In this study, an international team has published the results of a decade’s worth of work: they have developed a new mouse model with the same genetic alterations that cause human facioscapulohumeral muscular dystrophy (FSHD). This model can be used to evaluate and optimise future therapeutic strategies for FSHD. The molecular underpinnings of types 1 and 2 FSHD have only been fully understood within the last few years. In type 1 FSHD, which affects approximately 95% of people with the disorder, the underlying cause is a shortened section of DNA in the D4Z4 repeat region of chromosome 4, coupled with a disease-permitting sequence at the tip of chromosome 4. The shortened D4Z4 region leads to activation of genes that would normally be inactivated after early human development. Type 2 FSHD, which affects about 5% of people with the disease, is caused by the same disease-permitting sequence observed at the tip of chromosome 4. Despite these differences between FSHD types 1 and 2, the result is the same: inappropriate activation of at least one gene that normally would be silent after early development. It is this abnormal molecular process, which leads to the activation of the normally silent DUX4 gene, that is replicated by the newly developed mice. In both types of FSHD, the DUX4 gene produces DUX4 protein, which seems to disrupt muscle fibres and may affects other tissues as well.Unlike humans, mice do not normally have a D4Z4 repeat array that causes FSHD when modified. Therefore, FSHD mouse models have been particularly difficult to create. Previously developed FSHD mice replicated some aspects of the disease but not the actual underlying molecular defects. The new mice, called D4Z4-2.5 mice, mimic some of these underlying molecular causes. The mice show many, but not all, of the same physical consequences seen in humans with the disorder. The new FSHD mice share several important aspects of human FSHD, such as the production of DUX4 protein in some muscle cells and interference with maturation of muscle cells in which DUX4 was produced. In addition, when the researchers examined the activity of genes exposed to DUX4 in both mouse and human muscle cells, they found many similarities. Some of these, could potentially be developed as biomarkers to follow FSHD progression and treatment response.
