8. What causes FSHD?

Research published in 2010 identified a unifying cause of FSHD.  The bottom line is that there is a gene contained within the repeats on chromosome 4, called DUX4, that is usually turned off and therefore not functional in mature cells.  However, in patients with FSHD this gene is turned on in the muscle cells and the protein produced by this gene is toxic to muscle cells.  The turning on of this normally dormant gene is the cause for FSHD1 and FSHD2 even though the genetic defect that leads to this different for each:

  • FSHD1: The tip of chromosome 4 has a sequence of repetitive identical pieces of DNA, also called repeats.  Typically individuals without FSHD have between 10-100 repeats on each copy of their chromosome 4.  Each repeat contains the same sequence for the DUX4 gene. When the number of repeats is 10 or greater, the DNA containing this gene is tightly bound and the DUX4 gene is silenced. However, when you lose repeats and are down to 1-9 repeats, the DNA structure is loosened (Figure: unwound green line of the 1-9 repeats) and the DUX4 gene is turned on.  This will only occur, however, when there is a particular DNA sequence called the A sequence, after the last repeat which stabilizes the RNA produced from the DUX4 DNA.  The RNA is a copy of the DNA message that is then used to make the corresponding DUX4 protein.

cause of fshd

  • FSHD2In patients with FSHD2, the number of repeats on chromosome 4 is normal and yet the structure of the DNA is loosened by the reduction in the number of chemical bonds (called methylation) between the strands of the DNA.  In about 80% of patients with FSHD2, we now know that this reduction in methylation bonds that loosens the DNA structure, is caused by a mutation in a gene on chromosome 18 called SMCHD1 (Figure: indicated as SMCHD- above).  The protein produced by this gene is responsible for regulating how tightly bound DNA is on chromosome 4.  Like FSHD1, if this loosening happens in the setting of the A distal sequence, once again, the DUX4 gene is turned on producing its toxic protein.

In summary in both FSHD1 and 2 the normally dormant DUX4 gene is turned on and the resulting protein is toxic to muscle fibers.  In FSHD1 this happens because you lose a large number of repeats which loosens the DNA structure whereas in FSHD2 the DNA is loosened because another gene that produces a protein responsible for keeping the DNA tightly bound is mutated and the resulting protein is dysfunctional.



    1. What is FSHD?
    2. How is FSHD inherited?
    3. What are the Symptoms of FSHD?
    4. Does FSHD affect other parts of the body?
    5. Is infantile FSHD different from other forms of FSHD?
    6. What can someone with FSHD Expect as they age?
    7. How is FSHD Diagnosed?
    8. What causes FSHD?
    9. Are there any treatments for FSHD?

      For more information, please contact the Fields Center FieldsCenter@urmc.rochester.edu