The role of a novel nuclear envelope protein in the pathogenesis of cardiomyopathy

Dilated cardiomyopathy (DCM) is a common cardiac condition characterized by ventricular dilatation and reduced systolic function. Genetic mutations which alter cellular compartments and pathways of different subcellular systems have been identified in at least 30–35 % of DCM patients, among them mutations in nuclear envelope proteins.

A crucial point to maintain the shape and function of the nucleus is the cohesion and integrity of the nuclear envelope, which is kept up by the interaction of nuclear envelope proteins with Lamins and other proteins constituting the nuclear lamina. Furthermore, it has been shown, that inner nuclear membrane proteins interact with intra nuclear proteins and peripheral chromatin. Therefore, they may influence various nuclear functions, such as cell cycle regulation, mitosis, regulation of gene expression and the DNA-damage-response-system (Figure below). Due to this important role, mutations in genes coding for nuclear envelope proteins or components of the nuclear lamina may lead to severe diseases, called nuclear envelopathies and laminopathies.

Recently, we identified a new nuclear envelope gene mutation which is recessively inherited and leads to juvenile cataract and severe cardiomyopathy with sudden cardiac death. To characterize the cardiac phenotype in humans and to elucidate the molecular mechanisms in the pathogenesis of this cardiomyopathy we are currently performing in vitro studies on mutant tissue, cells and recombinant expressed proteins using co-immunoprecipitation, histology, immunohistochemistry, flow cytometry and life cell imaging.  Additionally, an in vivo CRISPR-Cas9 generated knock-out and knock in mouse model will help to understand disease process. So far, our data demonstrate that the mutation of this new nuclear envelope gene disrupts protein interactions, cell cycle progress and leads to a premature aging phenotype. In addition, it induces DNA repair deficiency upon different damage stimulations. Prospectively, investigations will focus on the role of this gene in DNA damage response pathway, cell division and proliferation functions.