FSHD1 or FSHD2: That is the question

Facioscapulohumeral muscular dystrophy (FSHD) is the 3rd most common form of muscular dystrophy. While the initial pattern of muscle involvement is familiar to most clinicians (facial weakness, scapular winging, and foot drop), the genetic mechanism likely is not and is unique for the dystrophies, with epigenetic de-repression playing a key role. Epigenetic repression is the mechanism by which our cells turn sections of our DNA off. If you think of our chromosomes like a series of cookbooks, and the genes like recipes, then the way we regulate which recipes are read is by epigentic repression, which in the cell is done by methylation or other chemical mechanisms. Highly methylated areas are turned off; this would be like a book in a store still shrink-wrapped in plastic, so you cannot read what is inside. Each area of the DNA can be separately regulated, and genes whose role is DNA methylation are called chromatin repressors. Most individuals (>95%) will have FSHD type 1 (FSHD1), due to a deletion of large repeated units (RU) on the long arm of chromosome 4, typically between 1 and 10 RU.¹ A minority of individuals will have FSHD type 2 (FSHD2): these individuals show digenic inheritance and have associated mutations in genes that have a role in chromatin repression (SMCHD1, DNMT3B).^2,3 The unified model for FSHD both emphasizes the epigenetic nature of FSHD and provides a link between FSHD1 and 2.⁴ In both FSHD type 1 and 2, there is decreased methylation in the D4Z4 region: in FSHD1 due to deletion of RU and in FSHD2 due to mutations affecting genes responsible for DNA methylation. To return to the cookbook metaphor, decreasing methylation on the DNA is like ripping the plastic shrink-wrap off the book, so now the recipes inside can be read. In addition to the epigenetic changes, both FSHD types 1 and 2 also require a permissive polymorphism providing a polyadenylation sequence to the DUX4 transcript (4qA allele). At its simplest level, FSHD is due to a toxic gain-of-function, where a gene contained in the D4Z4 repeats and is normally silenced, DUX4, gets “turned on,” which is toxic to cells.