In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. It is an autosomal-dominant myopathy caused by a reduction in the copy number of the D4Z4 macrosatellite repeat located at chromosome 4q35. Interestingly, the reduction of D4Z4 copy number is not sufficient by itself to cause FSHD. A number of epigenetic events appear to affect the severity of the disease, its rate of progression, and the distribution of muscle weakness. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, are altered at the disease locus, causing the de-regulation of 4q35 gene expression and ultimately FSHD.
Recent studies suggest that copy number variations (CNVs) are important for human phenotypic diversity and disease susceptibility. DNA repeats account for 55% of the human genome and a significant fraction of CNVs.
FSHD is an important pathology caused by CNVs of D4Z4 repeats. It is an extremely complicated and fascinating disease, and research into this topic is revealing much about the functional organization of our genome.
An increasing amount of evidence suggests that the 4q35 macrosatellite repeat D4Z4 plays a crucial role in the chromosomal organization of the FSHD region. There is a general consensus that the D4Z4 deletion in FSHD leads to epigenetic alterations that affect the expression profiles of genes within the FSHD region. Unfortunately, despite considerable effort, almost 20 years after the identification of the genetic defect underlying the disease, the causative FSHD gene(s) remains unknown, and no effective treatments for FSHD are currently available.
The heterogeneity in disease manifestation probably reflects heterogeneity in gene expression in FSHD. An interesting possibility, therefore, is that the complexity of FSHD could be explained by considering it to be a contiguous gene syndrome, where the epigenetic alteration of DUX4, FRG1, and other potential genes collaborate to determine the final phenotype. Finally, because DUX4 behaves as a transcriptional activator (Dixit et al., 2007), it could play a direct role in transcriptional overexpression of the other 4q35 genes, providing a unifying model for the molecular mechanism of the disease.