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. Author manuscript; available in PMC: 2021 Apr 15.
Published in final edited form as: Trends Mol Med. 2020 Oct 19;27(2):123–137. doi: 10.1016/j.molmed.2020.09.008

Figure 1. The genetics and molecular mechanism for FSHD.

Figure 1.

In a healthy individual, the subtelomeric region of chromosome 4q35 contains 11–100 highly compacted D4Z4 macro satellite repeats. FSHD occurs when two conditions in this region are met. First, there needs to be a relaxation of the chromatin structure, allowing expression of the DUX4 mRNA transcript. In FSHD1 (~95% of cases) contraction of the D4Z4 units (between 1–10 units) allows this change while in FSHD2 (~5% of cases) mutations in epigenetic modifiers such as SMCHD1, DNMT3B and LRIF1 results in hypomethylation to allow expression. The second condition is a permissive 4qA allele at the distal D4Z4 repeat. Unlike the non-permissive 4qB, 4qA contains a polyadenylation sequence (PAS) which adds a poly(A) tail to the DUX4 mRNA, stabilizing the transcript and allowing translation of the DUX4 transcription factor.