Muscle health depends on sugar superstructure

August 8, 2013
The diagram shows the structure of a critical portion of the glycan that controls the function of the dystroglycan (DG) protein. Without this sugar modification DG does not function properly, and glitches in the construction of the glycan cause the progressive muscle dysfunction and the brain abnormalities that characterize many forms of muscular dystrophy. Credit: University of Iowa

For many inherited diseases, such as cystic fibrosis or Huntington disease, the disease-causing genetic mutation damages or removes a protein that has an essential role in the body. This protein defect is the root cause of the disease symptoms.

However, for a group of muscular dystrophies known collectively as congenital muscular dystrophies (CMDs), the sequence of the protein that is central to normal function is typically unaffected. Instead, the defects lie in processing proteins—ones that are responsible for modifying the central protein by adding chains (glycans). Either loss of the glycans or disruption of their structure is sufficient to cause .

In a new study, published online Aug. 8 in the journal Science, a University of Iowa team led by Kevin Campbell, Ph.D., has pinpointed not just one, but three proteins that are required for constructing a key, early section of a critical . Mutations affecting any one of these three proteins can cause CMD disease in humans.

The central protein in CMDs is dystroglycan (DG). "It looks like at least 10 to 15 genes encode proteins that contribute to the glycan superstructure that makes DG effective," says Campbell, professor and head of and biophysics at the UI Carver College of Medicine, and a Howard Hughes Medical Institute investigator. "Our goal is to figure out the whole pathway by which the glycan structure is built, since defects in any of the proteins can potentially lead to disease. Knowing which genes are involved is expected to help us develop for these dystrophies, and also ways to screen for potential ."

Normally, DG is modified with a unique sugar chain that acts like glue, allowing DG to attach to other proteins and, by doing so, to reinforce cell membranes in many tissues—including muscle and brain. DG does not function properly without this sugar modification, and glitches in the construction of the glycan cause the progressive muscle dysfunction and the brain abnormalities that characterize many forms of muscular dystrophy.

Almost a dozen are now known to cause DG-related CMDs, which include Fukuyama Congenital Muscular Dystrophy, Walker-Warburg Syndrome, Muscle-Eye-Brain disease, and certain types of limb-girdle muscular dystrophy. All of these mutations affect proteins (enzymes) that are responsible for building DG's unique sugar chain.

The new study assigns a role to three of these causative mutations, showing that the three affected enzymes act sequentially to build an early section of DG's critical glycan. When any of these proteins are mutated, the sugar chain is not constructed correctly and the DG protein loses its function. The first author of the study was Takako Yoshida-Moriguchi, Ph.D., a UI research assistant professor in Campbell's lab

The three enzymes connect a series of sugars together to form the glycan; like stringing beads together to make a necklace. The starting point of the chain is a mannose sugar, which is attached to the backbone of the DG protein. The first enzyme analyzed in the study, called GTDC2, links a glucosamine (GlcNAc) sugar to this starting mannose. The second enzyme, B3GALNT2, then adds a galactosamine sugar to the GlcNAc. Only when this disaccharide is complete can a third enzyme—an unusual type of kinase called SGK196—add a phosphate group to the mannose at the beginning of the chain.

Earlier work from Campbell's lab has shown that this phosphate link is required for other enzymes to build the final section of the sugar chain—the part that actually allows dystroglycan to do its job.

"What I find really exciting is that even with the whole genome having been described, we are still finding novel enzymes that carry out functions we didn't know about even two or three years ago," Campbell says.

Identifying these enzymes and understanding their functions may eventually provide leads for developing therapies to treat CMD and other muscle diseases, Campbell adds.

Explore further: Study reveals enzyme function, could help find muscular dystrophy therapies

More information: "SGK196 is a Glycosylation-Specific O-Mannose Kinase Required for Dystroglycan Function" Science, 2013.

Related Stories

Study reveals enzyme function, could help find muscular dystrophy therapies

January 9, 2012
Researchers at the University of Iowa have worked out the exact function of an enzyme that is critical for normal muscle structure and is involved in several muscular dystrophies. The findings, which were published Jan. 6 ...

New model of muscular dystrophy provides insight into disease development

August 27, 2012
Muscular dystrophy is a complicated set of genetic diseases in which genetic mutations affect the various proteins that contribute to a complex that is required for a structural bridge between muscle cells and the extracellular ...

Genetic editing shows promise in Duchenne muscular dystrophy

June 4, 2013
Using a novel genetic 'editing' technique, Duke University biomedical engineers have been able to repair a defect responsible for one of the most common inherited disorders, Duchenne muscular dystrophy, in cell samples from ...

Recommended for you

Study finds walnuts may promote health by changing gut bacteria

July 28, 2017
Research led by Lauri Byerley, PhD, RD, Research Associate Professor of Physiology at LSU Health New Orleans School of Medicine, has found that walnuts in the diet change the makeup of bacteria in the gut, which suggests ...

Green tea ingredient may ameliorate memory impairment, brain insulin resistance, and obesity

July 28, 2017
A study published online in The FASEB Journal, involving mice, suggests that EGCG (epigallocatechin-3-gallate), the most abundant catechin and biologically active component in green tea, could alleviate high-fat and high-fructose ...

Manipulating a type of brain cell gets weight loss results in mice

July 28, 2017
A new study has found something remarkable: the activation of a particular type of immune cell in the brain can, on its own, lead to obesity in mice. This striking result provides the strongest demonstration yet that brain ...

Team finds link between backup immune defense, mutation seen in Crohn's disease

July 27, 2017
Genes that regulate a cellular recycling system called autophagy are commonly mutated in Crohn's disease patients, though the link between biological housekeeping and inflammatory bowel disease remained a mystery. Now, researchers ...

Study finds harmful protein on acid triggers a life-threatening disease

July 27, 2017
Using an array of modern biochemical and structural biology techniques, researchers from Boston University School of Medicine (BUSM) have begun to unravel the mystery of how acidity influences a small protein called serum ...

CRISPR sheds light on rare pediatric bone marrow failure syndrome

July 27, 2017
Using the gene editing technology CRISPR, scientists have shed light on a rare, sometimes fatal syndrome that causes children to gradually lose the ability to manufacture vital blood cells.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.