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April 16, 2009

SickKids scientists muscle in on cause of muscular dystrophy

An international group of researchers led by scientists at The Hospital for Sick Children (SickKids) Research Institute has found the gene that causes a form of muscular dystrophy. The study is published in the April 17 issue of Cell.

The discovery of the gene sheds light on what causes one form of muscular dystrophy called X-linked myopathy with excessive autophagy (XMEA). XMEA is a childhood-onset disease of skeletal muscles.

“This is a groundbreaking discovery that we hope will lead to finding a cure for XMEA and other forms of muscular dystrophy,” says Dr. Berge Minassian, SickKids neurologist and Scientist, Associate Professor of Paediatrics at the University of Toronto and Canada Research Chair in Pediatric Neurogenetics.

The scientists studied a component in the cell called an autophagosome. Minassian likens an autophagosome to a recycling plant. The machines (proteins) in the plant depend on acid to break down the materials that need to be recycled. An enzyme called V-ATPase is the plant’s acid making device. It has 14 components that must fit together in a particular way to function. A protein called VMA21 assembles these parts. The scientists found the gene that encodes VMA21.

Minassian says humans cannot live without VMA21. However, some people have mutations in the gene that codes for VMA21, and these mutations reduce the amount of VMA21 without altogether eliminating it. These individuals are able to construct the acid-making device, but not in sufficient quantities.

Fewer acid-making devices lead to less acid in the autophagosomes, decreased productivity of the recycling plant, and an accumulation of cellular junk. This results in the cells going on a major fast. The less material it takes in, the less it has to recycle, so the cells and the patient start living in near-starvation mode to survive. Secondly, the cell moves the expanded debris-filled recycling plant to its edge and makes the walls of the plant merge with the cell’s own outside wall. This creates an opening that connects the vast debris-filled structure to the outside of the cell, and all the junk is poured out of the cell.

The process takes place in all cells of people with insufficient amounts of VMA21, and the survive-on-less mode allows most organs to function. Muscles, however, cannot cope. Not only are they a busy place for recycling waste, they also provide amino acids to the rest of the body. Therefore, it is muscle cells that succumb and waste away, resulting in muscular dystrophy.

“To cure XMEA, we are looking for ways to increase the acidity of the autophagosomes,” says Minassian. “As well, we hope to uncover the precise mechanisms in other vacuolar diseases – diseases whose cause is currently unknown and are characterized by expanded debris-containing structures.”

Two research fellows at SickKids Research Institute, Nivetha Ramachandran and Iulia Munteanu, are listed as first authors of the paper, which has a total of 24 authors from 10 institutions in six countries – France, Japan, Finland, Italy, United States and Canada.

A patent application has been filed for the gene coding VMA21.

The research was supported by the Canadian Institutes of Health Research, Muscular Dystrophy Association, ALS Association and SickKids Foundation.

The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada’s most research-intensive hospital and the largest centre dedicated to improving children’s health in the country. As innovators in child health, SickKids improves the health of children by integrating care, research and teaching. Our mission is to provide the best in complex and specialized care by creating scientific and clinical advancements, sharing our knowledge and expertise and championing the development of an accessible, comprehensive and sustainable child health system. For more information, please visit www.sickkids.ca. SickKids is committed to healthier children for a better world.

For more information, please contact:

Matet Nebres
The Hospital for Sick Children
Phone: 416-813-6380
email: matet.nebres@sickkids.ca

Suzanne Gold
The Hospital for Sick Children
Phone: 416-813-7654 ext. 2059
email: suzanne.gold@sickkids.ca