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 wellcharacterized 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 Dinaciclib CDK inhibitor homologous to DUX4. DUX4c 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. is an actin-bundling protein associated with AP24534 muscle-attachment sites, specifically located to the Z-disc in mature muscle tissue.