University of Manchester scientists have mapped the mutations in the tiny protein chains that cause a subtype of muscular dystrophy. Published in the journal Nature Communications, the study provides a major insight into the muscular dystrophy subtype known collectively as Collagen VI-related dystrophy—or COL6-RD for short.

The team are the first ever to determine the high resolution structure of collagen VI- one of the networks of protein molecules that give our tissues mechanical strength and the ability to stretch and bend.

Called the extracellular matrix, the protein network also enables cells to sense their environment and communicate with one another in response to mechanical forces.

COL6-RD, which includes Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM), can cause a range of symptoms including muscle weakness, joint contractures, decreased muscle tone, and weak breathing muscles.

It is one of a number muscular dystrophy subtypes and others include the more prevalent Duchenne- caused by mutation of another protein—for which scientists are developing gene therapies.

However, so far equivalent therapies have not been developed for COL6-RD.

Collagens are the most abundant extracellular matrix proteins, and form long fibers many times smaller than a human hair, called microfibrils.

Collagen VI forms one type of microfibril, taking on the appearance of a large bead-like structure, consisting of three separate protein chains, that twist and fold together.

The research required the scientists to develop small fragments of collagen VI, which they called mini-collagens. Mini-collagens will be useful tools for studying or even treating the diseases associated with collagen VI mutations.

Lead author of the study Clair Baldock, Professor of Biochemistry at the University of Manchester said, “It is extremely important to understand where mutations in the tiny protein chains called collagen VI that cause a subtype of muscular dystrophy are, to help in the design of future treatments.

“Using a technique called cryogenic-electron microscopy—which can magnify collagen VI hundreds of thousands of times—we were able to determine the organization of parts of collagen VI and map the disease mutations.

“That provides an opportunity for scientists to design drugs which specifically target the mutations by focusing only on what’s broken.

She added, “We are the first group to determine the high resolution structure of collagen VI; until now, no- one has been able to show the locations of these mutations on the collagen VI structure.

“This is an important step along the path of finding ways to treat these types of muscular dystrophy and will provide momentum to accelerate scientific discovery in this area.

“We hope that our structure will provide vital information to help the scientific community develop treatments, such as gene therapy, for collagen VI-RD.

“This provides some hope to people with muscular dystrophy that one day treatments will be available to improve their quality of life and help them to stay active and independent.”