Researchers İdentify New Form Of Muscular Dystrophy

A strong 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."