FSHD is unlike most genetic conditions, where a mutation in a specific gene directly causes the disease. Instead, FSHD is caused by mutations that increase the production of a toxic protein known as DUX4. For this reason, FSHD is arguably one of the most complex genetic conditions currently known, involving a complicated interplay between genes and proteins in the muscle cell.
While there has been a massive amount of scientific progress, resulting in an improved understanding of the genetic mechanism for FSHD, we are still trying to completely understand how the genetic mutations cause the range of symptoms experienced by people.
Below we outline how FSHD types 1 and 2 develop. Clinically, FSHD 1 and FSHD 2 have the same symptoms, and a genetic test is the only way to tell them apart. Scientists are actively investigating the different ways the disease presents, and so it is likely that more subtypes of FSHD will be identified in the future as our knowledge improves.
Nearly all cases (around 95%) of FSHD are Type 1, caused by a mutation on chromosome 4. Chromosome 4 contains a series of repeated pieces of DNA called D4Z4 units. Normally, people have between 11 and 100 D4Z4 units. But in people with FSHD 1, the D4Z4 repeat region is shortened to 1 to 10 units.
The D4Z4 units act like a lock for this part of chromosome 4, preventing genes from being activated. With fewer D4Z4 repeats, a gene embedded in this region called DUX4 is activated. This leads to the unwanted production of the DUX4 protein. This sets off a chain of events that leads to loss of muscle function.
The exact mechanisms are still being studied, but it appears that production of the DUX4 protein causes damage to the muscle cells, causing muscles to waste away. DUX4 may also block normal muscle regeneration, preventing muscles from repairing any damage experienced through normal daily activities. DUX4 is also thought to cause an immune response which inflicts further damage on the muscles. As we learn more about the role of DUX4, the exact mechanisms for FSHD will become clearer.
FSHD type 2 represents about 5% of FSHD cases. FSHD 2 was discovered when a large family was found with FSHD symptoms without the shortening of the D4Z4 repeat region on chromosome 4. People with FSHD type 2 have more than 11 D4Z4 units, like people without FSHD.
Instead, FSHD type 2 may be caused by mutations in other genes, including SMCHD1, DNMT3B, and LRIF1. These then allow the activation of the DUX4 gene and unwanted production of the DUX4 protein.
For a further 1% of FSHD cases, a genetic cause has not yet been discovered. These cases are sometimes described as “FSHD3” and are an active area of research.
Dr. Peter Jones, PhD, of the Peter and Takako Jones Lab (University of Nevada, Reno School of Medicine) explains the differences between and similarities of FSHD1 and FSHD2.
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