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Why is FSHD so variable?

Posted by Dr. Gregory J Block on October 30, 2014

This years FSHD International Research Consortium was held in San Diego alongside the American Society for Human Genetics.  Many individuals from academic labs, research foundations, and industry joined for a two-day intensive discussion on this years research progress.   There's a lot going on in the FSHD research community, but I wanted to write an update on the interesting research being done to explain why the clinical severity of FSHD is so variable. 

5 years ago, there was considerable debate lingering about the root cause of FSHD; however, there is now a consensus that inappropriate activation of a protein called DUX4 in skeletal muscle causes FSHD.  FSHD is a variable disease, meaning that each person gets FSHD a little bit differently.  Regardless of the disease variation, almost all cases seem to involve DUX4 as the root cause.  This is a big deal. Some diseases, such as ALS, are complicated by the fact that mutations in different genes can all result in the same symptoms, thus there are multiple targets for one disease, and a target in one form of the disease may not be relevant for another. 

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But why all this variation? There were a number of talks at this years conference that reaffirmed that FSHD is an "epigenetic" disease.  Meaning that it's not the sequence of the DUX4 gene that causes FSHD, it's how the DUX4 gene is packaged. Packaging of DUX4 is carried out when a methyl group is attached to the DUX4 DNA sequence. Think of a methyl group like a bunch of tiny children trying to tackle a linebacker. The more children that are holding onto the linebacker, the less they can run!  

Dr. Richard Lemmers from Leiden University presented compelling data that the degree of methylation of DUX4 (the number of kids hanging off the linebacker) can help predict disease severity.   The story is, as always, is more complex than just methylation. How can you prove that these epigenetic changes are actually causing DUX4 to turn on?  Kyoko Yokimori presented data from a superb study that she carried out where she investigated the consequences of messing around with the epigenetic machinery on DUX4 expression (she locked the kids in the locker room). Her conclusions: if you mess up DUX4 packaging, voila! DUX4 turns on.   To all you journal clubs out there: Yokomori's paper is well worth a read.   By understanding how DUX4 is packaged, and every step that is required to turn it on in muscle, we will expand our repertoire of targets that may be therapeutic for FSHD.

Last, why do we care?  Why even study why a disease is variable? If we know the diagnosis is FSHD, why bother looking at the epigenetics.  The reason is because if we can correlate a genetic or epigenetic diagnosis with disease severity we can better manage the disease, and predict outcomes when we run clinical trials.

As always, feel free to e-mail us, facebook, or tweet us questions.