A newly developed research mouse that has the same combination of genetic alterations that causes human facioscapulohumeral muscular dystrophy (FSHD) is expected to change the way research in this disease is conducted, possibly speeding the development of therapies.
Unlike humans, mice normally do not have a DNA structure called a D4Z4 repeat array that, when altered, causes FSHD. Therefore, FSHD research mice 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 — dubbed 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.
MDA research grantee Silvère van der Maarel at Leiden University Medical Center in the Netherlands, and colleagues, published their findings online in PLoS Genetics April 4, 2013.
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 some 95 percent 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 "permissive" (disease-permitting) sequence at the tip of chromosome 4.
The shortened D4Z4 region relaxes the chromosome's structure in that area, which leads to activation of genes that normally would be inactivated after early human development.
Type 2 FSHD, affecting some 5 percent of people with the disease, is caused by the same "permissive" sequence at the tip of chromosome 4 that's seen in type 1 FSHD, coupled with a mutation in a gene on a different chromosome that causes relaxation of the D4Z4 region on chromosome 4 the same way the shortened section does in type 1.
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 wreak havoc in muscle fibers and may have troublesome effects in other tissues as well.
Only humans and other primates have the DNA for the DUX4 protein embedded in the D4Z4 region, so the scientists who developed the new FSHD mouse had to insert this gene and its surroundings into the rodent genome to recreate the effects of human FSHD in these animals.
The researchers say the new FSHD mice embody several important aspects of human FSHD, including:
In addition, when the investigators looked at the activity of genes exposed to DUX4 in both mouse and human muscle cells, they found many similarities. Some of these, they said, potentially could be developed as biomarkers to follow FSHD progression and treatment response.
The study authors note that the new FSHD mice did not have all of the muscle-related FSHD symptoms (such as limb muscle weakness), although they did show some delay in muscle regeneration after injury. It may take multiple rounds of muscle damage over time for obvious muscle abnormalities to develop.
The new mice, the study authors say, can be utilized to "evaluate and optimize future therapeutic strategies for FSHD."