Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Discovery of new form of dystrophin protein could lead to therapy for some DMD patients


Scientists have discovered a new form of dystrophin, a protein critical to normal muscle function, and identified the genetic mechanism responsible for its production.

Studies of the new protein isoform, published online Aug. 10 in Nature Medicine and led by a team in The Research Institute at Nationwide Children's Hospital, suggest it may offer a novel therapeutic approach for some patients with Duchenne muscular dystrophy, a debilitating neuromuscular condition that usually leaves patients unable to walk on their own by age 12.

Duchenne muscular dystrophy, or DMD, is caused by mutations in the gene that encodes dystrophin, which plays a role in stabilizing the membrane of muscle fibers. Without sufficient quantities of the protein, muscle fibers are particularly susceptible to injury during contraction. Over time, the muscle degenerates and muscle fibers are slowly replaced by fat and scar tissue. Many different types of mutations can lead to DMD, some of which block dystrophin production altogether and others that result in a protein that doesn't function normally.

In 2009, a team led by Kevin Flanigan, MD, a principal investigator in the Center for Gene Therapy at Nationwide Children's, published two studies describing patients whose genetic mutation was located in a exon 1, at the beginning of the gene. This mutation should have made natural production of functioning dystrophin impossible, resulting in severe disease.

... more about:
»DMD »IRES »RNA »exons »fibers »mutations »symptoms

However, the patients had only minimal symptoms and relatives carrying the same mutations were identified who were walking well into their 70s. Muscle biopsies revealed that, despite the genetic mutations, the patients were producing significant amounts of a slight smaller yet functioning dystrophin. In the 2009 studies, Dr. Flanigan's group demonstrated that translation of this dystrophin did not begin in exon 1, as usual, but instead began later in the gene in exon 6, although the mechanism controlling this alternate translation remained unknown.

In their latest study, Dr. Flanigan's team has found the explanation. In order to utilize the protein-building instructions they carry, exons are first transcribed into a final genetic blueprint called messenger RNA. Under normal conditions, the messenger RNA is marked at its very beginning by a special molecular cap that is critical for recruiting ribosomes, the cellular structures responsible for translation of the gene into a protein. Most cases of DMD are due to mutations that interrupt the translational activity of ribosomes.

In explaining the mild symptoms seen in many patients with mutations in the first exons of the dystrophin gene — including the group of patients they first described in 2009 — the researchers have now demonstrated that dystrophin can be produced by an alternate cellular mechanism in which capping of the messenger RNA is not required. This newly described mechanism makes use of an internal ribosome entry site, or IRES, found within exon 5 in the dystrophin gene, allowing initiation of protein translation within exon 6 that can then proceed in the normal fashion along the rest of the gene.

"This alternate translational control element is encoded within the dystrophin gene itself, in a region of the gene that evolution has highly conserved," Dr. Flanigan said. "This suggests that the dystrophin protein that results from its activation plays an important but as of yet unknown role in cell function — perhaps when muscle is under cell stress, one of the conditions under which IRES elements are typically activated."

Although clinical trials are currently investigating drugs to treat the more common gene mutations found in the middle of the dystrophin gene, no current therapies are specifically directed toward the approximately 6 percent of patients with mutations affecting the first four exons. Although many of these patients have relatively mild disease, many others have much more severe symptoms. If scientists could figure out a way to activate IRES in those patients, they may be able to produce enough dystrophin to lessen muscle degeneration, Dr. Flanigan said.

To study that possibility, his team is developing different approaches to trigger the IRES, using a new DMD mouse model they have developed. One of these approaches, called exon skipping, is based on the removal of an exon early in the gene in order to mimic the IRES-activating mutations found in minimally affected patients.

"Rather than intending this as a personalized therapy, we are developing this as a tool that could be used for all patients harboring a mutation within the first few exons of dystrophin," said Nicolas Wein, PhD, lead author of the new study and a postdoctoral scientist in the Center for Gene Therapy at Nationwide Children's. "Using this approach, we have already shown that we are able to restore running ability in our new mouse model of DMD. We hope to translate this into clinical trials in DMD patients in the future."


The research was supported in part by the National Institutes of Health and the nonprofit organization CureDuchenne.

Gina Bericchia | Eurek Alert!
Further information:

Further reports about: DMD IRES RNA exons fibers mutations symptoms

More articles from Health and Medicine:

nachricht Laboratory study: Scientists from Cologne explore a new approach to prevent newborn epilepsies
24.11.2015 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)

nachricht U of T research sheds new light on mysterious fungus that has major health consequences
23.11.2015 | University of Toronto

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Innovative Photovoltaics – from the Lab to the Façade

Fraunhofer ISE Demonstrates New Cell and Module Technologies on its Outer Building Façade

The Fraunhofer Institute for Solar Energy Systems ISE has installed 70 photovoltaic modules on the outer façade of one of its lab buildings. The modules were...

Im Focus: Lactate for Brain Energy

Nerve cells cover their high energy demand with glucose and lactate. Scientists of the University of Zurich now provide new support for this. They show for the first time in the intact mouse brain evidence for an exchange of lactate between different brain cells. With this study they were able to confirm a 20-year old hypothesis.

In comparison to other organs, the human brain has the highest energy requirements. The supply of energy for nerve cells and the particular role of lactic acid...

Im Focus: Laser process simulation available as app for first time

In laser material processing, the simulation of processes has made great strides over the past few years. Today, the software can predict relatively well what will happen on the workpiece. Unfortunately, it is also highly complex and requires a lot of computing time. Thanks to clever simplification, experts from Fraunhofer ILT are now able to offer the first-ever simulation software that calculates processes in real time and also runs on tablet computers and smartphones. The fast software enables users to do without expensive experiments and to find optimum process parameters even more effectively.

Before now, the reliable simulation of laser processes was a job for experts. Armed with sophisticated software packages and after many hours on computer...

Im Focus: Quantum Simulation: A Better Understanding of Magnetism

Heidelberg physicists use ultracold atoms to imitate the behaviour of electrons in a solid

Researchers at Heidelberg University have devised a new way to study the phenomenon of magnetism. Using ultracold atoms at near absolute zero, they prepared a...

Im Focus: Climate Change: Warm water is mixing up life in the Arctic

AWI researchers’ unique 15-year observation series reveals how sensitive marine ecosystems in polar regions are to change

The warming of arctic waters in the wake of climate change is likely to produce radical changes in the marine habitats of the High North. This is indicated by...

All Focus news of the innovation-report >>>



Event News

Fraunhofer’s Urban Futures Conference: 2 days in the city of the future

25.11.2015 | Event News

Gluten oder nicht Gluten? Überempfindlichkeit auf Weizen kann unterschiedliche Ursachen haben

17.11.2015 | Event News

Art Collection Deutsche Börse zeigt Ausstellung „Traces of Disorder“

21.10.2015 | Event News

Latest News

Harnessing a peptide holds promise for increasing crop yields without more fertilizer

25.11.2015 | Agricultural and Forestry Science

Earth's magnetic field is not about to flip

25.11.2015 | Earth Sciences

Tracking down the 'missing' carbon from the Martian atmosphere

25.11.2015 | Physics and Astronomy

More VideoLinks >>>