Wednesday, November 24, 2010

New FSHD Findings - Summary

(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.

Saturday, November 13, 2010

Inflammatory Role - Impacting FSHD Muscle Cells

J Clin Immunol. 2010 Nov 10. [Epub ahead of print]

CD8(+) T Cells in Facioscapulohumeral Muscular Dystrophy Patients with Inflammatory Features at Muscle MRI.

Institute of Neurology, Department of Neurosciences, Catholic University of Rome, largo Gemelli 8, 00168, Rome, Italy.


Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8(+) T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8(+)pSTAT1(+), CD8(+)T-bet(+) T cells and CD14(+)pSTAT1(+), CD14(+)T-bet(+) cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8(+)pSTAT1(+), CD8(+)T-bet(+) and CD14(+)pSTAT1(+) cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8(+) T cells, may favour FSHD progression by promoting active phases of muscle inflammation.
PMID: 21063901 [PubMed - as supplied by publisher]

Sunday, November 7, 2010

Dave Matthews & Tim Reynolds - Singing for Charity

Dave Matthews and Tim Reynolds will perform two unprecedented special benefit concerts on December 6th and 7th at Seattle’s McCaw Hall.  One hundred percent of the proceeds from these two shows will benefit charities selected by each ticket purchaser. 

Here’s how this works:

For each ticket you purchase for $135 for either show, you will receive a unique code worth $150 that you may use to direct a donation to any charity of your choosing on (a nonprofit organization that connects people to over 1.8 million charities).

Pacific Northwest Friends of FSH Research
Kirkland, WA 98033
Tax ID: 86-1108537

Have fun giving with your fellow concertgoers.  Consider making a collective impact by encouraging your neighbors and friends to all choose Friends of FSH Research!

Your directed donation is funded by Dave Matthews and a generous supporter.

100% of the proceeds will be donated the charity selected by the ticket purchasers.

Bottom line… See a great show while helping fund FSH Research!  THANKS!

Tuesday, November 2, 2010

Friends of FSH Research - An international research consortium shows that FSHD muscle nuclei are poised for expression of the toxic DUX4 protein

Friends of FSH Research - An international research consortium shows that FSHD muscle nuclei are poised for expression of the toxic DUX4 protein

Dr. Silvère van der Maarel

After their recent publication in Science, the same international research collaboration that includes research groups funded by the Friends of FSH Research has made further advancements in our understanding of the molecular cause of facioscapulohumeral dystrophy (FSHD). While their earlier work reported in Science provided genetic evidence that expression and stabilization of DUX4 is critically important for the development of FSHD, the recent report in PLoS Genetics provides an answer as to how a gene expressed at such low concentrations can be toxic to muscle. Low expression of DUX4 can either mean that all muscle nuclei express tiny amounts of the toxic DUX4 protein or that only few out of many nuclei express high levels of DUX4. In this report, the scientists provide compelling evidence for the latter scenario. This finding is important as it provides a model in which occasional bursts of DUX4 in muscle of patients with FSHD can explain the progressive nature of this disease. It also provides a clear target for the design of therapeutics for FSHD.

(read complete article on our website - Please donate to help us push this work toward a cure, thank you)