The cause of an incurable muscle-wasting disease – Emery-Dreifuss muscular dystrophy – has been pinpointed for the first time, scientists claim.

scientists examining dataShare on Pinterest
Dr. Sue Shackleton inspects images of muscle cells.
Image credit: University of Leicester

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited condition that causes muscle wasting and stiffening of the joints. The symptoms begin in early childhood and worsen to the point that patients have significantly reduced mobility in later life.

By the time EDMD patients reach adulthood, they also develop heart problems that put them at high risk of heart attack, requiring the insertion of a pacemaker.

The researchers behind the new study – which is published in PLOS Genetics – say that, in some patients, EDMD is caused by mutations in genes responsible for producing a “scaffold” for the nucleus of each cell.

In approximately half of all EDMD patients, however, no mutation has been identified in any of the identified genes.

Now, lead researcher behind the new study Dr. Sue Shackleton, senior lecturer in Biochemistry at the University of Leicester in the UK, describes how they have identified two new genes – SUN1 and SUN2 – that are responsible for causing EDMD in some of these patients.

Like the gene mutations that had previously been identified as compromising the integrity of the nucleus scaffold, SUN1 and SUN2 also produce proteins that form part of the scaffold structure.

The mutated versions of SUN1 and SUN2 interfere with connections between the nucleus and the rest of the cell, resulting in the nuclei being positioned abnormally within muscle cells.

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

She adds that this incorrect positioning could cause damage to the nuclei and also impair muscle contraction, which leads to muscle wasting and weakness:

We therefore believe that incorrect positioning of muscle nuclei may contribute to causing the symptoms of EDMD.”

The findings, she says, “offer the possibility for a novel drug target for the treatment of this disease in the future.”

However, Shackleton says that further research is needed to investigate the disease mechanism and increase understanding of the positioning of nuclei within healthy muscle cells.

In a linked comment, Dr. Marita Pohlschmidt, director of research at the Muscular Dystrophy Campaign, welcomes the results of the study, which she describes as “encouraging.”

“In the future, this will give more people an accurate genetic diagnosis,” Dr. Pohlschmidt says, “helping them to understand the risk of passing it on to their children and to make informed choices with regards to planning for a family.”

“An accurate genetic diagnosis,” she adds, “also means that patients will receive more precise information about the prognosis of the condition. Most importantly, a better understanding of the condition is crucial for the development of treatments for this complex and devastating condition.”

In March of this year, New York-based scientists at Weill Cornell Graduate School of Medical Sciences and the Sloan Kettering Institute of Memorial Sloan-Kettering Cancer Center investigated how skeletal muscle cells with unevenly spaced nuclei are implicated in EDMD.

In the embryonic and larval muscles of the fruit fly, the scientists mutated the Sunday Driver (or “Syd”) gene, which resulted in the unevenly spaced and clustered nuclei characteristic of EDMD. Flies with these abnormally positioned nuclei were shown to be weak crawlers, mimicking the disease state in humans.