Emery-Dreifuss muscular dystrophy (EDMD), a rare form of myopathy, is caused by mutations in either STA gene that encodes the nuclear membrane-associated protein emerin (X-EDMD), or LMNA gene that encodes the nuclear lamin A/C (AD-EDMD). Whilst other muscular dystrophies are due to the loss or altered expression of molecules located at the plasma membrane/cytoskeleton/extracellular matrix system, emerin and lamin A/C are localized at the nuclear envelope/nuclear matrix interface. Other apparently unrelated human diseases, such as a form of dilated cardiomyopathy (CMD1A) and Dunnigan-type familial partial lipodystrophy (FPLD), are also due to naturally occurring mutations within LMNA gene and have been thus defined "nuclear envelopathies". Different hypotheses have been proposed on EDMD pathogenesis, including the regulation of cell-type-specific gene expression by chromatin-nuclear envelope interactions. The control of gene expression through the release of template restriction depends on the chromatin organization that, in turn, is modulated by interactions with the nuclear envelope. Moreover, the nucleus is not only the final target of signals but, in response to them, activates an autonomous signaling pathway based on inositol lipids that are phosphorylated and hydrolyzed at specific intranuclear sites. The nuclear inositide signaling system is involved in key functions, such as the control of DNA synthesis and of transcript splicing, as well as in heterochromatin decondensation that represents a prerequisite of gene transcription. Chromatin remodeling complexes (CRC), that contain actin and actin-binding proteins, are modulated by inositol lipids at the nuclear matrix level. Therefore, it is conceivable that the altered expression of emerin and lamin A/C that interacts with nuclear actin may affect the chromatin arrangement and gene expression. This can result in modified patterns of development of some cell lineages of common mesenchymal origin and prevent correct mechanisms of differentiation of the muscle satellite cells in the adult.
ASJC Scopus subject areas
- Molecular Biology