New mechanism for Emery-Dreifuss muscular dystrophy

Published Date
05/02/2009
Author
Reason Digital
Category
Research

Scientists in the United States have suggested a possible mechanism responsible for the symptoms of autosomal dominant Emery-Dreifuss muscular dystrophy.

Contents:

What does the research show?

Mutations in the gene known as LMNA can cause autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD). Professor Tom Misteli’s group of researchers have proposed a new mechanism by which mutations in this gene cause the symptoms associated with the muscle pathology.Diagram of a cell showing the nucleus where the genetic information is stored.

Most of the proteins associated with muscular dystrophy play a structural role in holding muscle cells together. The LMNA gene however is known to code for two proteins known as lamin A and lamin C which are found located within the cell nucleus. The nucleus is a compartment of the cell that contains the cell’s genetic information.

Several mechanisms have been suggested in recent years as to how these nuclear proteins cause EDMD. In particular, the way that the heart cells of people with EDMD send chemical signals to communicate with their surroundings has been found to be faulty.

Muscle cells contain multiple nuclei, which run along the side of the muscle cells and also cluster around the point where the muscle cell contacts the nerve (called the neuromuscular junction). Using mouse models of AD-EDMD, the new research demonstrated that the muscle cells of these mice failed to position their nuclei in clusters at the point of nerve contact. This prevented the ‘instructions’, which tell the muscle whether to contract or relax, from passing effectively from nerve to muscle. This was due to the abnormal production of the lamin A and C proteins in these mice which in turn affected the positioning of two other nuclear proteins, both of which play a role in the correct positioning of the nuclei within the muscle cells.

The researchers also examined muscle biopsies from AD-EDMD patients. The muscle cells exhibited some signs of dysfunction that were similar to the mice when examined under the microscope, suggesting the authors are on the right track.

What does this mean for patients?

For approximately 40% of people diagnosed with AD-EDMD, the genetic cause is unknown. It is hoped that the observations made during this investigation may ultimately lead to the identification of additional genes that play a role in development of EDMD. 

A better understanding of the causative mechanism responsible for this disorder, and could enable the development of drugs and therapies in the future.

Background information on Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy encompasses a number of similar conditions that are inherited in different ways.  This condition is characterised by muscle weakness which is particularly noticeable in the shoulders, upper arms and lower legs.  It is a slowly progressive disorder affecting both sexes with first symptoms usually displayed between the ages of 17 and 40.  Muscle contractures and stiffness of the neck are also commonly associated with this disorder. A life-threatening complication of EDMD is the development of a severe heart condition by the age of 30, which disrupts the normal heart beat rhythm. This often results in sudden cardiac death in affected patients and carriers of the condition.

The most common form of EDMD is AD-EDMD which occurs due to mutations in the LMNA gene which lies on chromosome 1. This codes for the proteins lamin A and C, However, there is also an X-linked form of EDMD. Here, the genetic defect is in the emerin gene on the X chromosome and mainly affects only males.  Emerin is also a nuclear protein and binds to lamin A and C. Other rare forms of Emery-Dreifuss can be inherited in different ways.

Further information

The original paper is freely available at the Journal of Cell Biology. It is written in scientific language with no explanation in lay terms.

More information about Emery-Dreifuss muscular dystrophy.

The reference for the paper is: Alexandre Méjat, Valérie Decostre, Juan Li, Laure Renou, Akanchha Kesari, Daniel Hantaï, Colin L. Stewart, Xiao Xiao, Eric Hoffman, Gisèle Bonne, and Tom Misteli. Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy. The Journal of Cell Biology, Vol. 184, No. 1, 31-44

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