Progress in Understanding FSHD Molecular Pathology

Reprinted with permission from Genea Biocells Newsletter Feb 2017

Dr. Alan Colman - Senior Scientific Advisor, Genea Biocells

Facioscapulohumeral dystrophy (FSHD) follows myotonic dystrophy in being the most prevalent inherited muscular dystrophies in adults at almost 1:10,000 afflicted. FSHD is diagnosed from weakness in the facial, shoulder and upper arm muscles leading to loss of the ability to walk or raise arms, speech impediments and loss of facial expression. The disease can be confirmed by genetic detection of the D4Z4 repeat contraction or expression of the pathogenic gene DUX4. FSHD is a principal focus for Genea Biocells' (GBC) drug discovery efforts which it pursues through the use of pluripotent stem cell (PSC)-derived cellular models.

The severity of the most common form of this disease, FSHD1, is generally dependent on the number of D4Z4 macrosatellite repeats at the end of chromosome 4. In healthy people, this unit is typically repeated from 11-100 times and in afflicted people, usually less than 10 repeats. "Contraction" of this repeat number somehow triggers the activation of the DUX4 gene and the subsequent muscle pathology; generally the smaller the number of repeats, the more severe the disease although, as indicated above, healthy individuals have been observed with just one copy of the repeat. In most cases, the repeat array size in muscle tissue is inherited without alteration but in some 10-30% of cases further contraction of the locus can occur in somatic cells, leading to mosaic patients who have FSHD in some cells of their body but not others.

A newly published paper from Davide Gabellini's group (Casa et al. 2016) has shown for the first time a mechanism for FSHD1 induction of DUX4 gene expression due to D4Z4 repeat contraction. The researchers established that the DUX4 promoter present in the repeat sequence mediates the copy number dependent recruitment/binding of the polycomb repressive complex 1 (PRC1), and in the absence of sufficient bound PRC1, the DUX4 gene becomes active. Whilst there are many other repressive mechanisms active in the muscle cells, their effects are NOT copy number dependent and cannot explain general observations on the increasing severity of the disease as repeat copy numbers are decreased. This new finding, based on work in both mouse C2C12 cells and primary human muscle cells, marks a significant advance in our understanding of FSHD. What once seemed counterintuitive, more DUX4 protein expression with FEWER copies of the gene, is now beginning to make molecular sense.

These findings will no doubt open up new lines of study in FSHD toward a better understanding of the D4Z4 copy number dependence of the disease but there are other outstanding questions about the molecular underpinning of this disease, including :

  1. How does DUX4 expression mediate muscle cell toxicity?
  2. What is the mechanism underlying D4Z4 repeat expansion and contraction?

At the present time, no good animal models exist for FSHD, mainly because the DUX4 gene is primate specific. Thus non-human cell lines have little applicability in research of this disease and, as with many muscular dystrophies, human primary myoblasts are difficult to obtain due to invasiveness, lack of patient access and weakening patient muscle. GBC PSC-derived human myoblasts (see Caron et al. 2016, funded by FSHD Global) represent a robust, reproducible and scalable source for drug discovery and development for many muscular dystrophy indications. GBC has turned its attention particularly to FSHD with publication of the world's first stem cell derived FSHD model last year and recent presentations of data on small molecule regulators of DUX4 expression in muscle (funded by Friends of FSH Research). With GBC as collaborators of Davide Gabellini, the field should look forward to more advances in FSHD disease research, using pluripotent cell derived muscle towards disease understanding and therapeutic developments.

To learn more about our research and therapeutic developments for FSHD feel free to contact us directly at or visit our website