A new study unravels the molecular mechanism underlying a group of rare genetic disorders known as laminopathies, suggesting that they may in fact be epigenetic disorders.
Mutations in the gene encoding nuclear proteins called lamins cause a wide range of laminopathies, including muscle wasting disorders, nerve damage, heart muscle disease, and lipid disorders. Lamin A is filament that's part of a larger network of proteins, called the nuclear lamina, that serves as a scaffold to support the inner nuclear membrane or envelope. Lamin A is thought to play a key role in the epigenomic regulation of chromatin at the nuclear periphery, potentially influencing gene expression. However, the mechanism by which different mutations in lamin A trigger laminopathies remains poorly understood.
Jelena Perovanovic and colleagues zeroed in on lamin A mutations that cause a muscle wasting disorder known as Dreifuss-Emery muscular dystrophy (EDMD). Working in mouse and huma n muscle cells as well as fibroblasts from an EDMD patient, the researchers found that the disease-causing mutations enhanced the number of lamin A that physically tethered to chromatin. These physical interactions disrupted the expression of certain genes involved in cell fate and developmental pathways, potentially derailing normal muscle formation in EDMD.
Altogether, the findings shed light on how developmental epigenetic programming may go awry in EDMD and possibly other laminopathies.