Facioscapulohumeral Muscular Dystrophy (FSHD)

Principal investigator
Prof.dr.ir. Silvère M. van der Maarel

Facioscapulohumeral dystrophy (FSHD) is one of the most common forms of muscular dystrophy. Clinically FSHD is primarily characterized by the progressive and often asymmetric weakness and wasting of the facial, shoulder, and upper arm muscles. Disease onset as well as severity and progression is highly variable between individuals with FSHD. The disease mechanism behind FSHD is complex with there being both genetic and epigenetic contributing factors.

The majority of FSHD cases, referred to as FSHD type 1 or FSHD1, are caused by the contraction of the D4Z4 macrosatellite repeat located in the subtelomere of chromosome 4q. Unaffected individuals have a D4Z4 repeat consisting of greater than 8 units, while FSHD1 patients have a contracted D4Z4 repeat between 1 and 10 units. A copy of the DUX4 gene, encoding for a germline and cleavage stage transcription factor, is located within each D4Z4 unit of the macrosatellite repeat and is silenced in somatic cells. D4Z4 repeat contractions to a size of between 1-10 units result in local chromatin relaxation and the aberrant expression of DUX4 in the skeletal muscle of patients in a variegated pattern, with a few muscle cell nuclei expressing relatively high amounts of DUX4.

FSHD patients that show a variegated pattern of DUX4 expression because of D4Z4 repeat chromatin relaxation in skeletal muscle cells but who do not have contractions in the D4Z4 macrosatellite repeat are referred to as having FSHD type 2 or FSHD2. The majority of FSHD2 cases are attributed to mutations in the SMCHD1 gene, which encodes for a chromatin modifier that binds to the D4Z4 repeat and plays an important role in the regulation of DUX4 expression. A small proportion of SMCHD1 mutation negative FSHD2 patients can be explained by mutations in the DNMT3B gene, encoding a DNA methyltransferase necessary for establishing CpG methylation during development.

In both types of FSHD disease only manifests when an individual has a specific genetic background of chromosome 4 that is permissive for DUX4 expression. These permissive backgrounds contain a polyadenylation signal for DUX4, which is present on approximately half of the chromosomes 4 and referred to as 4qA or 4A. D4Z4 repeats on chromosomes 4qB (4B) and 10 are generally not permissive for DUX4 expression. 

Our research focuses on four themes: genetics, epigenetics, (high resolution) molecular aspects of FSHD pathogenesis, and disease models. Our hope is that we can translate this knowledge into novel treatment options.

Genetics
While historically FSHD1 and FSHD2 have been described as separate disease entities, our recent studies suggest that they are opposites of a disease spectrum in which genetics (the repeat size) and epigenetics (the activity of D4Z4 chromatin modifiers) contribute to DUX4 derepression and disease presentation in skeletal muscle. Given the large clinical heterogeneity, within this theme we mainly focus on genotype-phenotype relationships as well as on identifying new factors that contribute to DUX4 derepression in FSHD.

Epigenetics
The chromatin structure of the D4Z4 macrosatellite repeat is complex with many chromatin factors binding to the repeat and regulating DUX4 repression in somatic cells. The hierarchy and dependency of these factors is largely unknown, and their contribution to clinical variability is not well studied. In this theme we aim to characterize the epigenetic contributors to DUX4 repression in skeletal muscle with the objective to identify novel therapeutic avenues.

(High resolution) molecular aspects of FSHD pathogenesis
The molecular hallmark of FSHD is the variegated expression of DUX4 in myonuclei, with only a minority of nuclei expressing DUX4. We are using state-of-the-art single cell and single molecule technologies to understand the sequence of events that characterize FSHD pathology: DUX4 initiation, (DUX4-induced) cellular heterogeneity, progression and termination. 

Disease models
We also aim to generate and characterize a broad spectrum of FSHD disease models, to not only gain a deeper understanding of disease progression and pathogenesis but to further the resources available to the FSHD research community, and to develop therapy. 

We collaborate with world leading experts in academic institutes and industry: