In 1990, the genetic defect that underlies facioscapulohumeral muscular dystrophy (FSHD) was located on chromosome 4. Many investigators assumed that one gene would be found that, when flawed, would lead to the development of the symptoms recognized clinically as FSHD. This turned out not to be the case.
No genes were found in the region of chromosome 4 that's shortened in people with FSHD. Instead, the shortened strip of DNA is found in a part of the chromosome where there are no genes. The function of this type of DNA is the subject of scrutiny by research teams around the world.
Recent findings suggest that the flawed DNA on chromosome 4 may play an important role in telling the cell which genes should be processed into proteins and which shouldn’t. All cells have genes that are “turned on” (available to be processed for protein production) and others that are “turned off” (not available for processing). This gene regulation is what distinguishes one type of cell from another — for example, a muscle cell from a bone cell.
In 2002, MDA-funded scientists found that the shortened DNA segment on chromosome 4 may eliminate a site where a molecular braking system normally “lands” and keeps certain genes from being inappropriately turned on.
In 2009, MDA-supported researchers found that pieces of a gene called DUX4 are abnormally activated in FSHD-affected cells, leading to production of potentially toxic proteins. Reinstating the normal braking system or using some other method to block the erroneously activated genes or the proteins made from them seems a likely pathway for the eventual treatment of FSHD.
There may be additional factors involved in FSHD as well. The shortened stretch of DNA on chromosome 4 may, some experts say, change the shape of the chromosome and affect its interactions with distant genes or with an envelope that surrounds each cell nucleus.
For more about research in FSHD, see Impossible Things: Through the looking glass with FSH dystrophy researchers.