Feb. 2, 2009

EDMD Mice Defects May Shed Light on Disease

A multinational team coordinated by Tom Misteli at the National Cancer Institute of the National Institutes of Health in Bethesda, Md., has found that, in mice with a disease resembling Emery-Dreifuss muscular dystrophy (EDMD), lamin A or C 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.

Mutations in the lamin A/C gene on chromosome 1 and the emerin gene on the X chromosome can both cause EDMD, but the precise mechanisms by which they do so are still being identified.

Thanks to several research studies, some of which were conducted in the laboratory of MDA grantee Howard Worman at Columbia University, scientists understand that these mutations disrupt the A or C lamin proteins (made from the same gene), which lie just under the surface of each muscle-fiber nucleus; or the emerin protein, which forms spokelike projections between these lamins and the inner membrane of each nucleus.

The Misteli group, which published its findings Jan. 5 in the Journal of Cell Biology, says the nerve-muscle connections, known as 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.

The researchers say their results "strongly indicate" that neuromuscular junction defects 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.

Worman 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).