(This is a nice summary of recent research findings - from the UK Muscular dystrophy newsletter - you can read more about this work, and the work done by researchers funded by Friends of FSH Research on our website)
New research increases understanding of facioscapulohumeral muscular dystrophy.
An international group of scientists has shed further light on the molecular mechanism that causes facioscapulohumeral muscular dystrophy (FSH). Recent research has provided evidence that the piece of DNA that is changed in people with FSH contains a gene called DUX4, the function of which is so far unknown. The results of this new research provide evidence that the DUX4 gene can produce different versions of DUX4 protein and that the deletion in patients with FSH leads to the production of a version that is toxic for muscle cells. These important findings will be vital to bring scientists closer to developing a treatment.FSH is caused by changes to a region of DNA on chromosome 4 called D4Z4 that has the same piece of DNA code repeated many times. In healthy individuals the number of repeats varies between 11 and 100. People with FSH have less than 11 repeats. Recent research demonstrated that the repeated section of DNA contains a gene called DUX4. The reduction in the number of repeats on D4Z4 to less than 11 changes the way this piece of DNA is folded (this is known as the chromatin structure). This exposes the DNA code to be read by the cell, like opening a book. They also showed that an activation signal also needs to be present next to the DUX4 gene. In other words, the book needs to be open and the light switched on before you can read it. Read more about these previous results.
But this is not the whole story and this new research builds on these previous findings to further clarify the mechanism causing FSH.
What does the research show?The researchers analysed tissue samples to find out more about the protein that is produced from the instructions in the DUX4 gene. They found that the DUX4 protein was made in two forms - a full-length and a shortened version. The full-length protein could not be found in the muscles of people unaffected by FSH, instead the shorter version of the protein was found. Of the tissues they examined, the full-length version was only present in testes. However, muscle samples from people with FSH were found to be producing the full length DUX4 protein. It should be noted that in people with FSH only a very small proportion of muscle cells produce the longer version of the protein.
These results suggest that muscle cells actively read the DUX4 gene but the protein is processed differently in people with FSH. This leads to the production of the full-length version that is not found in the muscle cells of people unaffected with FSH. It is thought that the way the DNA is folded may be determining this. In healthy cells the DNA is more tightly coiled and this may be influencing the cell to "cut out" parts of the DUX4 protein to create the shortened version. The DNA in the FSH muscle is much more loosely folded, due to the smaller number of repeats, and so this signal to "cut out" part of the protein is missing.
The researchers also analysed "induced pluripotent stem cells" (iPS). These are made in the laboratory by reprogramming cells that already have a dedicated function, such as skin cells, so that they become stem cells. iPS cells are a useful tool for stem cell research and can be used to model disease processes. When researchers looked at iPS cells made from skin they found that they produced the full-length DUX4 protein which did not seem to be toxic for this cell type.
The researchers have suggested that the fact that the full-length version of the DUX4 protein is produced only in stem cells and testicular tissue might mean that it has a possible role during early development. In adult tissue, especially in muscle, the production of the full-length protein is switched off and the shorter version is produced. The changes in the DNA in people with FSH somehow have the effect that this switch is not happening. The muscle cells keep on making the full-length DUX4 protein that becomes toxic to the cells, inducing muscle damage.
What does this mean for patients?This research represents a big step forward in our understanding of what causes FSH, something that has prevented scientists moving forward to develop potential therapies. These new results will allow researchers to further clarify the role of the DUX4 gene and protein in the development of the condition.
It is still not fully understood what the function the DUX4 protein is and why the full-length DUX4 protein appears to be toxic to the muscle and researchers will continue to investigate this. This current piece of research and the other recent findings about FSH have however, highlighted a target which researchers can now take advantage of to potentially start developing a therapy for this condition.
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