Hic-5 deregulation in lamin A-C and emerin - associated myopathies -

Abstract

In higher eukaryotes, the nuclear lamina – a meshwork of type V intermediate filaments – underlies and associates with the nuclear side of the inner nuclear membrane. It consists of 2 classes of proteins; (1) A-type lamins are encoded by a single LMNA gene that gives rise to lamin A, lamin C, lamin C2, and lamin A delta 10 by alternative splicing; (2) B-type lamins include lamin B1 and lamin B2 that are encoded by the LMNB1 gene and lamin B3 encoded by LMNB2 gene. Lamins associate and interact with NE proteins such as emerin. Laminopathies are a group of genetic diseases that are a consequence of mutations or anomalous post-translational modifications of the NE and-or nuclear lamina proteins. Mutations in the LMNA gene are the most dominant form of these diseases, and they have effects on diverse tissue types, mainly skeletal and cardiac muscle tissues. Hence, our aim is to gain a better understanding of these mechanisms that allow different mutations of the ubiquitously expressed LMNA gene contribute to laminopathic tissue specific phenotypes, namely Emery-Dreifuss Muscular Dystrophy (EDMD) and Dilated Cardiomyopathy (DCM). Several studies have shown that mechanical and oxidative stress are key players in the manifestation of laminopathies. In this regard, hydrogen peroxide inducible clone-5 (Hic-5), an adaptor protein, is oxidative stress and TGF-β sensitive and reported to have critical roles in myogenesis and muscle differentiation. It is also implicated in several vital cellular processes, such as: cell growth, proliferation, differentiation, migration, and senescence. We hereby hypothesize that there exists a deregulation in hic-5 expression in lamin A-C and emerin – associated myopathies. In this study, we assessed the transcript and protein expression levels of hic-5 in mouse embryo fibroblast (MEF) lines derived from mice lacking either A-type lamin (Lmna---) or emerin (Emd--Y) which have the EDMD phenotype and mice homozygous for the N195K mutant (LmnaN195K-N195K) which have the