Mutation of WFS1 Gene Causes Debilitating Wolfram Syndrome

The researchers from the Washington University School of Medicine in St. Louis, the Joslin Diabetes Center in Boston and the Novartis institute for BioMeidical Research have identified a mechanism that leads to diabetes, hearing and vision loss.

All these diseases are triggered due to the 'Wolfram Syndrome' that is caused by mutations in a single gene. This disorder also causes nerve cell damage leading to motor difficulties and early death.

The mechanism they have identified is related to mutations in the WFS1 gene connected to insulin secreting beta cells.

The study carried in the journal Nature Cell Biology will help in understanding the Wolfram Syndrome and also may be important in treating milder forms of diabetes and disorders. About 1 in 500,000 people are affected with Wolfram syndrome.

Due to the syndrome the Insulin-secreting beta cells in the pancreas cannot make enough cyclic AMP. As a result, the pancreas produces and secretes less insulin, and the cells eventually die.

"We found something we didn't expect," says researcher Fumihiko Urano, MD, PhD, associate professor of medicine in Washington University's Division of Endocrinology, Metabolism and Lipid Research. "The study showed that the WFS1 gene is crucial to producing a key molecule involved in controlling the metabolic activities of individual cells. That molecule is called cyclic AMP (cyclic adenosine monophosphate)."

"I would compare cyclic AMP to money," Urano says. "You can't just take something you make to the store and use it to buy food. First, you have to convert it into money. Then, you use the money to buy food. In the body, external signals stimulate a cell to make cyclic AMP, and then the cyclic AMP, like money, can 'buy' insulin or whatever else may be needed."

"The reason patients with Wolfram syndrome experience so many problems are because mutations in the WFS1 gene interfere with cyclic AMP production in beta cells in the pancreas."

 "In patients with Wolfram syndrome, there is no available WFS1 protein, and that protein is key in cyclic AMP production," he explains. "Then, because levels of cyclic AMP are low in insulin-secreting beta cells, those cells produce and secrete less insulin. And in nerve cells, less cyclic AMP can lead to nerve cell dysfunction and death."

"I don't know whether we can find a way to control cyclic AMP production in specific tissues," he says. "But if that's possible, it could help a great deal."

"It's likely this mechanism is related to diseases such as type 2 diabetes," he says. "If a complete absence of the WFS1 protein causes Wolfram syndrome, perhaps a partial impairment leads to something milder, like diabetes."