Gene discovery linked to muscular dystrophy

An international research team led by scientists from the University of Leicester (UL), UK has pinpointed two new target genes that cause the muscle-wasting disease EDMD.

According to researchers, the discovery could lead to the development of novel drugs which would be able to tackle the disease effectively for the first time.

A full account of the study has been published in the journal PLOS Genetics.

Lead researcher, and UL biochemistry lecturer, Sue Shackleton said: “We are really excited to have identified mutations in two new genes - SUN1 and SUN2 - that are responsible for causing some cases of the muscle wasting disease Emery-Dreifuss muscular dystrophy.”

“Our findings offer the possibility for a novel drug target for the treatment of this disease in the future

Professor Sue Shackleton

EDMD causes muscle wasting and stiffening of the joints. These symptoms usually begin in early childhood and worsen over time, so that many patients have significantly reduced mobility later in life, Shackleton said.

“At the moment there is no cure for this disease and no effective treatment for the muscle wasting and joint stiffening,” she said.

Shackleton said that in some individuals, EDMD is caused by mutations in one of several genes that are responsible for producing proteins that form a structural support network, or ’scaffold’, for each cell’s nucleus.

Unfortunately, the reason why mutations in these genes cause this disease is not fully understood.

However, one theory suggests that the mutations weaken the scaffold structure, leading to damage and death of muscle cells as they continually contract and relax.

What has puzzled researchers, though, it that in roughly 50% of patients with EDMD, no mutation has been identified in any of these genes.

“[Fortunately] our research has identified two new genes that are responsible for causing EDMD in some of these individuals. The proteins produced by these genes also form part of the structural scaffold of the nucleus,” Shackleton said.

Key to this discovery is the identification of a novel way in which these mutations act in muscle cells, Shackleton said.

“Our research has shown that the mutated SUN1 and SUN2 proteins interfere with connections between the nucleus and the rest of the cell and that this results in abnormal positioning of the nuclei within the muscle cells.

“The nuclei are normally anchored at the edges of muscle cells, probably so that they do not get in the way of the main structures of the cell that are involved in muscle contraction.”

According to Shackleton, incorrect positioning could further damage the nuclei and could also impair muscle contraction, leading to the muscle wasting and weakness seen in EDMD sufferers.

Early research suggests that incorrect positioning of muscle nuclei may contribute to causing the symptoms of EDMD, but further research is now needed to investigate, and potentially confirm, this new disease mechanism and gather increased understanding of how nuclei are positioned in normal muscle cells.

“Our findings offer the possibility for a novel drug target for the treatment of this disease in the future,” Shackleton said.

EDMD, a genetically inherited disease, affects around 1,000 people in the UK, and more accurate genetic diagnosis could help people understand the risk of passing it on to their children.

Emily Beale, whose son Tayler, 11, has EDMD, said: “We are thrilled that someone is researching Emery-Dreifuss muscular dystrophy and we hope that Tayler will see a treatment within his lifetime.”