New research brings us closer to understanding the cause of FSH symptoms

Published Date
Kristina Elvidge

Scientists at the Fred Hutchinson Cancer Research Center in Seattle, USA, have published an exciting report on their latest facioscapulohumeral muscular dystrophy (FSH) research. Their findings bring us one step closer to understanding the complicated molecular mechanisms that underlie this condition.

Background information

Most patients with FSH are missing a small part of one of their chromosomes. This occurs in a region of DNA called ‘D4Z4’, which is located at the very end of chromosome number four. In a healthy person, D4Z4 contains between 11 and 150 copies of a gene called DUX4. Most patients with FSH, however, have only between one and ten copies. But why do they develop muscular dystrophy?

Several years ago, scientists came up with one possible answer: When D4Z4 is composed of many DUX4 copies the DNA becomes ‘locked’. As a result, the DUX4 gene is switched off or ‘silenced’. However, if there are only a few DUX4 copies, the DNA ‘relaxes’ and becomes accessible. When this happens, the DUX4 gene is switched on resulting in carbon copies of the gene being made – called RNA. These contain the instructions to build a DUX4 protein.

Most scientists believe that these out-of-control RNA messages cause the muscle weakness in FSH patients, probably because of the DUX4 protein they produce. It is possible that DUX4 protein or RNA could then disrupt the control of other genes, which ultimately causes the symptoms of the condition.Click here for a larger diagram.

What’s new in this study?

The scientists put the DUX4 gene into human muscle cells grown in the laboratory and used a microchip to measure what happened to all other genes in the genome. They found that more than 1,000 genes were turned on, and over 800 genes were turned off.

They also identified thousands of DUX4 ‘binding sites’ located in or near these genes. These binding sites could be thought of as DNA ‘post codes’ – unique places on chromosomes that are specifically visited by the DUX4 protein. When DUX4 interacts with the DNA at one of these postcodes, it can potentially switch nearby genes on or off.  This is the first study to report such a large number of DUX4 binding sites and identifying them is very important for our understanding of FSH.

The scientists then picked a subset of the DUX4 targets for further investigation. They observed that they are turned on only in muscle cells taken from FSH patients, but not in those taken from healthy individuals. This is exactly what the current theory would predict – as DUX4 protein is only made in the muscle tissue of FSHD patients. Accordingly, another elegant experiment showed that the target genes can be switched off again by blocking the DUX4 present in patients’ muscle samples.

But what function do these DUX4 target genes themselves have? It appears that at least a few of them play a role in the immune response. If their regulation is disrupted, this could explain some of the inflammation observed in muscles of FSH patients.

What does this mean for patients?

A lack of understanding of how the genetic mutation causes the symptoms of FSHD has in the past prevented scientists moving forward to develop potential therapies. This new research strongly supports the current theory of FSHD genetics: DUX4 changes the regulation of many other genes. This new research therefore confirms DUX4 as a possible therapeutic target for future research and scientists are already working on ways to block the production of DUX4.

In addition, understanding what genes and biological processes within the muscles are affected by the production of DUX4 may shed light on new ways that we may be able to intervene and alleviate the symptoms of the condition.

Further information

More information about FSH.

Find out about the FSH research we fund.

Many thanks to Andreas Leidenroth for writing this research summary. Andreas is a Muscular Dystrophy Campaign-funded PhD student researching FSH in Nottingham.

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The full original paper was published in the journal Developmental Cell and is only available after paying a fee. The article is written in technical language with no summary in layman’s terms. The references for the paper is:

Linda N. Geng et. al. DUX4 Activates Germline Genes, Retroelements, and Immune Mediators: Implications for Facioscapulohumeral Dystrophy. Developmental Cell – 17 January 2012 (Vol. 22, Issue 1, pp. 38-51)

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