3rd Nuclear Envelope Disease and Chromatin Organisation UK Meeting
Unravelling faulty biology in Emery-Dreifuss muscular dystrophy- Report by Dr. Juliet Ellis (King’s College London)
The Nuclear Envelope Disease and Chromatin Organisation was formed in 2006 and now meets annually, bringing together all the UK researchers and clinicians who investigate degenerative diseases associated with proteins located to the cell nucleus (collectively known as the ‘laminopathies’).
The 2008 meeting was held at King’s College, London, UK on 23 - 24 April 2008, to discuss the latest findings. Below, we describe our current understandings of the faulty biology present in the muscles of people suffering from Emery-Dreifuss muscular dystrophy (EDMD).
Contents:
- Improved genetic diagnosis
- How do nuclear proteins cause a muscular dystrophy?
- Severe form of EDMD first described
- Mouse models for EDMD
Improved genetic diagnosis
Two genes are already associated with EDMD. The first, which makes a protein called emerin, normally only affects boys, where as the second, affects boys and girls equally and makes a protein called lamin A/C. Both of these proteins are found in the nucleus of the cell, which is the part of the cell which contains our DNA. However, to date only 40% of patients clinically diagnosed with EDMD have either a faulty emerin or lamin A/C gene.
Scientists have believed for some time that other nuclear proteins can be responsible for EDMD too. Evidence to support this theory arises from two newly identified nuclear proteins, (nesprin-1 and nesprin-2), which have been shown to carry mutations in a few EDMD patients (in both boys and girls). Other nuclear proteins are now being screened in the same light. We can thus now offer a more accurate diagnostic service for patients who don’t have mutations in the emerin or lamin A/C genes but do have the clinical symptoms of EDMD.
How do nuclear proteins cause a muscular dystrophy?
Most of the proteins associated with MD play a structural role in holding muscle cells together. Thus, it is not immediately obvious how proteins of the nucleus could be involved in this function. Current evidence suggests that emerin, lamin A/C and nesprin all interact with one another and with other nuclear proteins such as SUN1, to form many different protein complexes in the nucleus. These protein complexes have related functions. Three of these functions were discussed at the meeting.
The first is that the nuclear protein complexes connect to filament-like proteins in the cell’s cytoplasm. These proteins in turn interact with the dystrophin-glycoprotein complex (DGC) at the cell surface. It is thus proposed that a defect in a nuclear protein can be transmitted to the cell surface, causing a breakdown in muscle cell integrity.
A second proposed function is linked to a defect in the rate at which muscle cells divide, a process known as proliferation. EDMD muscle cells have a fault in the pathway which regulates cell proliferation and thus the muscle encounters problems when it needs to repair itself.
Finally, nuclear proteins may be involved in maintaining DNA in its correct structure within the nucleus. DNA is not arranged randomly. Mutations which lead to EDMD may disrupt this DNA arrangement and this would have a knock-on effect to the function of other genes.
Severe form of EDMD first described
As diagnostic techniques for EDMD have improved it has become apparent that a few patients develop a very severe form of EDMD, which can affect boys or girls. In these cases, very severe MD symptoms develop before the age of 2 years. Because of the severity of the condition, it is suspected that two genes are affected. These patients all have mutations in lamin A/C and in some instances in the emerin gene too. However, other patients have a normal emerin gene and so it may be a mutation in one of the other nuclear proteins which is to blame.
Mouse models for EDMD
There exist several mouse models for EDMD. To mimic the clinical symptoms of EDMD the mice have had either their emerin, lamin A/C or nesprin genes removed. The mice develop similar, but not exact, pathology associated with EDMD. The mice will allow us to understand the disease in greater detail and in the future it is hoped that possible therapies can be first tested on them.
Further information and links
Click here for more information about Emery-Dreifuss muscular dystrophy.
