Facioscapulohumeral muscular dystrophy, or FSHD, primarily affects muscles of the face, shoulders and upper arms. It is the third most common muscular dystrophy, following Duchenne muscular dystrophy and myotonic muscular dystrophy, affecting 1 in 20,000 individuals 
. Onset of muscle weakness in FSHD patients most commonly occurs between puberty and the second decade of life, ultimately leading to patients becoming wheelchair-bound 
. Compared to the majority of muscular dystrophies, FSHD is unique in its very low rate of any respiratory or cardiac muscle involvement, which is often the eventual cause of death for patients with other forms of muscular dystrophy 
. As such, patients with FSHD typically live a normal lifespan, but suffer a severely decreased quality of life.
The molecular basis of FSHD is still under debate, although the genetic event linked with FSHD has been identified to be in the subtelomeric region on the long arm of chromosome 4 
. This region, denoted as 4q35, contains a series of 3.3 kb tandem repeat elements, which have been termed D4Z4 repeats 
. Unaffected individuals have 11 to 150 D4Z4 repeats, but patients with FSHD have had this region truncated to 10 or less 
. Efforts to identify the molecular basis of this disease have been hampered, however, because the truncation associated with FSHD is not within a well-characterized gene coding or promoter region.
Multiple models have been proposed to explain how a D4Z4 repeat truncation is linked to FSHD, reviewed in 
. The primary model is that the loss of D4Z4 repeats increases expression of a double homeobox transcription factor DUX4c
, a putative gene centromeric to the D4Z4 repeats and highly homologous to DUX4 
has been shown to be up-regulated in FSHD biopsies and primary myoblasts, possibly leading to induction of the MYF5
myogenic regulator, which serves to inhibit differentiation and activate proliferation 
. In addition, overexpression of DUX4
in other cell lines has been shown to cause apoptosis and impair myogenesis in both cell culture models and zebrafish development 
. A recent chromosomal analysis of affected and unaffected 4q35 alleles has determined that FSHD is linked to a single nucleotide polymorphism located distal to the last D4Z4 repeat 
, which stabilizes the DUX4
transcript through polyadenylation and may result in elevated protein levels and cytotoxicity via still unknown mechanisms.
A second model proposes that the loss of D4Z4 repeats may increase the available pool of a repressive complex comprised of YY1, HMG2B and nucleolin that is normally bound to D4Z4 repeats. YY1 interacts with Ezh2, a histone lysine methyltransferase, playing a key role in expression of muscle genes during embryonic development 
and MeCP2, a methyl CpG binding protein involved in Rett syndrome 
. In addition, YY1 may also be able to interact with the chromatin insulator CTCF 
. HMGB2 may affect the maintenance of heterochromatic regions by interacting with SP100B and subsequently HP1, establishing higher-order chromatin structures 
. In contrast, nucleolin may have an opposite effect on heterochromatin formation as it serves to decondense chromatin through displacement of histone H1 
. Perturbations in any of these proteins due to loss of D4Z4 repeats resulting in increased chromatin accessibility may cause gene deregulation in trans
and play a role in the pathogenesis of FSHD.
A third model suggests that D4Z4 may serve as nucleating sites for local transcriptional repression involving the previously mentioned YY1 complex. Loss of D4Z4 may lift repression in cis
of the 4q35 region and thus the nearby genes FRG1
and ANT1 
. Additionally, the identification of a nuclear matrix attachment site (S/MAR) and its disassociation from the nuclear matrix in FSHD patients may change the arrangement of DNA loop domains, causing increased transcription of FRG1
and FRG2 
. Presently, it is unclear as to which or how many of these many non-exclusive mechanisms play a causal role in the pathogenesis of FSHD.
Previously, it has been observed that there may be increased transcriptional activation of FRG1
, the three genes upstream of the D4Z4 tandem repeat elements, in muscle of human FSHD patients 
; however, these results were not observed in another patient study 
. Unfortunately, generating a relevant mouse model to study FSHD has been exceptionally difficult because mice do not have D4Z4 repeats in an analogous chromosomal setting. Acting under the assumption that overexpression of FRG1
plays a causative role in the development of FSHD, transgenic mice were generated expressing each of these individual genes under the human skeletal actin promoter, specific for expression in muscle, which resulted in the identification of a potential mouse model for FSHD. In contrast to transgenic mice overexpressing FRG2
, only transgenic mice overexpressing FRG1
appear to have symptoms characteristic of muscular dystrophy 
. It should be noted, however, that the FRG1
transgenic mouse model that resulted in dystrophic phenotypes had FRG1 skeletal muscle protein levels considerably higher than that observed in FSHD patients.
Facioscapulohumeral muscular dystrophy region gene-1 (FRG1
) is an actin-bundling protein associated with muscle-attachment sites, specifically located to the Z-disc in mature muscle tissue 
has been shown to play a crucial and specific role in muscle development of Xenopus laevis
, further implicating its importance in muscle development and maintenance 
. Recently, Bodega et al. showed that the FRG1
gene was prematurely expressed during FSHD myoblast differentiation, thereby suggesting that the number of D4Z4 repeats in the array may affect the correct timing of FRG1
Based on this work, we hypothesized that the dystrophic phenotype in FRG1 transgenic mice is caused, at least in part, by decreased proliferation in the muscle satellite cell population, which are the cells responsible for maintaining proper muscle regenerative potential. Satellite cells are often thought of as muscle stem cells, proliferating when there is a need for either muscle repair or growth and then differentiating into skeletal muscle. We have observed that increased levels of FRG1 impair normal satellite cell proliferation and may contribute to disease progression by limiting the pool of cells to repair damaged muscle and/or delaying the kinetics of repair.