Cause of FSHD
Decades of basic FSHD research have produced the broad consensus that FSHD is caused by the undue production of a protein called DUX4. When produced in skeletal muscle, DUX4 sets in motion a cascade of cellular events that eventually result in the devastating effects of FSHD. The expression levels of DUX4 in FSHD muscle cells are very low, but even these low amounts are able to start the toxic cascade and ultimately destroy the muscle cells.
The DUX4 protein is encoded by the DUX4 gene that resides in a repeating part of the DNA on chromosome 4 called the D4Z4 array. In muscle cells from healthy individuals, regulatory proteins tightly pack the D4Z4 array, so DUX4 is turned off. In FSHD patients this repression of DUX4 is insufficient, switching DUX4 on. At the genetic level, different types of FSHD have been identified, but these all converge on insufficient repression of DUX4. At the molecular level, therefore, these different FSHD types come down to the same thing.
Our single goal is to develop an FSHD therapy that restores DUX4 repression as much as possible.