Wednesday 6 April 2011
Stem cells give insight into myotonic dystrophy
Researchers studying human embryonic stems cells have found two new genes that may be involved in causing some of the symptoms of myotonic dystrophy. The two closely related genes were found to be less active in nerve cells affected by myotonic dystrophy. The researchers showed that this may be causing symptoms that some patients experience such as learning disabilities and daytime sleepiness and may also reduce the ability of the nerves to communicate effectively with the muscles. This new insight will help researchers develop treatments that can address the wide range of symptoms that patients experience.
Myotonic dystrophy has been described as the most variable inherited human disorder. Symptoms can include muscle stiffness and weakness, cataracts and abnormalities in the heart, brain and hormonal systems.
The most common type of myotonic dystrophy - type 1 - is caused by a mutation in a gene called myotonic dystrophy protein kinase, or DMPK for short. The DMPK gene normally contains a three letter code repeated five to about 35 times. In myotonic dystrophy type 1 (DM1), however, the DMPK gene contains from 50 up to more than 1,000 repeats.
The extra repeated section of genetic code in the DMPK gene is known to affect the activity of a protein called "muscleblind". This has a knock-on effect on several other genes which results in many of symptoms of this condition. A lot of research has focussed on muscleblind as a target for the development of therapies for myotonic dystrophy, but this new research has discovered two more genes that are affected by the changes to DMPK.
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What did this research show?
The research team led by Dr. Cecile Martinat, from France's Institute for Stem Cell Therapy, studied the differences between cells carrying the DM1 mutation and healthy cells.
The cells they used were derived from embryos carrying the DM1 mutation that were donated to research by couples undergoing pre-implantation genetic diagnosis. These embryonic stem cells are a useful tool for research because they can multiply indefinitely, making them available in large numbers. They can also be coaxed into developing into any type of cell which allows studies to be performed on the effect of a mutation on different cell types. In this study they were particularly interested in the effect on brain cells.
The researchers transformed human embryonic stem cells with and without the DM1 mutation into nerve cells found in the brain called "neural precursor cells". They then compared what genes were switched on and off. Several genes were found to be more or less active in the DM1 neurons compared to the healthy cells.
For their further studies they decided to concentrate on two closely related genes called SLITRK2 and SLITRK4 which were less active in the DM1 nerve cells. These genes were also found to be less active than usual in post-mortem brain tissue from people with DM1.
SLITRK proteins are known to be involved in the outgrowth of nerve cells and the formation of neuromuscular junctions, which are sites of communication between nerve and muscle cells. So the researchers transformed DM1 embryonic stem cells into a type of nerve cell called a motor neuron and grew them in a Petri dish together with muscle cells. They found that the change in SLITRK activity caused defects in the cell-cell connections that formed.
What does this mean for patients?
This new approach to studying the biology of myotonic dystrophy has found new genes that may account for the neurological symptoms that some patients experience such as learning disabilities and daytime sleepiness. Changes to the activity of these genes may also reduce the ability of the nerves to communicate effectively with the muscles.
It is still unclear how the mutation in the DMPK gene causes changes to the activity of the SLITRK genes, but it doesn't appear to be via the protein called muscleblind, which has been the focus of the development of treatments for myotonic dystrophy. Exactly how the activity of the SLITRK genes are being affected requires further investigation. However, this new insight will help researchers develop treatments that can address the wide range of symptoms that patients experience.
Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign said:
Type 1 myotonic dystrophy is a devastating condition for affected families and a large proportion of research is directed towards understanding the impact of the condition on muscle. However, some individuals experience daytime sleepiness and a certain disinterest in daily issues and this has immense implications for a person's quality of life. This new research provides new information about the impact of the mutation on the brain and this will be vital to understand the underlying processes that affect a person's behaviour. This is essential for the development of future treatments.
Dr Chris Turner, Consultant Neurologist at the Centre for Neuromuscular Disease, London, said:
This paper is a very exciting development in our understanding of the effects of myotonic dystrophy on the brain, nerves and muscles. Learning difficulties, excessive daytime sleepiness and brain abnormalities have been described over many decades but this is one of the first reports describing a link between the genetic abnormalities and nerve involvement in myotonic dystrophy. These symptoms often severely impair patient's quality of life and these new findings bring hope that targeted treatments will not be too far away.
Further information and links
Ask a question about this research or make a comment on TalkMD forum.
More information about myotonic dystrophy.
More myotonic dystrophy research news.
Read about stem cells in Target Research magazine.
Read about the myotonic dystrophy research we fund.
Clinical trials for myotonic dystrophy.
The full original paper published in the journal Cell Stem Cell and is only available after paying a fee. The article is written in technical language with no summary in layman's terms. The reference for the paper is:
Marteyn A, Maury Y, Gauthier MM, Lecuyer C, Vernet R, Denis JA, Pietu G, Peschanski M, Martinat C. Mutant Human Embryonic Stem Cells Reveal Neurite and Synapse Formation Defects in Type 1 Myotonic Dystrophy. Cell Stem Cell. 2011 Mar 30.
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