Emerin and inherited disease

Abstract

(cont.) nucleus and at the nuclear surface.

Mutations in the lamin A/C gene (Lmna) and the lamin-associated protein emerin gene (EM) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy, Charcot-Marie-Tooth Neuropathy and Hutchinson-Gilford progeria syndrome. The molecular mechanisms underlying the varied phenotypes are unknown, and both a mechanical stress hypothesis and an altered gene expression hypothesis have been proposed to explain the tissue specific effects observed in laminopathies. To investigate the role of emerin in mechanotransduction, lamin A/C deficient (Lmna⁻/⁻) fibroblasts, and emerin deficient (EM⁻/y) fibroblasts were studied for nuclear mechanical properties, cytoskeletal stiffness, and mechanical strain-induced signaling. EM⁻/y fibroblasts exhibited similar cell sensitivity, nuclear and cytoskeletal properties compared to wild type cells under stress and strain. Interestingly, both Lmna⁻/⁻ and EM⁻/y fibroblasts had impaired mechanotransduction, characterized by attenuated expression of the mechanosensitive genes egr-1, iex-1, and txnip in response to mechanical stimulation. In addition, NF-rB signaling appeared disturbed in Lmna⁻/⁻ cells, but normal in EM⁻/y fibroblasts. The relationship between changes in cytoskeletal stiffness recently discovered in Lmna⁻/⁻ cells and nuclear mechanics under strain was explored using a computational finite elemental model. Analysis of the several models using variations in material properties and cell geometry revealed that nuclear shape, material properties of the cytoskeleton and nucleus, as well as the size and location of strain application on the cell are important parameters in determining the magnitude of stress and strain within the