Italian researchers make a major discovery into a common form of muscular dystrophy

A new study, published in the international scientific journal Cell, has identified that a novel defect in gene regulation, never before seen in a human disease, is the cause of one of the most common forms of muscular dystrophy: Facioscapulohumeral muscular dystrophy (FSHD). The discovery gives hope to the 500,000 people around the world affected by the slowly crippling disease, which causes progressive loss of control of facial, shoulder, upper arm, hip girdle and leg muscles, making it difficult to walk, lift the arms or even smile.

The research also identified a potential therapeutic target for the disease and may be of help in explaining other enigmatic diseases including some forms of diabetes and cancer. It was in part funded by the FSHD Global Research Foundation, an Australian organisation.

“This breakthrough has been a long time coming and I am incredibly proud that this research was funded by charitable donations raised by our foundation in Australia,” said Bill Moss AM, Chairman of the Sydney-based foundation.

“The discovery encourages us to work harder to raise more funds to attempt to find a treatment or cure for this debilitating disease.”

This work was described in a paper published in Cell by Davide Gabellini, a researcher in the Dulbecco Telethon Institute at the IRCCS San Raffaele in Milan, Italy, where he directs the Gene Expression and Muscular Dystrophy Unit.

For years, the mechanism underlying the FSHD disease has eluded scientists, but this study sheds light by describing an entirely new and complex mechanism.

FSHD occurs because a piece of genetic material (RNA) that does not produce any protein (noncoding) allows neighbouring genes to become hyperactive. In 1992, the cause of FSHD had been traced to the deletion of genetic material (DNA) in a region on chromosome 4, which consists of repeating units of DNA called D4Z4. At that time, many scientists had assumed that FSHD would follow the classic mechanism of other genetic diseases: mutation of a gene within the D4Z4 with loss of its ability to produce a protein. Subsequent research, conducted by Gabellini when he was in the US, indicated the opposite: FSHD is not caused by the loss of a protein, but by an excess of protein production.

The next step was to understand how D4Z4 is able to regulate this protein production from within the FSHD region of the chromosome. With this new study, the group directed by Gabellini has shown that the loss of repeated sequences in D4Z4 allows for the production of new noncoding genetic material (RNA) that researchers have called DBE-T. DBE-T was found to be directly responsible for the activation and protein production from genes in the FSHD chromosome region.

“The mechanism we described is new and represents an interesting model to address other complex diseases in which the classical candidate gene approach has not been successful,” said Gabellini.

From examining muscle biopsies, Gabellini and his colleagues, Daphne Cabianca and Valentina Casa, found that DBE-T genetic material (RNA) is produced exclusively in FSHD patients, not in healthy subjects. They also demonstrated experimentally that, by blocking the production of DBE-T RNA, one can produce a normalisation of gene expression in the FSHD chromosome region. This suggests that DBE-T may be a valid therapeutic target for the control of the FSHD disease. Similar DNA regions that do not produce proteins (noncoding) are repeated thousands of times in our chromosomes and represent over 50% of human genetic material (DNA), but have until recently been mostly ignored.

“There is a good chance that alterations in other repetitive sequences in our genome are responsible for bad gene regulation in other diseases,” said Gabellini. For example, regions of DNA are repeated near the insulin gene and their alteration may predispose to diabetes.

Moss concluded: “I’d like to congratulate Davide Gabellini and his team and thank all the Australians who have supported the work of the FSHD Global Research Foundation in Australia.”

On 14 July, the foundation will hold its annual black tie Chocolate Ball in Sydney to raise funds to continue to support FSHD research.