Featured Research

from universities, journals, and other organizations

New form of muscular dystrophy identified: Mutation in important muscle protein causes muscle disease and cognitive impairment

Date:
March 10, 2011
Source:
University of Iowa Health Care
Summary:
An international collaboration and a single patient with mild muscle disease and severe cognitive impairment have allowed researchers to identify a new gene mutation that causes muscular dystrophy. Furthermore, by engineering the human gene mutation into mice, the researchers have created a new mouse model that could help screen potential drugs to treat this type of muscular dystrophy.

An international collaboration and a single patient with mild muscle disease and severe cognitive impairment have allowed University of Iowa researchers to identify a new gene mutation that causes muscular dystrophy.

Furthermore, by engineering the human gene mutation into a mouse, the researchers, led by Kevin Campbell, Ph.D., professor and head of molecular physiology and biophysics at the UI Carver College of Medicine and a Howard Hughes Medical Institute investigator, have created a new mouse model that could help screen potential drugs to treat this type of muscular dystrophy.

The study, which is published in the March 10 issue of the New England Journal of Medicine, also ties together almost two decades of research on dystroglycan, an important muscle protein that is abnormal in a group of congenital muscular dystrophies, which often involve brain abnormalities.

Normal dystroglycan protein is extensively modified with added sugar chains. This modification allows dystroglycan to interact with other cellular proteins and by doing so provide structural strength and integrity to cell membranes in many tissues, including muscle and brain.

Several enzymes are involved in adding sugar chains onto the dystroglycan protein, and mutations in these enzymes cause congenital muscular dystrophies collectively known as secondary dystroglycanopathies. In these disorders, which include Fukuyama Congenital Muscular Dystrophy, Walker-Warburg Syndrome, Muscle-Eye-Brain disease, Congenital Muscular Dystrophy 1C and 1D, and limb-girdle muscular dystrophy 2I, too few sugar groups are added to the dystroglycan protein. The resulting dystroglycan does not attach properly to other proteins leading to muscle and neurological problems.

"In all these muscular dystrophies, the core dystroglycan protein is normal, so there was always the question of, 'Did the sugar-adding enzymes act on other proteins as well as dystroglycan, and could those other unknown proteins be important for muscular dystrophy?'" said Campbell, who also is a UI professor of internal medicine and neurology and holds the Roy J. Carver Chair of Molecular Physiology and Biophysics. "Finding a mutation in the dystroglycan protein itself, which produces similar muscle and brain problems as are seen in these 'secondary' muscular dystrophies, suggests that dystroglycan is the major substrate, and probably the only substrate, in these other diseases."

Campbell's team, including UI postdoctoral fellow Yuji Hara, Ph.D., collaborated with colleagues in Turkey, Switzerland, England, New York and California to study the mutation found in a Turkish patient with a mild muscular dystrophy and severe cognitive impairment.

The team found that all genes for the known sugar-adding enzymes were normal, but there was a single mutation in the gene for the dystroglycan protein. Further analysis showed that the mutated protein did not get its full complement of added sugar molecules, and was not able to interact efficiently with its normal cell partners either in muscle or brain. The researchers showed that the mutation blocked normal interaction between dystroglycan and one of the sugar-adding enzymes, thus disrupting the addition of sugar chains required for dystroglycan to function.

The researchers then engineered the genetic mutation into mouse dystroglycan and found that the animals have muscle and brain abnormalities similar to the Turkish patient and to patients with the secondary dystroglycanopathies. Taken together, the data strongly suggests that the mutation causes neurological problems as well as muscle disease as a consequence of impaired dystroglycan modification.

"A particularly exciting aspect of this study is the new mouse that we have developed, which has the mutation in the dystroglycan protein," Campbell said. "It will give us a really good model to test therapies for their potential to boost the action of the sugar-adding enzymes and see if that helps reduce the severity of the muscle and neurological symptoms."

With the discovery of the mutation in the dystroglycan protein itself, Campbell's team has found an example of a new disease class known as primary dystroglycanopathy.

Although this finding is based on only one patient, Campbell noted that the mutation produced such mild muscle disease, especially compared to the severe cognitive symptoms, that it was not immediately obvious that the patient had a muscular dystrophy.

"This might mean that there are other patients who have not been correctly diagnosed as having a muscular dystrophy because their major symptoms are cognitive rather than muscular," he said. "Sometimes you just need that first patient case for clinicians to recognize that they have patients whose symptoms may also be caused by a particular mutation."

The study was funded in part by a National Institutes of Health grant for the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at the UI and the Muscular Dystrophy Campaign.


Story Source:

The above story is based on materials provided by University of Iowa Health Care. Note: Materials may be edited for content and length.


Journal Reference:

  1. Yuji Hara, Burcu Balci-Hayta, Takako Yoshida-Moriguchi, Motoi Kanagawa, Daniel Beltrán-Valero de Bernabé, Hülya Gündeşli, Tobias Willer, Jakob S. Satz, Robert W. Crawford, Steven J. Burden, Stefan Kunz, Michael B.A. Oldstone, Alessio Accardi, Beril Talim, Francesco Muntoni, Haluk Topaloğlu, Pervin Dinçer, Kevin P. Campbell. A Dystroglycan Mutation Associated with Limb-Girdle Muscular Dystrophy. New England Journal of Medicine, 2011; 364 (10): 939 DOI: 10.1056/NEJMoa1006939

Cite This Page:

University of Iowa Health Care. "New form of muscular dystrophy identified: Mutation in important muscle protein causes muscle disease and cognitive impairment." ScienceDaily. ScienceDaily, 10 March 2011. <www.sciencedaily.com/releases/2011/03/110309182654.htm>.
University of Iowa Health Care. (2011, March 10). New form of muscular dystrophy identified: Mutation in important muscle protein causes muscle disease and cognitive impairment. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2011/03/110309182654.htm
University of Iowa Health Care. "New form of muscular dystrophy identified: Mutation in important muscle protein causes muscle disease and cognitive impairment." ScienceDaily. www.sciencedaily.com/releases/2011/03/110309182654.htm (accessed July 29, 2014).

Share This




More Health & Medicine News

Tuesday, July 29, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Deadly Ebola Virus Threatens West Africa

Deadly Ebola Virus Threatens West Africa

AP (July 28, 2014) — West African nations and international health organizations are working to contain the largest Ebola outbreak in history. It's one of the deadliest diseases known to man, but the CDC says it's unlikely to spread in the U.S. (July 28) Video provided by AP
Powered by NewsLook.com
$15B Deal on Vets' Health Care Reached

$15B Deal on Vets' Health Care Reached

AP (July 28, 2014) — A bipartisan deal to improve veterans health care would authorize at least $15 billion in emergency spending to fix a veterans program scandalized by long patient wait times and falsified records. (July 28) Video provided by AP
Powered by NewsLook.com
Two Americans Contract Ebola in Liberia

Two Americans Contract Ebola in Liberia

Reuters - US Online Video (July 28, 2014) — Two American aid workers in Liberia test positive for Ebola while working to combat the deadliest outbreak of the virus ever. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Traditional African Dishes Teach Healthy Eating

Traditional African Dishes Teach Healthy Eating

AP (July 28, 2014) — Classes are being offered nationwide to encourage African Americans to learn about cooking fresh foods based on traditional African cuisine. The program is trying to combat obesity, heart disease and other ailments often linked to diet. (July 28) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins