DUX4

Facioscapulohumeral muscular dystrophy

Changes in the D4Z4 region of chromosome 4, which contains the DUX4 gene, cause facioscapulohumeral muscular dystrophy. This disorder is characterized by muscle weakness and wasting (atrophy) that worsens slowly over time. Two types of the disorder have been described: type 1 (FSHD1) and type 2 (FSHD2). Both types result from hypomethylation of the D4Z4 region, in which the DNA has fewer methyl groups attached than normal. In FSHD1, hypomethylation occurs because the D4Z4 region is abnormally shortened (contracted), containing between 1 and 10 repeats instead of the usual 11 to 100 repeats. In FSHD2, hypomethylation most often results from mutations in a gene called SMCHD1, which normally hypermethylates the D4Z4 region.

Hypomethylation of the D4Z4 region prevents the DUX4 gene from being silenced in cells and tissues where it is usually turned off, such as adult muscle cells. However, hypomethylation of the D4Z4 region results in facioscapulohumeral muscular dystrophy only when it occurs with a "permissive" chromosome 4. The "permissive" chromosome contains a working pLAM sequence, which allows protein to be produced from the abnormally active DUX4 gene. Researchers believe that the protein influences the activity of other genes, particularly in muscle cells. However, it is unknown how presence of the DUX4 protein damages or destroys these cells, leading to progressive muscle weakness and atrophy.