Sep. 29, 1998 St. Louis, Oct. 1, 1998 -- Reporting in the Oct. 1 issue of the journal Nature Genetics, investigators at Washington University School of Medicine in St. Louis say they have identified the first gene known to cause a form of insulin-dependent diabetes in children.
Studying blood samples from six families affected by the disorder, the investigators found that mutations in a gene on chromosome 4 cause a disorder called Wolfram Syndrome. The disorder is characterized by insulin-dependent diabetes and vision problems, with eventual blindness. The syndrome also can include diabetes insipidus, a pituitary gland disorder associated with intense thirst and the need to excrete large amounts of urine. Some people with Wolfram Syndrome also lose their hearing.
The disorder is caused by mutations in a single gene called WFS1, the researchers found. Identification of that gene could provide important information about several disorders, but the investigators are particularly excited about how it might affect the understanding and treatment of the more common forms of diabetes, which affect more than 20 million people in the United States.
"We know that mutations in several genes predispose a person to diabetes, but unlike this one, they do not cause the disease," explained senior investigator M. Alan Permutt, M.D., professor of medicine. "If you have a mutation in this Wolfram gene, you get diabetes. So I believe this is the first gene that, when mutated, clearly leads to insulin-dependent diabetes."
Wolfram Syndrome is a rare form of insulin-dependent diabetes that strikes children at about age 6. By age 8 or 10, the children also develop visual impairment and subsequently go blind. Most suffer from progressive neurodegeneration and die in their 30s.
Since Wolfram Syndrome was identified more than 60 years ago, researchers had suspected that it was inherited. Often, parents of affected children are related to one another, and though the parents do not have the disease, several of their children may. The disorder affects about one in 100,000 individuals.
While working to isolate the gene, the researchers obtained much of the genetic material from three large families living in isolated regions of Japan. These families, who had been described in the Japanese scientific literature, were inbred and had multiple children with Wolfram Syndrome.
The paper's lead author, Hiroshi Inoue, M.D., is a professor of internal medicine at Yamaguchi University School of Medicine in Japan. While Inoue's colleague, Yukio Tanazawa, M.D., was doing postdoctoral work in Permutt's lab in 1993, he arranged for physicians in Japan to travel to the areas where the families lived, draw blood samples and send those samples to St. Louis for DNA analysis. Five years later, those samples, along with others from families in the United states, Australia and Saudi Arabia, helped Inoue and the team isolate the gene WFS1.
Although the disorder is rare, Permutt believes the discovery of the WFS1 gene may have important therapeutic implications. Mutations in this one gene cause insulin-secreting islet b-cells in the pancreas to die prematurely. Therefore, Permutt believes the protein involved may play a role in more common forms of diabetes.
"The gene encodes a large, unusual protein that appears necessary for normal survival of islet b-cells," he explained. "When examined post-mortem, patients with Wolfram Syndrome have no evidence of any insulin-secreting cells, and we believe this pathway could be activated not only in Wolfram Syndrome but also in the destruction of b-islet cells associated with other types of insulin-dependent diabetes."
The protein also appears important to nerve cells. Permutt and colleagues found that the WFS1 gene is expressed at the highest levels in the pancreatic islets, brain and heart.
Mutations in the gene altered the structure of the protein in some of the affected families, but in other cases, affected children had mutations that prevented the gene from encoding the protein at all. So, while important to health, Permutt believes the protein has little effect on development.
"The affected children develop completely normally until they are 6 to 8 years old, so we assume that this protein is not required for development of the nervous system or the islets because many of these children, in effect, don't have it, and they do well during early years of life. We do believe, however, that the protein is required for long-term survival of these cells," he said.
Permutt and colleagues think that defects in the gene trigger programmed cell death in islets and neurons. This process normally removes surplus or defective cells. The intact WFS1 protein, therefore, may be essential for islet and neuronal cell life, preventing these cells from succumbing to programmed cell death.
"Some of these molecules keep the cell alive, and when they are mutated, the cell dies. On the other hand, some molecules, when activated, actually induce the death of cells," he explained. "Our current working hypothesis is that this particular protein is part of a pathway necessary for survival of the islets, and what is so interesting is that it's not related to any already discovered proteins. We think it may represent a new family of proteins involved in the survival of cells."
Permutt intends to create an animal model of Wolfram Syndrome. Because the gene also is found in mice, the researchers will try to eliminate or mutate it in order to study how loss of the protein affects islets and neurons. This animal model may be useful for testing new therapies as well.
Gaining a better understanding of how the WFS1 protein contributes to the survival or death of those cells may give researchers clues about how to treat not only Wolfram Syndrome but also other diseases, such as insulin-dependent diabetes. But even if the discovery of this particular gene does not lead to therapies, it could provide some clues about the genetic roots of other types of diabetes.
Permutt credits progress in the Human Genome Project for the discovery. "These experiments simply could not have been done 10 years ago," he explained. "We are really benefiting from the genome science that is ongoing today. Genome scientists created the markers that allowed us to isolate this gene, and the same is true for most genes that are being discovered today."
Inoue, H., et. al. A Gene Encoding a Transmembrane Protein Is Mutated in Patients with Diabetes Mellitus and Optic Atrophy (Wolfram Syndrome). Nature Genetics, vol. 20, no. 2, pp. 143-148, Oct. 1, 1998.
This work was supported by grants from the National Institutes of Health, the Ministry of Education, Science, Sports and Culture of Japan and the American Diabetes Association.
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