Figure 1.

Pathological mechanism in FSHD. In normal individuals the chromatin is tightly wound keeping DUX4 in a repressed state. In FSHD1 deletion of a critical number of D4Z4 repeats opens up the chromatin structure allowing DUX4 to be expressed. However this only occurs when the D4Z4 deletion occurs on a permissive genetic background, the A allele, which contains a polyadenylation sequence which stabilizes the nascent DUX4 transcripts. In FSHD2 patients do not have deletions in the D4Z4 region, but do have decreased methylation, which in approximately 2/3 of patients is associated with mutations in the SMCHD1 gene. Decreased methylation also causes an opening of chromatin structure, and when this occurs on a permissive genetic background containing the A allele, DUX4 can be expressed. In both expression of DUX4 is believed to cause disease in a toxic gain-of-function fashion.