Mutations in the lamin A/C gene on chromosome 1 and the emerin gene on the X chromosome both can cause Emery-Dreifuss muscular dystrophy (EDMD), but the precise mechanisms by which they do so are still being identified.
Now, a multinational team has found that, in mice with an EDMD-like disease, lamin protein defects interfere with the way cell nuclei normally localize in skeletal-muscle fibers at the point where each fiber receives signals from a nerve cell.
The researchers say their results "strongly indicate" that defects at the neuromuscular junction (where nerve and muscle connect) contribute to the lamin A/C type of human EDMD, and provide insights into at least one cellular and molecular mechanism operating in this disease.
The team, coordinated by Tom Misteli at the National Cancer Institute of the National Institutes of Health in Bethesda, Md., published its findings Jan. 5, 2009, in the Journal of Cell Biology. Investigators found that the neuromuscular junctions are abnormally organized in these mice and that nerve-to-muscle signals are altered. They say humans with lamin A/C-related EDMD show similar molecular defects in their muscles.
MDA grantee Howard Worman at Columbia University, who has conducted several studies of the molecular consequences of EDMD, cautions that heart-muscle cells, which are severely affected in lamin-related EDMD, do not have neuromuscular junctions, demonstrating that a different disease mechanism exists in these cells.
In October 2008, Worman's group identified a signaling pathway in the heart called ERK as a mechanism of cardiac damage in lamin A/C-related EDMD. (See Research Updates, Quest, January 2009.