Facioscapulohumeral muscular dystrophy (FSHD) is an inherited neuromuscular disorder that causes weakness most prominently of the muscles in the face, shoulder blades, and upper arms. It often progresses to cause widespread muscle weakness, as well as loss of hearing.
The region of our chromosomes that causes FSHD contains a section with multiple identical units of DNA called D4Z4 repeats. Each repeat contains a copy of a gene called DUX4. This gene is used during fetal development, but in adulthood, the DNA in this region is normally “condensed,” or packed tightly together, which prevents the cellular machinery from reading the DUX4 gene. As a result, no protein is made from it once fetal development is completed.
In FSHD, multiple D4Z4 units are lost, which de-condenses the DNA and reactivates the DUX4 gene, allowing aberrant production of the DUX4 protein. Many FSHD researchers now believe that elevation of DUX4 protein causes the symptoms of FSHD. Only one copy of this flaw is needed to cause the disease, which can therefore be inherited from either parent if they have that flaw.
Mutations in SMCHD1 can also cause FSHD
In about 5% of FSHD patients, the D4Z4 region is of normal length. In these patients, mutations in a different gene, called SMCHD1, cause the DNA in the vicinity of the D4Z4 repeats to be opened up, allowing the DUX4 gene to be read and protein to be produced.
The symptoms of FSHD are widely thought to be due to elevation of the DUX4 protein. Therefore, treatment strategies contemplated include reducing expression of the protein, interfering with the function of the protein, and mitigating the effects of the protein.