When Dr. M. Alan Permutt, a physician-scientist at Washington University, died in June, he left behind an important finding: the WSF1 gene.

Permutt discovered it in 1998 and found that mutations in the gene were the marker for a rare disorder known as Wolfram syndrome.

Parents usually realize their children have the condition when they're diagnosed with type I diabetes. Eventually it causes hearing and vision loss, as well as nerve cell damage and motor difficulties. Life expectancy for those who have it is about 30.

Dr. Fumihiko Urano, associate professor of endocrinology, metabolism and lipid research at Washington U., continued Permutt's work and was part of a team that recently identified the mechanism behind that mutation.

The findings will not only help scientists understand Wolfram syndrome but could also lead to new treatments for type 2 diabetes and common neurological diseases, such as Alzheimer's disease and Parkinson's disease.

Urano didn't initially intend to study Wolfram syndrome. He was looking at a type of cell stress called endoplasmic reticulum dysfunction and its role in diabetes and aging. Every cell has endoplasmic reticulum. It's a network of membranes that synthesizes lipids and proteins, regulates calcium in the cell, transports cellular materials and signals death of the cell.

"We hypothesized that the Wolfram gene is a prototype of endoplasmic reticulum," he said.

With that in mind, he and Permutt established an international registry of patients with Wolfram syndrome in 2010. And rather than just study what goes wrong during the genetic mutation, they also tried to understand the basic functions of the WFS1 gene by studying patient samples and creating animal models.

They found that the WFS1 gene helps produce cyclic adenosine monophosphate or cyclic AMP that is crucial for producing insulin. The mutation in the gene disrupts the production of cyclic AMP. A lack of cyclic AMP can also lead to nerve cell dysfunction and even death.

"We were kind of surprised to know that WSF1 is so important for the production of cyclic AMP," Urano said. "It's such a fundamental function of our cells, and that's why patients with Wolfram have many manifestations including diabetes, optic atrophy, hearing loss and nerve damage."

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Work at Washington U. holds hope for those with Wolfram syndrome

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