS in the case of lamin intermediate filaments.