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 transcription factor normally expressed in the germline, is located within each D4Z4 unit of the macrosatellite repeat and is silenced in somatic cells, likely by  repeat mediated epigenetic silencing. 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 gene expression by maintaining high levels of CpG methylation. 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. In the case of FSHD1 D4Z4 repeat contraction must occur on a chromosome 4 that contains 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. FSHD2 individuals must also carry a 4qA chromosome for SMCHD1 or DNMT3B mutations to result in disease. Thus, both forms of FSHD are digenic disorders requiring two independent genetic features to result in disease.

Our research focuses on the genetic, epigenetic, and molecular aspects of FSHD pathogenesis. We also aim to generate and characterize 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. Due to the high clinical variability present between FSHD individuals we additionally strive to understand how genetic and epigenetic variation can contribute to the heterogeneity of disease severity.  Our hope is that by uncovering the genetic and epigenetic differences between individuals that contribute to disease penetrance and severity we can translate this knowledge into novel treatment options.

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