The D4Z4 unit contains a gene called DUX4, which is toxic to muscle cells. In a series of landmark studies that unfolded over the past several years, an international team discovered that DUX4 is normally only expressed during embryonic development and in the male germline (in stem cells that give rise to sperm). DUX4 is not supposed to be active in other tissues, and the D4Z4 units act like bricks in a firewall, preventing the information in the DUX4 gene from getting out.
In FSHD patients, however, the reduced number of D4Z4 weakens the firewall, allowing DUX4 to be abnormally expressed in adult muscle in a quite remarkable pattern; only a small subset of muscle cell nuclei expresses abundant levels of DUX4. The result is devastating, as skeletal muscles degenerate, typically in the face (facio-), shoulder blades (scapula-) and upper arms (humeral), the anatomical areas initially affected that gave rise to the name of this dystrophy. The weakened muscles make it difficult for patients to blink or smile, or raise their arms overhead. FSHD can also affect leg and hip muscles, leading to falls, broken bones and dependence on a scooter or wheelchair. Some patients endure hearing loss and/or abnormalities of blood vessels in the back of the eye.
Around 500,000 people have FSHD worldwide. It is among the three most common muscular dystrophies, and between one and two percent of the general population carries a genetic risk factor linked to FSHD.
The newly published mouse model contains 2.5 copies of the D4Z4 unit, a truncated number comparable to that seen in human FSHD patients. A second line of mice was created with 12.5 D4Z4 units, corresponding to an unaffected person. Both mouse models had high levels
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