A Long-Awaited Mouse Offers a New Animal Model for FSH Muscular Dystrophy

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In a project started ten years ago with a grant from the FSH Society, a mouse engineered with the genetic defect for facioscapulohumeral muscular dystrophy (FSHD) was unveiled today. The patient-driven charity hailed the latest advance against one of the most common and devastating muscular dystrophies.

Dr. Silvère van der Maarel

We hope that in the near future these mouse models will serve an important purpose in drug development programs for FSH dystrophy.

It’s a truism of medical research that humans are cheaper and better to study than animals. People don’t require sterile cages, gourmet chow or 24/7 monitoring by a battalion of technicians. And because of species differences, diseases and cures in animals often don’t accurately portray the human condition. Still, animals remain invaluable because they can be manipulated and probed in ways that human volunteers (and ethical boards) might frown upon.

When a disease is unique to humans, creating an animal model presents a particular challenge. Such has been the case with facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies. Past efforts resulted in mice that exhibited features of FSHD, but which required cranking up the expression of genes under conditions that researchers fear were too dissimilar to the human disorder.

Now an international team has published a mouse model that appears more promising. The result of a decade’s worth of work, during which scientific understanding of FSHD exploded, the new mouse was published today in an exhaustive, 58-page article in PLoS Genetics. “We hope that in the near future these mouse models will serve an important purpose in drug development programs for FSHD,” remarked senior author Silvère van der Maarel of Leiden University in the Netherlands.

Other members of the team work at the Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; King’s College London, United Kingdom; Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; and the University of Rochester Medical Center, Rochester, New York, USA.

The herculean project was initiated in 2003 by the FSH Society’s Marjorie Bronfman Fellowship grant. The patient-driven charity was seeking a definitive mouse model based on a genetic unit called D4Z4. Normally, people have ten or more of these units, repeated one after the other near the tip of chromosome 4. The majority of FSHD patients, in contrast, have fewer than ten.

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 of DUX4 in germline cells, as well as in embryonic stem cells and in developing embryos. Only in mice with 2.5 D4Z4 units, was DUX4 also seen in all skeletal muscles, albeit at low levels and in highly variable ways.

Further detailed analysis of DUX4 expression revealed that mice with 2.5 D4Z4 units also had the remarkable DUX4 expression pattern seen in human FSHD patients: only a small subset of muscle cell nuclei expressed abundant levels of DUX4. In mice with 12.5 units of D4Z4, by contrast, DUX4 was almost completely absent from muscles.

In terms of molecular activity, DUX4 in muscle cells appeared to trigger other genes in networks similar to those previously reported in tissue collected from human FSHD patients. In addition, the D4Z4 units in these mice had reduced levels of “methylation”, which one can think of as the “mortar” that seals together the D4Z4 bricks in the firewall. With less methylation, the system cannot suppress the expression of toxic DUX4. The mice with 12.5 D4Z4 units had high levels of methylation, which was consistent with their low expression of DUX4.

In other words, these “D4Z4-2.5” mice appear to faithfully mimic key features of FSHD. But the researchers warn that the differences between the 2.5-unit and 12.5-unit mice could potentially be caused by as-yet-unknown differences in the genome sites where the D4Z4 units were inserted in the two mouse strains. In addition, it took the researchers 450 tries before they succeeded in generating the D4Z4-2.5 line, so there could be some unique mechanism at work in this line.

Nonetheless, the researchers are optimistic that the new mouse will provide new insights into DUX4’s role in FSHD. For example, they hope to learn “why, how and when are sudden bursts of DUX4 expression in skeletal muscle regulated.” In addition, they say, “As it was recently demonstrated that the detrimental effects of DUX4 expression in mouse muscle can be reversed by RNA interference, our model may also serve well therapeutic intervention studies targeting DUX4 expression in skeletal muscle.”

The seed planted by the FSH Society generated additional major funding from other sources (including the Prinses Beatrix Spierfonds, National Institutes of Health, Muscular Dystrophy Association, Stichting FSHD, Friends of FSH Research, Fields Center for FSHD and Neuromuscular Research, the Geraldi Norton Foundation and the Eklund Family) to complete the ten-year analysis of the new mouse model. “I am very grateful to the Society for their longstanding support of our studies,” says Van der Maarel.

“Through advocacy and strategic investments in research, the FSH Society has helped bring the FSHD field to the threshold of drug discovery,” says June Kinoshita, Executive Director of the Society. But with the U.S. National Institutes of Health facing a $2.4 billion reduction in its budget because of the sequester, this is a critically important time for private donors and the public to keep funds flowing to FSHD research, she says. “We have to make sure patients today will be helped in their lifetimes.”

In addition to investing in scientific research, the FSH Society offers a community of support, news and information for FSHD patients and families, as well as to anyone experiencing symptoms and needs help finding qualified physicians to diagnose their condition. The Society was recently awarded its fifth consecutive Charity Navigator 4-star rating, placing it among the top-performing charities in America.

The FSH Society can be contacted at 781-301-6060 or on the Web at http://www.fshsociety.org.

Krom YD, Thijssen PE, Young JM, den Hamer B, Balog J, et al. (2013) Intrinsic Epigenetic Regulation of the D4Z4 Macrosatellite Repeat in a Transgenic Mouse Model for FSHD. PLoS Genet 9(4): e1003415. doi:10.1371/journal.pgen.1003415

The article is available online at: http://www.plosgenetics.org/doi/pgen.1003415

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