Facioscapulohumeral Muscular Dystrophy (FSHD)

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 mostly 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, or by mutations in the LRIF1 gene encoding a protein that interacts with SMCHD1.

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 five themes: genetics, epigenetics, (high resolution) molecular aspects of FSHD pathogenesis, disease models, and preclinical therapy development.

Our hope is that we can translate this knowledge into novel treatment options.