In the last 5 years, an impressive series of genetic diseases (16 distinct diseased phenotypes have been so far identified), affecting metabolic and/or developmental processes, have been demonstrated to be caused by mutation of LMNA gene and collectively referred to as laminopathies. Most of these diseases are characterized by dystrophic/degenerative processes affecting different tissues and organs. Nuclear defects, consisting in heterochromatin focal or total loss and in nuclear lamina thickening or invagination, characterize the cells from laminopathic patients. Furthermore, accumulation of pre-lamin A has been demonstrated to occur, at least in a large group of laminopathies. These findings suggest a possible pathogenic mechanism for laminopathies. The cells bearing mutated pre-lamin A could not be able to maintain the chromatin organization required by differentiation programs, which represents an epigenetic marker of each cell lineage undergoing a differentiation process. These alterations have been demonstrated to be due to a lack of mutant lamin A to physiologically interact with heterochromatin-associated proteins, including HP1. The use of specific drugs that interfere with the maturation of lamin A allowed us to demonstrate that the accumulation of farnesylated pre-lamin A induces the appearance of nuclear phenotypes similar to those occurring in progeric syndromes. Furthermore, LMNA mutations found in several laminopathies reduce the transcriptional capability of the cells accumulating pre-lamin A. Therefore, the pathogenic mechanism of laminopathies appears to involve alterations of the chromatin organization and transcriptional capability required by differentiation programs, not necessarily during early embryogenesis, in which cells lack lamin A/C, but in adult cell populations capable of differentiating under specific stimuli. These cells, that constitute the stem reservoir of several adult tissues, and that are typically represented by mesenchymal stromal cells, in the presence of mutant lamin A/C, and of accumulating pre-lamin A, present phenotypic alterations of the chromatin pattern and impairment of gene expression mechanisms. This could result in an accelerated cellular senescence, which could be characterized by the presence of progerin in progeric laminopathies, and of pre-lamin A in other laminopathies, in which not all tissues but specific tissues are involved. In fact, lamins and lamin-associated proteins, by constituting a platform for the interaction with transcription factors, may contribute to a fine modulation of gene expression programs, typical of each cell lineage.
ASJC Scopus subject areas
- Molecular Biology