Nuclear deformation and anchorage defect induced by DCM mutants in lamin A

Abstract

1 Dilated Cardiomyopathy (DCM) is one of the different types of laminopathies caused by the 2 mutations in A-type lamins in somatic cells. The involuntary cyclic stretching of cardiac 3 muscle cells, as observed in normal physiological conditions is perturbed in DCM which 4 afflict patients globally. As A-type lamins are principal components in nuclear mechanics, we 5 have investigated the effect of the DCM causing mutants-K97E, E161K and R190W on 6 nuclear stretching and deformation by static and dynamic strain inducing experiments. All 7 the mutants exhibited differential nuclear structural aberrations along with a tilt in the 8 nuclear axis compared to the direction of the cell axis and a significant decrease in the lamina 9 thickness which reflected the lower mechanical rigidity. These phenotypes could potentially 10 lead to defects in nuclear anchorage to the actin filaments thereby resulting in the misshapen 11 and misaligned nucleus. 12 13 14

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“…Lamin A mutation is one of the common causes of DCM. Lamin A is an intermediate filament protein existing in the nuclear membrane and nucleoplasm and is a fiber structure providing support for the nuclear membrane (11,12). Lamin A mutation is characterized by atrioventricular conduction block, elevated serum creatine kinase level and skeletal muscle involvement in some cases.…”