Chromosome 4 Gene Implicated in FSH Dystrophy

Researchers at the Institute of Genetics, University of Nottingham (UK), with colleagues there and at other British institutions, say they’ve found the first clear evidence for the existence of a gene in the region of chromosome 4 known to be associated with facioscapulohumeral muscular dystrophy (FSHD). The team, which included MDA grantee Jane Hewitt at Nottingham, says the find offers a new avenue of research in the study of the disease.

Although missing pieces (deletions) in the D4Z4 region of chromosome 4 have long been known to cause FSHD, the exact mechanism by which that happens is still not understood.

Until now, the search for a gene in the implicated region has proven elusive, and numerous theories to explain the relationship between D4Z4 and FSHD have been proposed (see “Impossible Things,” Quest, March-April 2007).

In a paper currently in press and posted online May 1 on the American Journal of Human Genetics Web site, Hewitt and colleagues describe how they probed the origins and function of the DUX4 gene in the D4Z4 region.

Using DNA sequence data from human and animal genome projects, the researchers traced the evolutionary history of the DUX4 gene and identified it or similar genes in a variety of species, including some of the higher primates (chimpanzee, orangutan and rhesus macaque) and nonprimates (tree shrew, mouse and rat). The researchers say the widespread nature of DUX4 supports its having an important function and implies that it probably carries instructions for (codes for) a protein.

They describe a model of FSHD in which deletions in the D4Z4 region of chromosome 4 could cause overactivity of the DUX4 gene, leading to overproduction of the DUX4 protein.

Evidence for a DUX4 coding function in humans has never been demonstrated, but the researchers say there are several ways this might be explained. The protein might be produced only rarely; or it may be limited to a particular developmental time frame or spatial location; or it may possess characteristics that make it resistant to traditional identification methods.

Current explanations for FSHD don’t take into account a coding function for the D4Z4 region, and researchers disagree about whether an existing mouse model of FSHD reflects the human disease. (That model is based on overproduction of the FRG1 protein from a gene near, but not inside, the D4Z4 region.)

Hewitt and colleagues say the identification of a D4Z4 region and a DUX4-like gene in the mouse provide a basis for developing an additional FSHD mouse model that may offer important clues to the disease.