Genetic and epigenetic contributors to FSHD

Abstract

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscle disorder characterized by distinct chromatin changes including DNA hypomethylation of the D4Z4 macrosatellite repeat array on a disease-permissive 4qA allele and aberrant expression of the D4Z4-embedded DUX4 retrogene in skeletal muscle. Insufficient epigenetic repression of the D4Z4 repeat is the result of at least two different genetic mechanisms leading to two forms of disease, FSHD1 and FSHD2. In the case of FSHD1, a contraction of the D4Z4 repeat array is disease causing whereas FSHD2 is most often caused by mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene. Recent studies indicate that a combination of genetic and epigenetic factors that act on the D4Z4 repeat array determine the probability of DUX4 expression in skeletal muscle and disease penetrance and progression.

Figure 1. Genetic basis of FSHD1 and FSHD2

Two genetic forms of FSHD are known. The most common form, FSHD1, is caused by contraction of the D4Z4 repeat array to a size of 1–10 units. In controls the D4Z4 repeat arrays (triangles) vary between 11–100 units and adopt a repressed chromatin structure (brown) in somatic cells such as skeletal muscle. CEN indicates the centromeric end and TEL indicates the telomeric end. Upon contraction the D4Z4 chromatin structure becomes derepressed (green) facilitating the expression of the DUX4 retrogene of which a copy is embedded within each unit. DUX4 (white boxes with open reading frame in black) within the D4Z4 unit does not have a polyadenylation signal (PAS), but, in somatic cells can make use of a polymorphic PAS immediately distal to the D4Z4 repeat present on 4qA but not on 4qB chromosomes. Thus, only on 4qA chromosomes, D4Z4 chromatin derepression leads to the production of DUX4 protein. SMCHD1 is a chromatin modifier that binds to the D4Z4 repeat to keep the D4Z4 chromatin structure in a repressed state in somatic cells. Individuals with a mutation in SMCHD1 (asterisk), in combination with a DUX4 polyadenylation signal, can express DUX4 in their muscles. This is called FSHD2.

Figure 2. D4Z4 repeat array sizes in FSHD1 and FSHD2

Recent studies indicate a gradient of probability of disease presentation with increasing repeat sizes. While individuals with 1–3 units on a FSHD-permissive (DUX4 polyadenylation signal-containing) allele are almost exclusively severely affected early onset cases, individuals with 4–10 units show much more clinical variability ranging from severely affected individuals to asymptomatic gene carriers. In part, this variability can be explained by differences in epigenetic susceptibility to somatic expression of DUX4. This is best exemplified in SMCHD1 mutation carriers. SMCHD1 can act as disease gene in FSHD2 or as modifier gene in FSHD1, depending on the consequence of the mutation. Mutations that lead to SMCHD1 haploinsufficiency only cause FSHD in combination with intermediate sized D4Z4 repeat arrays of 8–16 units, while SMCHD1 mutations that are likely to exert a dominant negative effect, can cause FSHD also with longer D4Z4 repeat arrays.